CN104994891A

CN104994891A - Drug delivery medical device

Info

Publication number: CN104994891A
Application number: CN201380066590.1A
Authority: CN
Inventors: J.B.麦克莱因; C.D.泰勒; M.M.法根
Original assignee: MiCell Technologies Inc
Current assignee: MiCell Technologies Inc
Priority date: 2012-10-18
Filing date: 2013-10-18
Publication date: 2015-10-21
Also published as: CA2888776A1; JP2015533305A; WO2014063111A1; CN110935070A; HK1213503A1; AU2013331003B2; WO2014063111A8; EP2908874A1; AU2013331003A1; EP2908874A4; CA2888776C

Abstract

The invention discloses a drug delivery medical device. The coating includes particles of a pharmaceutical agent. Each particle of the particles of the pharmaceutical agent is at least partially encapsulated in a polymer material. A method of releasing a pharmaceutical agent at a target site is also disclosed. The method includes the steps of providing a device including a balloon, and a coating on at least a portion of the balloon, the coating including particles of a pharmaceutical agent, and each particle of the pharmaceutical agent is at least partially encapsulated in a polymer material; positioning the device to allow the balloon to reach the target site; and inflating the balloon of the device.

Description

Drug delivery medical device

The cross reference of related application

This application claims the rights and interests of the U.S. Provisional Application numbers 61/715,768 submitted on October 18th, 2012; And the U.S. Provisional Application number 61/548 that the PCT application PCT/US2012/060896 submitted to that relates on October 18th, 2012, on October 18th, 2011 submit to, 650, the U.S. Provisional Application submitted to for 29th of December in 2011 number 61/581, the PCT application PCT/US2012/046545 that on July 12nd, 544 and 2012 submits to, respective content is attached to herein by reference and in full.

Background of invention

Needs can fast, effectively, can to reappear and on the specific position safely drug delivery formulation being transferred to health from the surface of percutaneous medical treatment device (coating)/among medical treatment device technology.

Summary of the invention

There is provided herein medical treatment device, described device comprises balloon and the coating gone up at least partially at balloon, and wherein said coating comprises the granule of medicament, and each granule of its Chinese medicine is encapsulated in the polymeric material at least partly.

In one embodiment, at least 50% medicament surface area encapsulating in the polymeric material.In another embodiment, at least 75% medicament surface area encapsulating in the polymeric material.In another embodiment, at least 90% medicament surface area encapsulating in the polymeric material.In another embodiment, at least 95% medicament surface area encapsulating in the polymeric material.

In one embodiment, the average thickness of polymeric layer is 2 microns-20 microns.In another embodiment, the average thickness of polymeric layer is 5 microns-15 microns.In another embodiment, the average thickness of polymeric layer is about 10 microns.

In one embodiment, the degree of crystallinity of medicament is at least 5%.In another embodiment, the degree of crystallinity of medicament is at least 20%.In another embodiment, the degree of crystallinity of medicament is 25%-95%.

In one embodiment, the mean diameter of the medicament of encapsulating is 5 nm-150 nm.In another refining (refinement), the mean diameter of medicament is 10 nm-100 nm.In another embodiment, the mean diameter of the medicament of encapsulating is 1 micron-50 microns.In another embodiment, the mean diameter of the medicament of encapsulating is 1 micron-20 microns.In another embodiment, the mean diameter of the medicament of encapsulating is 1 micron-10 microns.In one is refining, the mean diameter of the medicament of encapsulating is 1 micron-5 microns.

In one embodiment, the weight ratio of medicament and polymeric material is 1:99-70:30.In another embodiment, the weight ratio of medicament and polymeric material is 25:75-40:60.In another embodiment, the weight ratio of medicament and polymeric material is 40:60-60:40.

In one embodiment, by the mixture of spraying dry medicament, polymer and solvent, medicament is encapsulated in polymeric layer at least partly.In one is refining, mixture is solution, and solvent is polar non-solute.In another is refining, polar non-solute is selected from oxolane, acetonitrile and their mixture.In another kind is refining, mixture is slurry, and solvent is water.

In one embodiment, by spraying on the granule of medicament and dry can the solution of polymer of bio-absorbable, medicament is encapsulated in the polymeric material at least partly.In one is refining, solution comprises polymer and polar non-solute.In another is refining, polar non-solute is selected from oxolane, acetonitrile and their mixture.

In one embodiment, by adding the granule of polymer in drum container to medicament, medicament is encapsulated in the polymeric material at least partly.In one is refining, the mean diameter of the granule of polymer is 10 microns-100 microns.In another kind is refining, the granule of polymer adds with the 100 μ g-1000 μ speed of g/ minute.In another kind is refining, the granule of polymer adds with the 300 μ g-500 μ speed of g/ minute.

In one embodiment, by forming the mixture based on emulsion comprising medicament and polymeric material, being separated with the mixture based on emulsion with by the medicament of polymer-encapsulating, medicament is encapsulated in polymeric layer at least partly.In one is refining, polymeric material is the mixture of PVA or PLGA.In another is refining, the lactic acid of PLGA: the weight ratio of glycolic is about 60:40 for about 40:60-.In another kind is refining, medicament is unbodied.

In another is refining, by forming the mixture based on emulsion comprising medicament and polymeric material, evaporate a part of emulsion, and filter remaining emulsion, medicament is encapsulated in the polymeric material at least partly.In another is refining, by the medicament settling flux of encapsulating and lyophilizing.In another kind is refining, by the first polymer solution, the second polymer solution, terpolymer solution and liquid medicine being merged, form the mixture based on emulsion.In another is refining, first and terpolymer solution comprise the first polymer and water.In another is refining, the first polymer is PVA.In another is refining, the polymer concentration of the first polymer solution is about 1%-about 5%.In another kind is refining, the polymer concentration of terpolymer solution is about 0.5%-about 2%.In another kind is refining, the second polymer solution comprises the second polymer and organic solvent.In another is refining, the second polymer is PLGA.In another kind is refining, organic solvent is dichloromethane.In another kind is refining, liquid medicine comprises medicament and polar non-solute.In another is refining, aprotic solvent is dimethyl sulfoxide.In another kind is refining, by making liquid medicine mix with the second polymer solution, adds the first polymer solution to this mixture, this mixture of homogenize, and add terpolymer solution, form emulsion.

In another kind is refining, medicament is crystallization.In a further embodiment, by forming the mixture based on emulsion comprising medicament and at least one polymer, and filter emulsion, medicament is encapsulated in the polymeric material at least partly.In another is refining, by the medicament settling flux of encapsulating and lyophilizing.In another kind is refining, by the first polymer solution, the second polymer solution, terpolymer solution and crystallization medicament being merged, form the mixture based on emulsion.In another is refining, the first polymer solution comprises the first polymer and organic solvent.In another is refining, the first polymer solution and the second polymer solution are merged, allow organic solvent evaporation.In another is refining, the first polymer is PLGA.In another kind is refining, organic solvent is dichloromethane.In another kind is refining, second and terpolymer solution comprise the second polymer and water.In another is refining, the second polymer is PVA.In another is refining, the polymer concentration of the second polymer solution is about 0.5%-about 2%.In another kind is refining, the polymer concentration of terpolymer solution is about 1%-about 5%.In another kind is refining, by the first polymer solution is mixed to form emulsion with the second polymer solution, make medicament mix to form suspension with terpolymer solution, and emulsion and suspension are merged, form emulsion.

In one embodiment, medicament is macrolide immunosuppressant.In one is refining, macrolide immunosuppressant is rapamycin or derivatives thereof, prodrug, hydrate, ester, salt, polymorphic, derivant or analog.In another kind is refining, macrolide immunosuppressant is selected from rapamycin, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl) benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxy ethyl)] benzyl-rapamycin, 40-O-pi-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4 (S)-Ji)-propyl-2'-alkene-1'-base]-rapamycin, (2':E, 4'S)-40-O-(4', 5'-dihydroxy penta-2'-alkene-1'-base)-rapamycin, 40-O-(2-hydroxyl) ethoxy carbonyl methyl-rapamycin, 40-O-(3-hydroxyl) propyl group-rapamycin, 40-O-(6-hydroxyl) hexyl-rapamycin, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl rapamycin, 40-O-[(3S)-2,2-dimethyl dioxolane-3-base] methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxy third-1-base]-rapamycin, 40-O-(2-acetoxyl group) ethyl rapamycin, 40-O-(2-nicotinoyl oxygen base) ethyl rapamycin, 40-O-[2-(N-morpholino) acetoxyl group] ethyl rapamycin, 40-O-(2-N-imidazole radicals acetoxyl group) ethyl rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl) acetoxyl group] ethyl rapamycin, 39-O-demethyl-39,40-O, O-ethylidene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxyl) ethyl rapamycin, 28-O-methyl-rapamycin, 40-O-(2-amino-ethyl)-rapamycin, 40-O-(2-acetamidoethyl)-rapamycin, 40-O-(2-nicotinoyl amino-ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazoles is-2'-base carbethoxyl group acylamino-also) ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamino group ethyl)-rapamycin, 40-O-(2-tolylsulfonyl-amino-ethyl)-rapamycin, 40-O-[2-(4', 5'-di ethoxy carbonyl-1', 2', 3'-triazole-1'-base)-ethyl]-rapamycin, 42-table-(tetrazole radical) rapamycin (tacrolimus) and 42-[3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester] rapamycin.In another kind is refining, medicament is rapamycin.

In one embodiment, comprise can the polymer of bio-absorbable for polymeric material.In one is refining, the polymer of bio-absorbable can be selected from polylactide (PLA); PLGA (PLGA); Condensing model; Poe; Poly-(N-(2-hydroxypropyl) Methacrylamide); Poly-(dl-lactide) (DLPLA); Poly-(l-lactide) (LPLA); PGA (PGA); Poly-(dioxanone) (PDO); Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester copolymer (PGA-TMC); L-PLGA (PGA-LPLA); Dl-PLGA (PGA-DLPLA); L-lactide-dl-lactide copolymer (LPLA-DLPLA); Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester-dioxanone terpolymer) (PDO-PGA-TMC), poly arginine, polyvinyl alcohol (PVA), and composition thereof or copolymer.In another kind is refining, can the polymer of bio-absorbable be PLGA, PVA, poly arginine, or their mixture.In another is refining, can the polymer of bio-absorbable be the mixture of PLGA and PVA.

In one embodiment, polymeric layer comprises PLGA.In one is refining, polymeric layer is prepared by PLGA.In another embodiment, polymeric layer comprises poly arginine.In one is refining, polymeric layer is prepared by poly arginine.In one is refining, PLGA comprises about 50:50 lactic acid: glycolic.In another embodiment, polymeric layer comprises lasting polymer.

In one embodiment, medical treatment device is also included in the binding agent that the outer surface of the granule of the encapsulating of medicament deposits.In one is refining, the weight ratio of binding agent and polymer is 1:99-25:75.In another kind is refining, the weight ratio of binding agent and polymer is 1:99-10:90.

In one embodiment, by the solution of spraying and dry adhesive on the granule of the encapsulating of medicament, deposit binder.In one is refining, solution comprises binding agent and water.

In one embodiment, binding agent comprise following one of at least: poly arginine, poly arginine 9-L-pArg, DEAE-dextran (DEAE-cellulose-dextran), DMAB (two (dodecyl) ditallowdimethyl ammonium bromide), PEI (polymine), TAB (four (dodecyl) ammonium bromide) and DMTAB (dimethyl two (myristyl) ammonium bromide).In one is refining, binding agent is poly arginine.In another is refining, the mean molecule quantity of poly arginine is about 70kDa.In another kind is refining, the mean molecule quantity of poly arginine is 5-15kDa.

In one embodiment, use eSTAT coating process on balloon, deposit the granule of the encapsulating of medicament.

In one embodiment, after making balloon inflation, the medicament of medical treatment device release at least 3%.In another embodiment, after making balloon inflation, the medicament of medical treatment device release at least 5% or at least 10%.In another embodiment, make balloon inflation after 72 hours, medical treatment device release is at least about 2 ng/mg, at least about 3 ng/mg, at least about 5 ng/mg, at least about 10 ng/mg, at least about 20 ng/mg, at least about 30 ng/mg, or at least about the medicament of 40 ng/mg.

In one embodiment, balloon is for having the turnover balloon of nearly chamber (abluminal) side; Wherein on the side, nearly chamber of turnover balloon, provide coating.In one is refining, balloon overturns in conduit.In another is refining, utilize balloon inflation pressure or the far-end by being moved balloon by balloon in distally, or their combination, balloon can be pushed out conduit.In another kind is refining, the balloon of reversing overturns on the outside of conduit.In another is refining, in the outside of conduit, controlled the treated length of the balloon reversed by the balloon partly not overturning reversing.In another kind is refining, medical treatment device is also included in the sheath provided on the balloon of reversing.In another kind is refining, once the balloon of coating arrives therapentic part, arrange near therapentic part, arrange in treatment site, contiguous therapentic part, in therapentic part distally, or in therapentic part, sheath regracting.

In one embodiment, medical treatment device also comprises setting for blocking the closer that body fluid flows towards balloon before balloon inflation.In one is refining, closer comprises the second balloon.In another kind is refining, balloon comprises the first and second parts, and Part I comprises closer, and Part II comprises coating.In another kind is refining, balloon comprises distal node and adjacent node, and wherein distal node comprises coating, and wherein adjacent node comprises closer, or wherein adjacent node comprises coating, and wherein distal node comprises closer.In another is refining, the distal part of balloon is coated with, and wherein the neighbouring part of balloon is uncoated, and wherein the neighbouring part of balloon is closer, or, wherein the neighbouring part of balloon is coated with, and wherein the distal part of balloon is uncoated, and wherein the distal part of balloon is closer.

Additionally provide a kind of method at target site release medicine herein, described method comprises generator, this device comprises balloon and the coating gone up at least partially at balloon, and its floating coat comprises the granule of medicament, and each granule of its Chinese medicine is encapsulated in the polymeric material at least partly; Arrangement apparatus arrives target site to allow balloon; With the balloon inflation making device, wherein after making balloon inflation, at least some medicament is released into target site.

In one embodiment, target site is blood vessel, such as tremulous pulse.

Combine by reference

The all publications mentioned in this manual and patent application incorporated herein by reference, to just looking like that the special and single instruction of each single publication or patent application is with identical degree incorporated herein by reference.The U.S. Provisional Application number 61/081 that the application relates on July 17th, 2008 and submits to, 691, the U.S. Provisional Application number 61/226 submitted on July 16th, 2009, 239, the U.S. Provisional Application number 61/212 submitted on April 17th, 2009, 964, the U. S. application number 12/504 submitted on July 16th, 2009, 597, the U. S. application number 12/729 submitted on March 23rd, 2010, 580, the PCT application PCT/US2009/050883 that on July 16th, 2009 submits to, the PCT application PCT/US2010/042355 that the PCT application PCT/US2010/028253 and 2010 submitted on March 23rd, 2010 submits to 16, on July.The content of these applications is attached to herein by reference and in full.

Accompanying drawing is sketched

New feature of the present invention describes especially in the dependent claims.By reference to describing the following the detailed description and the accompanying drawings wherein utilizing the illustrative embodiment of principle of the present invention, will the better understanding to the features and advantages of the present invention be obtained, wherein:

Fig. 1 indicates for preparation F3, F5 and F7, at different time points, from the average percentage of the sirolimus of balloon eluting;

Fig. 2 describes the example using sirolimus to be coated with the eSTAT process of 12 angioplasty balloons;

Fig. 3 describes according to RESS process coating balloon;

Fig. 4 describes the method preparing coating agent according to an embodiment herein.

Fig. 5 is according to an embodiment herein, the SEM image of the microparticle of encapsulating rapamycin; With

Fig. 6 is according to another embodiment herein, the SEM image of the microparticle of encapsulating rapamycin.

Detailed Description Of The Invention

Below the present invention is explained in more detail.This description is not intended to wherein can perform all different modes of the present invention or can join characteristic inventory of the present invention.Such as, the feature illustrated about an embodiment can be incorporated in other embodiment, and can delete from this embodiment about the feature that a specific embodiments illustrates.In addition, in view of not departing from the disclosure of the present invention, numerous change of various embodiment in this paper and interpolation be it will be apparent to those skilled in the art that.Therefore, following description is intended to specific embodiments more of the present invention are described, not exclusively specifies its all exchange, combination and change.

Definition

The following word used in this manual and phrase generality are intended to have implication described below, except the situation wherein using them to indicate other situation.

" matrix " used herein refers to any surface expecting deposited coatings thereon.Biologic medical graft is special concern of the present invention; But the present invention is not intended to be limited to such matrix.It will be appreciated by those skilled in the art that matrix alternately can benefit from coating process described herein, such as drug core, as a part for sensing equipment or as the component (such as, test strip) in diagnostic kit.The example of the matrix that method of the present invention can be used to be coated with comprises surgery device or medical treatment device, such as, conduit, balloon, cutting balloon, wire, sleeve pipe, instrument, orthotic device, structure implantation thing, support, stent-grafts, graft, vein cavity filter, heart valve, marrowbrain fluid branch road, pacemaker electrode, axius coronary artery branch road, intracardiac lead, artificial heart etc.

" biologic medical graft " used herein refers to any graft of the health for inserting human or animal experimenter, includes but not limited to support (such as, coronary stent, vascular stent comprises periphery support and graft support, urological stents, urethra/prostate bracket, rectum support, esophageal stents appear, gallbladder support, pancreas support), electrode, conduit, wire, transplantable pacemaker, cardioverter or Sirecard shell, joint, screw, rod, eye graft, hip nail, hone lamella material, graft, stapling apparatus, blood vessel week is wound around, stitching thread, binding, for hydrocephalic branch road, dialysis graft, colostomy bag accessories apparatus, ear catheter, for the wire of pacemaker and transplantable cardioverter and Sirecard, vertebra disk, nail, suture anchor, hemostasis stops, fixture, screw, sheet material, clip, vascular graft, tissue adhesive and sealant, organization bracket, various types of dressing (such as, wound dressing), bone substitute, endoluminal device, vascular support etc.

Graft can be formed by any suitable material, include but not limited to polymer (comprising stable or inert polymer, organic polymer, organic-inorganic copolymer, inorganic polymer and biodegradable polymer), metal, metal alloy, inorganic material such as silicon and complex thereof, comprise the layer structure of the coating of core and one or more different materials with a kind of material.The matrix prepared by conductive material promotes Electrostatic.But the present invention considers to use Electrostatic described herein, in conjunction with there is low conductivity or being non-conductive matrix.When adopting non-conductive matrix, in order to strengthen Electrostatic, by matrix process, such as, near matrix, keep highfield simultaneously.But, in some embodiments, when using coating to matrix, do not adopt Electrostatic.In some embodiments of method provided herein and/or device, matrix neutral in coating process.In some embodiments of method provided herein and/or device, between matrix and coating apparatus, do not produce current potential.

The experimenter that can use or insert biologic medical graft of the present invention wherein comprises people experimenter's (comprising masculinity and femininity experimenter and baby, teenager, teenager, adult and old man experimenter) and animal subjects (including but not limited to pig, rabbit, mice, Canis familiaris L., cat, horse, monkey etc.), for veterinary's object and/or medical research.

Biological graft used herein can comprise the medical treatment device of not Permanent implantation.In some embodiments, biological graft can comprise based on the of short duration device for experimenter.For limiting examples, biologic medical graft can be balloon, and it is of short duration in making tube chamber expand, and can exit and/or remove from experimenter during medical procedure or subsequently subsequently.In some embodiments, biological graft can temporarily be transplanted, and keeps the limited time, such as, during a part of medical procedure, or the only limited time (being sometimes less than Permanent implantation), or can of short duration transplanting and/or be temporarily placed in experimenter.In some embodiments, biological graft is not transplanted, but only inserts in experimenter during medical procedure, and removes from experimenter before completing medical procedure or when completing subsequently.In some embodiments, biological graft is not forever transplanted, because it absorbs completely (that is, being absorbed completely by experimenter) in experimenter again again.In a preferred embodiment, biologic medical graft is expandable balloon, it can expand in the cated tube chamber of tool (natural existence or non-natural exist) thereon, its (at least partly) discharges from balloon, and when balloon is removed from tube chamber, stay in tube chamber.

The example of the medicament be combined with the present invention comprises rapamycin, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl) benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxy ethyl)] benzyl-rapamycin, 40-O-pi-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4 (S)-Ji)-propyl-2'-alkene-1'-base]-rapamycin, (2':E, 4'S)-40-O-(4', 5'-dihydroxy penta-2'-alkene-1'-base)-rapamycin, 40-O-(2-hydroxyl) ethoxy carbonyl methyl-rapamycin, 40-O-(3-hydroxyl) propyl group-rapamycin, 40-O-(6-hydroxyl) hexyl-rapamycin, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl rapamycin, 40-O-[(3S)-2,2-dimethyl dioxolane-3-base] methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxy third-1-base]-rapamycin, 40-O-(2-acetoxyl group) ethyl rapamycin, 40-O-(2-nicotinoyl oxygen base) ethyl rapamycin, 40-O-[2-(N-morpholino) acetoxyl group] ethyl rapamycin, 40-O-(2-N-imidazole radicals acetoxyl group) ethyl rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl) acetoxyl group] ethyl rapamycin, 39-O-demethyl-39,40-O, O-ethylidene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxyl) ethyl rapamycin, 28-O-methyl-rapamycin, 40-O-(2-amino-ethyl)-rapamycin, 40-O-(2-acetamidoethyl)-rapamycin, 40-O-(2-nicotinoyl amino-ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazoles is-2'-base carbethoxyl group acylamino-also) ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamino group ethyl)-rapamycin, 40-O-(2-tolylsulfonyl-amino-ethyl)-rapamycin, 40-O-[2-(4', 5'-di ethoxy carbonyl-1', 2', 3'-triazole-1'-base)-ethyl]-rapamycin, 42-table-(tetrazole radical) rapamycin (tacrolimus) and 42-[3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester] rapamycin (sirolimus).In some embodiments, the activating agent of device provided herein, coating and/or method comprises macrolide immunosuppressive drug.In some embodiments, macrolide immunosuppressive drug comprise following in one or more: rapamycin, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl) benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxy ethyl)] benzyl-rapamycin, 40-O-pi-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4 (S)-Ji)-propyl-2'-alkene-1'-base]-rapamycin, (2':E, 4'S)-40-O-(4', 5'-dihydroxy penta-2'-alkene-1'-base)-rapamycin, 40-O-(2-hydroxyl) ethoxy carbonyl methyl-rapamycin, 40-O-(3-hydroxyl) propyl group-rapamycin, 40-O-(6-hydroxyl) hexyl-rapamycin, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl rapamycin, 40-O-[(3S)-2,2-dimethyl dioxolane-3-base] methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxy third-1-base]-rapamycin, 40-O-(2-acetoxyl group) ethyl rapamycin, 40-O-(2-nicotinoyl oxygen base) ethyl rapamycin, 40-O-[2-(N-morpholino) acetoxyl group] ethyl rapamycin, 40-O-(2-N-imidazole radicals acetoxyl group) ethyl rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl) acetoxyl group] ethyl rapamycin, 39-O-demethyl-39,40-O, O-ethylidene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxyl) ethyl rapamycin, 28-O-methyl-rapamycin, 40-O-(2-amino-ethyl)-rapamycin, 40-O-(2-acetamidoethyl)-rapamycin, 40-O-(2-nicotinoyl amino-ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazoles is-2'-base carbethoxyl group acylamino-also) ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamino group ethyl)-rapamycin, 40-O-(2-tolylsulfonyl-amino-ethyl)-rapamycin, 40-O-[2-(4', 5'-di ethoxy carbonyl-1', 2', 3'-triazole-1'-base)-ethyl]-rapamycin, 42-table-(tetrazole radical) rapamycin (tacrolimus) and 42-[3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester] rapamycin (sirolimus).Activating agent is optional from macrolide immunosuppressive drug, its prodrug, hydrate, ester, salt, polymorphic, derivant and analog.Activating agent is optional from sirolimus, its prodrug, hydrate, ester, salt, polymorphic, derivant and analog.

If expected, medicament can also the form of their pharmaceutically acceptable salt or derivant (refer to keep the biological effectiveness of the compounds of this invention and character and be not biology or other less desirable salt) use, and when chiral acti ve composition, the mixture of optically active isomer and racemate or diastereomer can be adopted.Equally, medicament can comprise following in one of at least: its prodrug, hydrate, ester, salt, polymorphic, derivant and analog.

Medicament can be antibiotic agent, as described herein.

In some embodiments of method provided herein, coating and/or device, control the size of activating agent in the coating.In some embodiments, activating agent is sirolimus, and the average-size of its sirolimus (average diameter) for following one of at least: 1.5 μm, 2.5 μm, 645nm, 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the median size of its sirolimus be following one of at least: 1.5 μm, 2.5 μm, 645nm, 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the average-size of its sirolimus (average diameter) for following one of at least: about 1.5 μm, about 2.5 μm, about 645nm, about 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the median size of its sirolimus be following one of at least: about 1.5 μm, about 2.5 μm, about 645nm, about 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and in its sirolimus, the sirolimus of at least 75% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, activating agent is sirolimus, and in its sirolimus, the sirolimus of at least 50% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, activating agent is sirolimus, and in its sirolimus, the sirolimus of at least 90% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.

In some embodiments of method provided herein and/or device, macrolide immunosuppressive drug is at least 50% crystallization.In some embodiments, macrolide immunosuppressive drug is at least 75% crystallization.In some embodiments, macrolide immunosuppressive drug is at least 90% crystallization.In some embodiments of method provided herein and/or device, macrolide immunosuppressive drug is at least 95% crystallization.In some embodiments of method provided herein and/or device, macrolide immunosuppressive drug is at least 97% crystallization.In some embodiments of method provided herein and/or device, macrolide immunosuppressive drug is at least 98% crystallization.In some embodiments of method provided herein and/or device, macrolide immunosuppressive drug is at least 99% crystallization.

In some embodiments of method provided herein and/or device, medicament is at least 50% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 75% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 90% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 95% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 97% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 98% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 99% crystallization.

" prodrug " adds the group of the larger dissolubility of imparting and derivative derivative compound for the compound by sending to expectation.Once in the body, prodrug is worked by enzyme (such as, esterase, amidase or phosphatase), to produce reactive compound usually.

" anticarcinogen ", " antitumor agent " or " chemotherapeutics " refer to any medicament that can be used for treating neoplastic conditions.In apparatus and method used in the present invention, be used for the treatment of in the business application of cancer, clinical evaluation and clinical front development, there is available many chemotherapeutics.

" stability " used herein refers to its final product form, the stability (stability of the medicine such as, in the support of coating) of the medicine in the coating of substrate deposit.In some embodiments, term " stability " and/or " stable " to be defined as in final product form 5% or less drug degradation.In some embodiments, term definition of stability is in final product form 3% or less drug degradation.In some embodiments, term definition of stability is in final product form 2% or less drug degradation.In some embodiments, term definition of stability is in final product form 1% or less drug degradation.

In some embodiments, after device sterilizing, medicament be following one of at least: 50% crystallization, 75% crystallization, 80% crystallization, 90% crystallization, 95% crystallization, 97% crystallization and 99% crystallization.In some embodiments, medicament degree of crystallinity is stablized, wherein compared with the degree of crystallinity of medicament, the degree of crystallinity of medicament is stable following one of at least after sterilization: 1 week after sterilization, 2 weeks after sterilization, 4 weeks after sterilization, 1 month after sterilization, 2 months after sterilization, 45 days after sterilization, 60 days after sterilization, 90 days after sterilization, 3 months after sterilization, 4 months after sterilization, 6 months after sterilization, 9 months after sterilization, 12 months after sterilization, 18 months and 2 years after sterilization after sterilization.In some embodiments, medicament degree of crystallinity is stablized, wherein compared with the degree of crystallinity of medicament, the degree of crystallinity of medicament is stable following one of at least before sterilization: 1 week after sterilization, 2 weeks after sterilization, 4 weeks after sterilization, 1 month after sterilization, 2 months after sterilization, 45 days after sterilization, 60 days after sterilization, 90 days after sterilization, 3 months after sterilization, 4 months after sterilization, 6 months after sterilization, 9 months after sterilization, 12 months after sterilization, 18 months and 2 years after sterilization after sterilization.In such embodiments, different devices can be tested, to be determined at the stability of the time point medicament of expectation by identical manufacture batch.

In some embodiments, medicament degree of crystallinity is stable following one of at least: 1 week after sterilization, 2 weeks after sterilization, 4 weeks after sterilization, 1 month after sterilization, 2 months after sterilization, 45 days after sterilization, 60 days after sterilization, 90 days after sterilization, 3 months after sterilization, 4 months after sterilization, 6 months after sterilization, 9 months after sterilization, 12 months after sterilization, 18 months and 2 years after sterilization after sterilization.

In some embodiments, after sterilization to put sometime the medicament degree of crystallinity on the device of test from put the different of degree of crystallinity of testing on the second device by the device of same batch and the medicament manufacture of same batch in the testing time before sterilization can not more than 1%, 2%, 3%, 4% and/or 5% (namely, degree of crystallinity declines no more than 99-94% crystallization, and such as, it is 5 % difference in crystallinity; Degree of crystallinity declines no more than 99-95% crystallization, and it is 4% difference in crystallinity; Degree of crystallinity declines no more than 99-96% crystallization, and such as, it is 3% difference in crystallinity; Degree of crystallinity declines no more than 99-97% crystallization, and such as, it is 2% difference in crystallinity; Degree of crystallinity declines no more than 99-98% crystallization, and such as, it is 1% difference in crystallinity; In other example, crystallization initiation degree percent is one of following: 100%, 98%, 96%, 97%, 96%, 95%, 90%, 85%, 80%, 75%, 70%, 60%, 50%, 30%, 25% and/or between any number).

In some embodiments, after sterilization can not more than 1% from the different of degree of crystallinity of the medicine putting the medicament from same batch tested before making medicament sterilizing in the testing time in the degree of crystallinity putting the medicament on the device of test sometime, 2%, 3%, 4% and/or 5%.

In some embodiments, after sterilization, between two testing time points, the degree of crystallinity of medicament declines can not more than 1%, 2%, 3%, 4% and/or 5%, and neither one time point is greater than 2 years after sterilization.In some embodiments, after sterilization, between two testing time points, the degree of crystallinity of medicament declines can not more than 1%, 2%, 3%, 4% and/or 5%, and neither one time point is greater than 5 years after sterilization.In some embodiments, two time points comprise following in two: 1 week after sterilization, 2 weeks after sterilization, 4 weeks after sterilization, 1 month after sterilization, 2 months after sterilization, 45 days after sterilization, 60 days after sterilization, 90 days after sterilization, 3 months after sterilization, 4 months after sterilization, 6 months after sterilization, 9 months after sterilization, 12 months after sterilization, 18 months after sterilization, 2 years after sterilization, 3 years after sterilization, 4 years and 5 years after sterilization after sterilization.

" polymer " used herein refers to a series of repeated monomer unit being cross-linked or being polymerized.Any suitable polymer can be used for carrying out the present invention.Also may can comprise two kinds, three kinds, four kinds or more and plant different polymer by polymer of the present invention.In some embodiments of the present invention, a kind of polymer is only used.In certain embodiments, the combination of two kinds of polymer is used.The combination of polymer can be different ratios, has coating of different nature to provide.The polymer of apparatus and method used in the present invention comprises such as, stable or inert polymer, organic polymer, organic-inorganic copolymer, inorganic polymer, can bio-absorbable, can non-bioresorbable, can resorbent, degradable and biodegradable polymer.Polymer chemistry those skilled in the art are familiar with the heterogeneity of polymerizable compound.

In some embodiments, coating also comprises polymer.In some embodiments, activating agent comprises polymer.In some embodiments, polymer comprise following one of at least: poly-alkylmethacrylate, alkylene vinyl acetate copolymer, polyolefin, polyurethane, condensing model, aliphatic polycarbonate, polyhydroxyalkanoatefrom, containing silicone polymer, poly-alkylsiloxane, aliphatic polyester, PGA, polylactide, PLGA, poly-(6-caprolactone), poly-four halogen alkene, polystyrene, poly (phosphasones), its copolymer and combination thereof.

In embodiments, after the transfer, the deliquescing of polymer energy, such as, due to hydration, degraded or the combination by hydration and degraded.In embodiments, when getting involved the hydrolysis of position due to polymer, polymer is being suitable for from matrix transfer, free and/or dissociation.In various embodiments, device be coated with can following one of at least resorbent can the polymer of bio-absorbable: about 1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about 180 days, about 6 months, about 9 months, about 1 year, about 1-about 2 days, about 1-about 5 days, about 1-about 2 weeks, about 2-about 4 weeks, about 45-about 60 days, about 45-about 90 days, about 30-about 90 days, about 60-about 90 days, about 90-about 180 days, about 60-about 180 days, about 180-about 365 days, about 6 months-Yue 9 months, about 9 months-Yue 12 months, about 9 months-Yue 15 months and about 1 year-Yue 2 years.

The example of polymer used in the present invention includes but not limited to polycarboxylic acids, cellulosic polymer, protein, polypeptide, polyvinyl pyrrolidone, maleic anhydride polymer, polyamide, polyvinyl alcohol, poly(ethylene oxide), glucosaminoglycan, polysaccharide, polyester, aliphatic polyester, polyurethane, polystyrene, copolymer, silicone, containing silicone polymer, poly-alkylsiloxane, poe, condensing model, the copolymer of vinyl monomer, Merlon, polyethylene, polypropylene (polypropytenes), polylactic acid, polylactide, polyglycolic acid, PGA, PLGA, polycaprolactone, poly-(6-caprolactone), polyhydroxybutyrate valerate, polyacrylamide, polyethers, dispersions of polyurethanes, polyacrylate, acrylic latex dispersions, polyacrylic acid, poly-alkylmethacrylate, alkylene vinyl acetate copolymer, polyolefin, aliphatic polycarbonate, polyhydroxyalkanoatefrom, poly-four halogen alkene, poly (phosphasones), poly-four halogen alkene, poly (phosphasones) and composition thereof, combination and copolymer.

Polymer of the present invention can be natural or synthesis origin, comprise gelatin, chitosan, dextrin, cyclodextrin, poly-(ammonia ester), poly-(siloxanes) or silicone, poly-(acrylate) be poly-(methyl methacrylate) such as, poly-(butyl methacrylate) and poly-(2-hydroxyethyl methacrylate), poly-(vinyl alcohol), poly-(alkene) is poly-(ethylene) such as, poly-(isoprene), halogenated polymer such as poly-(tetrafluoroethene)-and derivant and copolymers are as usually used as those of Teflon (R) production marketing, poly-(vinylidene fluoride), poly-(vinyl acetate), PVP, poly-(acrylic acid), polyacrylamide, vinyl-vinyl acetate copolymer, PEG, poly-(propylene glycol), poly-(methacrylic acid), etc..

Suitable polymer also comprises absorbable and/or can resorbent polymer, comprise following polymer, the combination of following polymer, copolymer and derivant: polylactide (PLA), PGA (PGA), PLGA (PLGA), condensing model, poe, poly-(N-(2-hydroxypropyl) Methacrylamide), poly-(l-agedoite), comprise derivant DLPLA: poly-(dl-lactide); LPLA: poly-(l-lactide); PDO: poly-(dioxanone); PGA-TMC: Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester copolymer; PGA-LPLA:l-PLGA; PGA-DLPLA:dl-PLGA; LPLA-DLPLA:l-lactide-dl-lactide copolymer; And PDO-PGA-TMC: Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester-dioxanone terpolymer) and combination.

In some embodiments of device provided herein, coating and/or method, polymer comprises PLGA.In some embodiments of method provided herein, coating or device, PLGA comprises about 50:50 lactic acid: glycolic.PLGA can have following one of at least: MW is for about 30KDa and Mn be about 15KDa, and Mn is about 10KDa-about 25 KDa and MW is about 40KDa for about 15 KDa-.In some embodiments of method provided herein, coating or device, PLGA comprises 50:50 lactic acid: glycolic.In some embodiments of method provided herein, coating or device, PLGA comprises 40:60-60:40 lactic acid: glycolic.In some embodiments of method provided herein, coating or device, PLGA comprises 45:55-55:45 lactic acid: glycolic.In some embodiments of method provided herein, coating or device, PLGA comprises 48:52-52:48 lactic acid: glycolic.In some embodiments of method provided herein, coating or device, PLGA comprises 49:51-51:49 lactic acid: glycolic.Time as used herein, the ratio about lactic acid in PLGA and glycolic uses term " about " to refer to 40:60-60:40, or 45:55-55:45, or the ratio ranges of 48:52-52:48 or 49:51-51:49, depends on embodiment.

" copolymer " used herein refers to the polymer be made up of two or more different monomers.Copolymer also and/or alternatively can refer to random, block, graft copolymer well known by persons skilled in the art.

" biocompatible " used herein refer to when with animal organize close contact time, do not cause animal injury or dead or do not induce any material of adverse effect in animal.Adverse effect comprises such as inflammation, infection, fibrosed tissue formation, cell death or thrombosis.Term " biocompatible " and " biocompatibility " are art-recognized when using herein and refer to that object itself to host (such as, animal or human) nontoxic, and also do not degrade under the speed producing by-product (such as, monomer or oligomeric subunits or other by-product) under toxic concentration (if degraded), cause inflammation or stimulate or induction of immunity reaction in host.Any theme composition does not need the purity with 100% just to think biocompatible.Therefore, theme composition can comprise 99%, and 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even less biocompatible medicament, such as, comprise polymer described herein and other material and excipient, and be still biocompatible." biocompatible " used herein refers to when causing animal injury or dead or induce any material of adverse effect in animal during close contact with organizing of animal.Such adverse effect is such as described above.

Term " can bio-absorbable ", " biodegradable ", " can bioerosion ", " can non-bioresorbable " and " can be resorbent " be art-recognized synonym.These terms are used interchangeably in this article.Can the polymer of bio-absorbable be usually different from non-can the polymer of bio-absorbable, be that the former can be absorbed during use (such as, degrading).In certain embodiments, such application relates to application in body, such as in vivo, and in some other embodiment, such application relates to external application.Generally speaking, the degraded being attributable to biological degradability relates to the depolymerization of bio-absorbable can become its component subunit, or makes polymer digest (such as, passing through Biochemical processes) to become less non-polymeric subunits.In certain embodiments, biodegradation occurs by enzyme mediation, degrades under other chemical species in water (hydrolysis) and/or health or the two existence.The Bioabsorbable of polymer can externally indicate, and as described herein, or passes through method known to those skilled in the art.The testing in vitro of the Bioabsorbable of polymer does not need cell alive or other biologic material to carry out eucoen absorbent properties (such as, degrade, digest).Then absorb, absorb again, absorb, absorb, corrode and also can to use with term " can bio-absorbable ", " biodegradable ", " can bioerosion " and " can non-bioresorbable " synonym therefore.The mechanism of degradation of polymer of bio-absorbable can include but not limited to bulk degradation, surface corrosion and combination thereof.

Term used herein " biodegradation " comprises the biodegradation of two kinds of usual types.The degradation rate of biodegradable polymer depends in part on many factors usually, comprise the crosslinking degree of the chemical identity of the key of responsible any degraded, molecular weight, degree of crystallinity, biological stability and such polymer, the physical characteristic (such as, shape and size) of graft and the pattern given and position.Such as, molecular weight is larger, then degree of crystallinity is higher and/or biological stability is larger, any can the biodegradation of polymer of bio-absorbable usually slower.

" degraded " used herein is instigated converting compounds or is reduced to a kind of less complex, such as, by dividing one or more atomic group.The degraded of coating can reduce the cohesion and tacky adhesion of coating and device, thus promotes that coating is transferred to intervention position.

Term used herein " lasting polymer " refer to can not bio-absorbable (and/or can not bioerosion and/or not biodegradable and/or can not non-bioresorbable) polymer, be therefore Biostatic.In some embodiments, device comprises lasting polymer.Polymer can comprise crosslinked lasting polymer.The example of biocompatible lasting polymer includes but not limited to: polyester, aliphatic polyester, condensing model, polyethylene, poe, polyphosphazene, polyurethane, polycarbonate urethane, aliphatic polycarbonate, silicone, containing silicone polymer, polyolefin, polyamide, polycaprolactam, polyamide, polyvinyl alcohol, acrylate copolymer, acrylate, polystyrene, epoxide, polyethers, cellulose, expanded ptfe, phosphocholine, polyethylene glycol phthalate, polymethyl methacrylate, poly-(ethyl methacrylate/n-BMA), poly-terephthaldehyde supports C, vinyl-vinyl acetate copolymer, polyalkyl methacrylate, alkylene vinyl acetate copolymer, polyolefin, poly-alkylsiloxane, polyhydroxyalkanoatefrom, poly-Fluoroalkyloxy is phosphazine, poly-(styrene-b-isobutene .-block-styrene), polybutyl methacrylate, polybutadiene and blend thereof, combination, homopolymer, condensation polymer, alternately, block, tree-shaped, crosslinked and copolymer.Polymer can comprise thermosets.The transplantable medical treatment device that polymer can be coating provides intensity.The transplantable medical treatment device that polymer can be coating provides persistency.By setting up laminated coating; coating provided herein and coating process provide essence to protect by these; laminated coating can be can bio-absorbable or lasting or their combination, and it can active agent delivery and the container sent wherein provides both elasticity and radial strength.

" morphology that treatment is expected " used herein refers to total form and the structure of medicament, once at substrate deposit, to provide in ex-vivo storage, body the optimal conditions of preserving and/or discharging in body.Such optimal conditions can include but not limited to the rate of release of the shelf life (that is, storage stability) improved, the body internal stability improved, good biocompatibility, good biological usability or adjustment.Usually, for the present invention, the morphology of the expectation of medicament is crystallization or hypocrystalline or unbodied, but this can vary widely, depend on many factors, include but not limited to the character of medicament, the condition of storage of expection of disease, before use matrix of to be treated/prevention or any position of biologic medical graft in health.Preferably the medicament of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5% and/or 100% be crystallization or hypocrystalline form.

In some embodiments of method provided herein and/or device, its Chinese medicine is at least 50% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 75% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 90% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 95% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 97% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 98% crystallization.In some embodiments of method provided herein and/or device, medicament is at least 99% crystallization.

" stabilizing agent " used herein refers to any material of the stability keeping or strengthen biological agent.Ideally, these stabilizing agents are categorized as by FDA (Food and Drug Adminstration) (FDA) and are usually considered as being safe (GRAS) material.The example of stabilizing agent includes but not limited to carrier protein such as albumin, gelatin, metal or inorganic salt.The pharmaceutically acceptable excipient that can exist can find further in relevant document, such as at Handbook of Pharmaceutical Additives:An International Guide to More Than 6000 Products by Trade Name, Chemical, Function, and Manufacturer (medicated premix handbook: the world more than 6000 kinds of products is guided, by trade name, chemistry, function and manufacture); Michael and Irene Ash (editor); Gower Publishing Ltd.; Aldershot, Hampshire, Britain, 1995.

" intervention position " used herein refer to that coating expection is sent (by from matrix transfer, free and/or dissociation) to health in position.Getting involved position can be around any material in the medium of device, such as, and tissue, cartilage, body fluid, etc.Getting involved position can be identical with therapentic part, that is, the material that coating is sent wherein is the identical tissue needing treatment.Alternatively, getting involved position can be separated with therapentic part, needs diffusion subsequently or transhipment medicine or other medicament away from getting involved position.

" compressed fluid " used herein refers to be the fluid with considerable density (such as, >0.2 g/cc) of gas at standard temperature and pressure." supercritical fluid ", " used herein near critical fluids ", " nearly supercritical fluid ", " critical fluids ", " fine and close fluid " or " fine and close gas " refers to compressed fluid under the following conditions, wherein temperature is at least 80% of fluid critical temperature, pressure is at least 50% of fluid critical pressure, and/or density is+50% of fluid critical density.

The example being applicable to the material of proof supercritical of the present invention or near critical behavior includes but not limited to carbon dioxide, isobutene., ammonia, water, methanol, ethanol, ethane, propane, butane, pentane, dimethyl ether, xenon, sulfur hexafluoride, halo and part halogenated material such as Chlorofluorocarbons (CFCs), HCFC, hydrogen fluorohydrocarbon, perfluoroparaffin (such as perfluoromethane and perfluoropropane, chloroform, isceon, dichlorodifluoromethane, dichlorotetra-fluoroethane) and their mixture.Preferably, supercritical fluid is HFC-236fa (FC-236EA) or 1,1,1,2,3,3-HFC-236fa.Preferably, supercritical fluid is HFC-236fa (FC-236EA) or 1,1,1,2,3,3-HFC-236fa, for PLGA polymer coating.

" sintering " used herein instigates partial polymer or whole polymer to become continuously the process of (such as, forming continuous polymer film).As discussed in this article, control sintering process, to produce completely conformal continuous polymer (fully sintered) or to produce continuous coated region or territory, to produce space (interruption) in the polymer simultaneously.Equally, control sintering process, make to obtain between different polymer (such as, polymer A and B) or keep some to be separated and/or produce between discrete polymer beads being separated.By sintering process, improve the adhesive property of coating, to reduce in use coating peeling off from Matrix separation during handling.As described herein, in some embodiments, sintering process is controlled, to provide the incomplete sintering of polymer.In the embodiment relating to not exclusively sintering, form the polymer with continuous domain and space, gap, chamber, hole, passage or crack, the therapeutic agent that they provide space to discharge under controlled conditions for chelating.Depend on the character of polymer, the size of polymer beads and/or other polymer property, Compressed Gas, fine and close gas, near critical fluids or super-critical fluids can be adopted.In an example, carbon dioxide, for the treatment of the matrix being coated with polymer and medicine, uses dry powder and RESS Electrostatic coating methods.In another example, isobutene. is used for sintering process.In other example, adopt the mixture of carbon dioxide and isobutene..In another example, 1,1,2,3,3-HFC-236fa is used for sintering process.

When amorphous materials is heated to the temperature exceeding its glass transition temperature, or when crystalline material is heated to the temperature exceeding phase transition temperature, the molecule comprising material more easily flows, this so that mean that they have more activity, therefore be easier to reaction, such as, be oxidized.But when amorphous materials remains on the temperature lower than its glass transition temperature, its molecule is fixed substantially, be therefore comparatively not easy to reaction.Equally, when crystalline material remains on the temperature lower than its phase transition temperature, its molecule is fixed substantially, is therefore comparatively not easy to reaction.Therefore, under temperate condition (such as deposition described herein and sintering condition), the minimum degradation that drug component makes cross reaction and drug component is processed.The ability avoiding conventional solvent is related to by the reaction of the minimized type of process of the present invention, free radical, remaining solvent, proton material, polarity-proton material, oxidizing initiators and autoxidation initiator is exposed to by reducing it, itself so make the minimize oxidation of medicine, be no matter unbodied, hypocrystalline or crystal form.

" rapid expanding of supercritical solution " used herein or " RESS " relate to dissolve polymer in the compressed fluid (being generally supercritical fluid), then under lower pressure (usually close to atmospheric condition) in room rapid expanding.Supercritical fluid solution is by little opening rapid expanding, and it, with reducing density, reduces the solvability of fluid, and cause polymer beads coring and increment.By keeping in room " cloud " of the insulation of gas, the atmosphere of room remains electric neutrality state.Adopt carbon dioxide, nitrogen, argon, helium or other suitable gas, be transferred to surrounding to prevent electric charge from matrix.

" the electrostatic rapid expanding of supercritical solution " used herein or " e-RESS " or " eRESS " refer to that the rapid expanding of Electrostatic as described herein and supercritical solution as described herein combines.In some embodiments, the electrostatic rapid expanding of supercritical solution refers to the Electrostatic as this area describes, such as, at U.S. Patent number 6,756, in 084, " Electrostatic deposition of particles generated from rapid expansion of supercritical fluid solutions (electrostatic precipitation of the granule produced by the rapid expanding of supercritical fluid solution) ", it is attached to herein by reference and in full.

Electrostatic is used in the upper deposited coatings of device (such as, balloon), and can be described as in this article " eSTAT ".Attract via eSTAT, coating is applied to balloon, the device that wherein positively charged coating applications is electronegative.Such as, in some embodiments, attract the sirolimus of crystal form to be applied to balloon, the balloon of wherein positively charged drug particles coating zone negative charge via eSTAT.In some embodiments, sirolimus balloon is coated with has intrinsic positive charge.

Fig. 2 describes the example using sirolimus to be coated with the eSTAT process of 12 angioplasty balloons.In this embodiment process, the bell jar 2 of 8 liters of aluminium foil coatings is placed in place, but not electrical ground.The sirolimus (15.5 mg) of grinding is placed on and pulse pneumatic valve 20 (Swagelok, Inc., supplement figure S16) Swagelok 1/2 that connects " in T-shaped filter 18 (Swagelok; Inc.; supplement figure S15), this pulse pneumatic valve 20 is attached with the cylinder of compressed nitrogen 22.T-shaped filter is connected with eSTAT nozzle 14 on an opposite end, this nozzle is via 1/2 " (external diameter) polypropylene tube 16 is installed to 3/8 of amendment " Swagelok BULKHEAD UNION (Swagelok, Inc., supplement figure S17) 1/2 " × 3/8 " Swagelok reducing joint.Balloon 4 is installed for 2 times in position at bell jar.In this example, the balloon that 12 3.0 mm are wide is once coated with the sirolimus 6 of positively charged grinding.Balloon 4 can have various length, such as the length of 17 mm-23 mm, but, in other embodiments, other size can be used.In some embodiments, less or more balloon can be once coated with.The balloon 4 used during coating process be usually arranged on there is the tinsel 10 arranged wherein conduit 8 on, conduit 8 and high voltage power supply 12 (such as Spellman SL30 high voltage power supply) coupling, such as, this high voltage can be set as-15kV.

In some embodiments, the length of balloon can be any length of 5 mm-35 mm, or any following length, such as: about 5 mm, about 7 mm, about 8 mm, about 10 mm, about 12 mm, about 13 mm, about 15 mm, about 18 mm, about 20 mm, about 21 mm, about 23 mm, about 25 mm, about 28 mm, about 30 mm, about 32 mm, about 33 mm and about 35 mm.When using in the context in balloon length, term " about " may imply that such as, and 10%, 25%, 50%, 0.1 mm, 0.25 mm, 0.5 mm, 1 mm, the change of 2 mm and 5 mm, depends on embodiment.

In some embodiments, the diameter (that is, width) of balloon can be any diameter of 1.5 mm-6.0 mm, or any following diameter, such as: about 1.5 mm, about 1.8 mm, about 2.0 mm, about 2.25 mm, about 2.5 mm, about 2.75 mm, about 3.0 mm, about 3.25 mm, about 3.5 mm, about 3.75 mm, about 4.0 mm, about 4.25 mm, about 4.5 mm, about 4.75 mm, about 5.0 mm, about 5.25 mm and about 5.5 mm.When using in the context at balloon diameter (or width), term " about " may imply that such as 10%, 25%, 50%, 0.1 mm, 0.25 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.75 mm, and the change of 1 mm and 2 mm, depends on embodiment.

In some embodiments, a minimum once coating balloon.In some embodiments, once coating is following one of at least: at least 3 balloons, at least 5 balloons, at least 6 balloons, at least 8 balloons, at least 10 balloons, at least 12 balloons, at least 15 balloons, at least 16 balloons, at least 20 balloons, at least 24 balloons and at least 30 balloons.

These balloons can be coated with polymer (such as PLGA) in advance or can not be coated with in advance.Realize coating balloon by various means, such as dip-coating, spraying, or use the coating of RESS method.Such as, via the rapid expanding (RESS) of supercritical solution, by polymer (such as, PLGA) balloon is applied to, wherein solute (such as, PLGA) be dissolved in supercritical fluid, lead to low temperature and lower pressure region by short nozzle subsequently, use and reduce pressure and rapid expanding suddenly.These conditions cause the PLGA rapid precipitation of dissolving as thin powder, have narrow particle size distribution, cause uniform coating on angioplasty balloons.

Fig. 3 describes an example for using PLGA to be coated with the RESS process of balloon 4.In container 24, load PLGA, wherein it is dissolved in the HFC236ea from HFC236ea cylinder 26, and HFC236ea delivers to container 24 by syringe pump 28 (such as, Isco260D syringe pump).Therefore, PLGA and HFC236 ea forms supercritical solution, it is stirred under high pressure (5500 psi) in mixing room, the visual field (50cc).Send PLGA solution by syringe pump 30 (such as, Isco260D syringe pump), it send solution, subsequently by the pneumatic operated valve 34 of the timing of heating at 137 DEG C by unit heater 32 (have temperature and control feedback).Subsequently by by rustless steel sheath (such as, inch rustless steel sheath) around capillary tube 36 (such as, PEEKsil capillary tube 1/16 " micron inside diameter × 10, external diameter × 100 cm long) send PLGA solution.The nozzle 40 passing through (such as, via rustless steel sheath) electrical ground subsequently sprays PLGA.When PLGA solution leaves nozzle 40, spray PLGA as dry PLGA granule 42, owing to comprising the solution rapid expanding of PLGA and HFC236ea.The balloon 4 used during coating process be usually arranged on there is the tinsel 10 wherein arranged conduit 8 on, conduit 8 is electrical ground 44.Tinsel 10 can with high voltage power supply 12 (such as Spellman SL30 high voltage power supply) coupling, to promote to use activating agent eSTAT to be coated with balloon, but, in the RESS process described in this embodiment, balloon electrical ground, and does not have electric current to flow from power supply 12.

When combining consideration, Fig. 2 and 3 indicates the single equipment that can be coated with according to both RESS process and eSTAT process.The element of drawing in fig. 2 and describe can be drawn similarly in figure 3, and vice versa.Alternatively, independent coating apparatus can be used for being coated with separately according to RESS process and eSTAT process.

" dispersion of the solution enhancing of supercritical solution " used herein or " SEDS " relate to the spray process for generation of polymer beads, when compressed fluid (such as, supercritical fluid, preferred supercritical CO ₂) when being used as the diluent of the wherein vehicle (soluble polymeric thing and the vehicle both compressed fluid) of dissolve polymer, form polymer beads.By meeting containing the first-class of polymer solution with containing the second of diluent compressed fluid, mixing of compressed fluid diluent and the solution containing polymer can be realized, such as, in a nozzle or pass through the multiple nozzle of use.Solvent in a polymer solution can be the mixture of a kind of compound or two or more compositions and can be or comprise alcohol and (comprise glycol, triol, etc.), ether, amine, ketone, carbonic ester or alkane or hydrocarbon (aliphatic series or aromatics) or can be the mixture of compound, the mixture of such as alkane, or one or more alkane and other compound be one or more alcohol (such as, 0 or the C of 0.1-5% such as ₁-C ₁₅alcohol, comprises glycol, triol, etc.) mixture that combines.See such as U.S. Patent number 6,669,785, it is attached to herein by reference and in full.Solvent optionally can contain surfactant, such as, also at U.S. Patent number 6, and 669, describe in 785.

In an embodiment of SEDS process, the second co-spray of the first-class of the fluid of the polymer dissolved in common solvent with compressed fluid will be included in.The polymer beads produced as second is used as diluent, and it weakens the solvent in first polymer solution.Stream and the polymer beads of the fluid of present merging flow out to collection container from nozzle assembly.By deciding following process variable: the condition of the flow velocity of temperature, pressure, first solvent composition, first flow velocity, second, the composition (wherein soluble additive can be joined in Compressed Gas) of second and trap receptacle, realize controlling particle diameter, particle size distribution and morphology.Usual trap receptacle contains at least 5-10 doubly (5-10 doubly) atmospheric fluid-phase.

" coating of electrostatic dry powder end " used herein or " e-DPC " or " eDPC " refer to Electrostatic as described herein and dry powder coating compositions.Use Electrostatic, e-DPC such as, at device or other substrate deposit material (comprise, the solid of polymer or impermeable dispersion) as dry powder, so that powder particle is attracted to matrix.Dry powder spraying (" dry powder coating " or " DPC ") is for well known in the art, and dry powder spraying and Electrostatic coupling have been described, such as at U.S. Patent number: 5,470,603,6,319,541 and 6,372, describe in 246, be attached to herein all by reference and in full.In WO2008/148013 " Polymer Films for Medical Device Coating (polymeric film for medical treatment device coating) ", such as describe the method for deposited coatings, it is attached to herein by reference and in full.

" dipping process " used herein and " spray process " refer to the method for the coated substrates described in detail in this area.These processes can be used for making with medicament coated medical device.Such as at U.S. Patent number 7, other local spraying described of 419,696 " Medical devices for delivering a therapeutic agent and method of preparation (medical treatment device and preparation method for delivering therapeutic agents) " and this paper can relate to coating or the dry powder coating of on matrix, spraying or spraying with spray gun skim dissolving.Dip-coating relates to such as impregnation matrix in a liquid, is removed subsequently and drying.Dip-coating describes in such as U.S. Patent number 5,837,313 " Drug release stent coating process (drug releasing stent coating process) ", and it is attached to herein by reference and in full.

Comprise the medicine that strengthens by method of the present invention or biology medicament " bulk properties " character of coating comprise such as: adhesion, smoothness, conformability, thickness and composition mixing.

" electrostatic belt electric charge " used herein or " current potential " or " Electrostatic " refer to the granule compared with spraying, and the matrix with different electrostatic potentials is collected the granule that spraying produces.Therefore, about the granule left, matrix is in attractability electromotive force, and this causes arrested particles on matrix.That is, matrix and granule oppositely charged, and strengthen the gaseous medium transport particles by trap receptacle on the surface of matrix via electrostatic attraction.This can realize as follows: by making particle charge lotus (such as under a current potential, negative charge) and under contrary current potential, make matrix electrically charged (such as, positive charge), or by some other processes that Electrostatic those skilled in the art can easily imagine, make particle charge lotus and make matrix ground connection, or make matrix electrically charged and make granule ground connection on the contrary.

" by the agent of e-RESS, e-SEDS or e-DPC process position activity, and not making matrix electrically charged " used herein refers to deliberately not make these processes any of the electrically charged enforcement of matrix.It should be understood that it is electrically charged that matrix may become not expressly during these processes any.

" by the agent of e-RESS, e-SEDS or e-DPC process position activity, and between matrix and coating apparatus, not producing current potential " used herein refers to do not have intentional these processes any producing current potential and implement between matrix and coating apparatus.It should be understood that possible not expressly produces current potential between matrix and coating apparatus during these processes any.

" intimate mixture " used herein refers to two or more materials, compound or the material that are uniformly distributed or are dispersed in together.

" layer " used herein refers to covering surfaces or forms the material covering part or part.Two different layers can have lap, thus can with the material from another layer from the material of a layer.By measuring the distance between material, the contact between the material can measuring different layers.Such as, Raman spectroscopy can be used for the material of two layers identified from closely contiguous existence each other.

Although consider the layer limited by uniform thickness and/or regular shape herein, some embodiments described herein relate to and have different-thickness and/or erose layer.The material of a layer may extend to the space occupied in a large number by the material of another layer.Such as, have in the coating of three layers, formed as the first polymeric layer, medicament layer and the second polymer layer in order, the material from the second polymer layer of last deposition may extend in the space occupied in a large number by the material of medicament layer in this sequence, thus can with the material from medicine layer from the material of the second polymer layer.Also consider that the material from the second polymer layer extends by the whole layer occupied in a large number by medicament, and with the material from the first polymeric layer.

But; it should be noted that; contact between material from the second polymer layer (or first polymeric layer) and the material (such as, medicament crystal grain or its part) from medicament layer must not imply and form mixture between the material from first or the second polymer layer and the material from medicament layer.In some embodiments, layer can be limited by the physical three-dimensional space occupied by the crystalline particle of medicament (and/or biology medicament).Consider that such layer may be that continuous print or possibility are discontinuous, because the physical space occupied by the crystal grain of medicament can such as be interrupted from the polymeric material of adjacent polymeric layer.Adjacent polymeric layer can be the layer close with the pharmacy particle physics in medicament layer.Similarly, adjacent layer can be the deposition of pharmacy particle wherein with the process steps forming medicament layer just before or lucky after process steps in the layer that formed.

As described herein, it is favourable that deposition of material provided herein and layer are formed, and is that medicament mainly retains in crystalline form during whole process.Although polymer beads may contact with pharmacy particle, key-course forming process, to avoid, during the device forming coating, forming mixture between pharmacy particle and polymer beads.

In some embodiments, coating comprises multiple layer at substrate deposit, and wherein at least one layer comprises activating agent.In some embodiments, at least one layer comprises polymer.In some embodiments, polymer is can bio-absorbable.In some embodiments, activating agent and polymer in identical layer, in independent layer or formed overlapping layer.In some embodiments, multiple layer comprises the five layers: first polymeric layer of following deposition, the first active agent layer, the second polymer layer, the second active agent layer and trimerization nitride layer.

In some embodiments of method provided herein and/or device, coating comprises multiple layer at substrate deposit, and wherein at least one layer comprises activating agent.In some embodiments, at least one layer comprises polymer.In some embodiments, polymer is can bio-absorbable.In some embodiments, activating agent and polymer in identical layer, in independent layer or formed overlapping layer.In some embodiments, coating comprises multiple layer at substrate deposit, and wherein at least one layer comprises medicament.In some embodiments, medicament and polymer in identical layer, in independent layer or formed overlapping layer.In some embodiments, multiple layer comprises the five layers: first polymeric layer of following deposition, the first active agent layer, the second polymer layer, the second active agent layer and trimerization nitride layer.In some embodiments, multiple layer comprises the five layers: first polymeric layer of following deposition, the first medicament layer, the second polymer layer, the second medicament layer and trimerization nitride layer.In some embodiments, multiple layer comprises the five layers: first polymeric layer of following deposition, the first active biological medicament layer, the second polymer layer, the second active biological medicament layer and trimerization nitride layer.

In some embodiments, be greater than on the delivery zone of exterior surface area of matrix, device provides coating to intervention position.In some embodiments, the region of sending is greater than the exterior surface area at least 110% of matrix.In some embodiments, the region of sending is greater than the exterior surface area at least 110%-200% of matrix.In some embodiments, the region of sending is greater than outer surface of matrix contact area at least 200%.

" laminated material coating " used herein refers to the coating be made up of the material of two or more layers.Means for generation of laminated material coating as described herein (such as, comprise can the polymer of bio-absorbable and the laminated material coating of medicament) can comprise and use medicine described herein and polymer-coated support (e-RESS, e-DPC, compression-gas sintered).This process comprises implements multiple and sequential application step (using the sintering step being used for polymeric material), wherein can deposit different materials in each of the steps, therefore, produce the structure with the lamination of the numerous layers (at least 2 layers) comprising polymeric layer and medicament layer, to build resulting device (such as, the support of laminated material coating).

" part of coating " used herein and " part of activating agent " refer to dissociate from matrix, dissociation and/or be transferred to gets involved the coating at position or the amount of activating agent or percent, or the delivery sites of specifying, during a certain Delivery time section, or amount to from start to finish in whole delivery process.In embodiments, apparatus and method of the present invention be suitable for dissociating, dissociation and/or shift coating and/or the activating agent of certain tittle.

Such as, in embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or be suitable for, dissociation free from matrix and/or be transferred to getting involved position at least about the coating of 99%.In embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or be suitable for, dissociation free from matrix and/or be transferred to getting involved position at least about the activating agent of 99%.

The part of coating and/or dissociate from device matrix, the part of the coating of dissociation or transfer be subject to any below or below the impact of combination: such as, the size of device matrix, shape and pliability, size, shape, surface quality and get involved position condition (such as, blood or lymph circulation, temperature, etc.), comprise concrete activating agent and for the composition of the coating of the specific polymers compositions of coating, these components relative scale, use any releasing agent and matrix characteristics.In these and other aspect of apparatus and method of the present invention any one or be multiplely suitable for that impact is free, dissociation and/or the coating of transfer and/or the part of activating agent, as desired, to produce the clinical effectiveness of expectation.

" substantially all coatings " used herein refer to exist on device at least about 50% before use, at least about 75%, at least about 85%, at least about 90%, at least about 95%, at least about 97% and/or coating at least about 99% percent.

" at least partially matrix " used herein refers to matrix that is a certain amount of and/or percent.In the embodiment of the apparatus and method of the present invention of coating on " at least partially matrix " wherein, refer to that coating is at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% matrix." at least partially matrix " is can in the embodiment of bio-absorbable wherein, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or be can bio-absorbable at least about the matrix of 99%.

At or activating agent transfer coated from matrix in the context getting involved position, " transfer at least partially " used herein refers to be transferred to from matrix get involved the coating at position or the amount of activating agent and/or percent.Coating or activating agent are transferred to the embodiment of the apparatus and method of the present invention getting involved position from matrix at least partially wherein, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating or activating agent from matrix be transferred to get involved position.In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating be suitable for from matrix be transferred to get involved position.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 10%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 20%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 30%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 50%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 75%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 85%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 90%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 95%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the coating of 99%.When the percent with reference to coating uses, " about " used herein may imply that 1%-5%, the scope of 5%-10%, 10%-20% and/or 10%-50% (as the percent of the percent of the coating of transfer, or as the change of the percent of the coating shifted).

In some embodiments, be suitable in the coating layer portion that shifts the after stimulation at least one in the surface, nearly chamber of the distal surface of matrix, the intermediate surface of matrix, the neighbouring surface of matrix and matrix.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, device is suitable for transfer and is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% do not exist coating stimulate coating.

In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% activating agent be suitable for from matrix be transferred to get involved position.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 10%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 20%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 30%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 50%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 75%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 85%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 90%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 95%.In some embodiments, be suitable for being transferred to from matrix getting involved position at least about the activating agent of 99%.When the percent with reference to activating agent uses, " about " used herein may imply that 1%-5%, the scope of 5%-10%, 10%-20% and/or 10%-50% (as the percent of the percent of the activating agent of transfer, or as the change of the percent of the activating agent shifted).

In some embodiments, be suitable in the active agent moiety that shifts the after stimulation at least one in the surface, nearly chamber of the distal surface of matrix, the intermediate surface of matrix, the neighbouring surface of matrix and matrix.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, device is suitable for transfer and is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% do not exist coating stimulate activating agent.

In some embodiments, device is suitable at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating from matrix be transferred to get involved position.In some embodiments, device is suitable for the coating at least about 10% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 20% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 30% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 50% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 75% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 85% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 90% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 95% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the coating at least about 99% to be transferred to from matrix to get involved position.When the percent with reference to coating uses, " about " used herein may imply that 1%-5%, the scope of 5%-10%, 10%-20% and/or 10%-50% (as the percent of the percent of the coating of transfer, or as the change of the percent of the coating shifted).

In some embodiments, at least one of the coating layer portion shifted after stimulation in the surface, nearly chamber of the distal surface of matrix, the intermediate surface of matrix, the neighbouring surface of matrix and matrix.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, device is suitable for transfer and is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% do not exist coating stimulate coating.

In some embodiments, device is suitable at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% activating agent from matrix be transferred to get involved position.In some embodiments, device is suitable for the activating agent at least about 10% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 20% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 30% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 50% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 75% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 85% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 90% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 95% to be transferred to from matrix to get involved position.In some embodiments, device is suitable for the activating agent at least about 99% to be transferred to from matrix to get involved position.When the percent with reference to activating agent uses, " about " used herein may imply that 1%-5%, the scope of 5%-10%, 10%-20% and/or 10%-50% (as the percent of the percent of the activating agent of transfer, or as the change of the percent of the activating agent shifted).

In some embodiments, at least one of the coating layer portion shifted after stimulation in the surface, nearly chamber of the distal surface of matrix, the intermediate surface of matrix, the neighbouring surface of matrix and matrix.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, device is suitable for transfer and is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80%, be less than the activating agent that there is not coating stimulation of about 90%.

Dissociate the context of coating and/or activating agent at intervention position from matrix, " free at least partially " used herein refers to getting involved amount and/or the percent of coating or the activating agent dissociated from matrix at position.In the embodiment of apparatus and method of the present invention, wherein coating or activating agent dissociate from matrix at intervention position at least partially, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating or activating agent intervention position from matrix dissociate.In some embodiments, device is suitable for from matrix free at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating.In some embodiments, device is suitable for the coating at least about 10% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 20% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 30% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 50% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 75% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 85% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 90% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 95% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 99% to dissociate to intervention position from matrix.When the percent with reference to coating uses, " about " used herein may imply that 1%-5%, the scope of 5%-10%, 10%-20% and/or 10%-50% (as the percent of the percent of free coating, or as the change of the percent of the coating of dissociating).

In some embodiments, at least one of free after stimulation coating layer portion in the surface, nearly chamber of the distal surface of matrix, the intermediate surface of matrix, the neighbouring surface of matrix and matrix.

In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, device is suitable for dissociating and is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80%, be less than the coating that there is not coating stimulation of about 90%.

Getting involved position from the context of matrix dissociation coating and/or activating agent, " dissociation at least partially " used herein refers to getting involved position from the amount of the coating of matrix dissociation and/or activating agent and/or percent.Coating and/or activating agent are getting involved position from the embodiment of the apparatus and method of the present invention of matrix dissociation at least partially wherein, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating and/or activating agent intervention position from matrix dissociation.

In some embodiments, device is suitable at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating from matrix dissociation.In some embodiments, device is suitable for the coating at least about 10% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 20% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 30% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 50% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 75% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 85% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 90% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 95% to dissociate to intervention position from matrix.In some embodiments, device is suitable for the coating at least about 99% to dissociate to intervention position from matrix.When the percent with reference to coating uses, " about " used herein may imply that 1%-5%, the scope of 5%-10%, 10%-20% and/or 10%-50% (as the percent of the percent of the coating of dissociation, or as the change of the percent of the coating of dissociation).

In some embodiments, after stimulation at least one of the coating layer portion of dissociation in the surface, nearly chamber of the distal surface of matrix, the intermediate surface of matrix, the neighbouring surface of matrix and matrix.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, device is suitable for dissociation and is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80%, be less than the coating that there is not coating stimulation of about 90%.

Getting involved in the context of position at coating and/or activating agent, " deposition at least partially " used herein refers at the intervention coating of site deposition and/or the amount of activating agent and/or percent.In the embodiment of apparatus and method of the present invention, wherein site deposition got involved by coating and/or activating agent at least partially, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating and/or activating agent intervention site deposition.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, Energy Deposition deposition is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% coating, there is not at least one stimulated in coatings and substrate in described coating.

Getting involved in the context of position at coating and/or activating agent, " sending at least partially " used herein refers to be delivered to and gets involved the coating at position and/or the amount of activating agent and/or percent.In the embodiment of apparatus and method of the present invention, wherein coating and/or bioactive agent delivery will deliver to intervention position at least partially, will at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating and/or bioactive agent delivery deliver to get involved position.

In some embodiments, device is suitable at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating be delivered to get involved position.In some embodiments, device is suitable for the coating at least about 10% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 20% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 30% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 50% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 75% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 85% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 90% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 95% to be delivered to and gets involved position.In some embodiments, device is suitable for the coating at least about 99% to be delivered to and gets involved position.When the percent with reference to coating uses, " about " used herein may imply that 1%-5%, the scope of 5%-10%, 10%-20% and/or 10%-50% (as the percent of the percent of the coating of sending, or as the change of the percent of the coating of sending).

In some embodiments, at least one of the coating layer portion sent after stimulation in the surface, nearly chamber of the distal surface of matrix, the intermediate surface of matrix, the neighbouring surface of matrix and matrix.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, device is suitable for sending and is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80%, be less than the coating that there is not coating stimulation of about 90%.

In some embodiments, deposit coating be at least partially included in get involved site deposition at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, Energy Deposition deposition is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% coating, there is not at least one stimulated in coatings and substrate in described coating.

Make in the context that adhere in coating and intervention position at least partially, " adhesion at least partially " used herein refers to getting involved amount and/or the percent of coating and/or the activating agent of adhering at position.In the embodiment of apparatus and method of the present invention, wherein coating and/or activating agent are adhered at intervention position at least partially, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating and/or activating agent intervention position adhesion.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, adhesion can be adhered and is less than about 1%, is less than about 5%, be less than about 10%, be less than about 15%, be less than about 25%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% coating, there is not at least one stimulated in coatings and substrate in described coating.In some embodiments, device comprises and the adhering element stimulating co-operate to adhere with intervention position to make coating.In some embodiments, device comprises the adhering element that coating and matrix are adhered, until use stimulation to stimulate.

To adhere to or in the context of adhering at matrix and coating, " adhesion " used herein, " adhesion ", " adhesion ", " adhesion ", " adhesion ", " adhesion " and relevant term refer to that the interaction between matrix and coating is enough strong, to stimulate (such as, machinery, chemistry, heat, electromagnetism or sound stimulation) front, keep coating and matrix to associate reaching the regular hour to measure, be intended to cause coated free, dissociation and/or transfer.Refer to that coating and target tissue region and/or the interaction got involved between position are enough to keep coating and target tissue region and/or get involved position associate and reach the processing time as desired and measure at coating and target tissue region and/or these identical terms of using in getting involved between position interactional context, such as, at least about 12 hours, about 1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about 180 days, about 6 months, about 9 months, about 1 year, about 1-about 2 days, about 1-about 5 days, about 1-about 2 weeks, about 2-about 4 weeks, about 45-about 60 days, about 45-about 90 days, about 30-about 90 days, about 60-about 90 days, about 90-about 180 days, about 60-about 180 days, about 180-about 365 days, about 6 months-Yue 9 months, about 9 months-Yue 12 months, about 9 months-Yue 15 months and about 1 year-Yue 2 years.

" balloon " used herein refers to pliable and tough bag, its natural or non-natural body lumen or intracavity inflatable, or for generation of chamber, or for expanding existing chamber.Balloon can be of short duration in expansion tube cavity or chamber, and can exit and/or remove from experimenter during medical procedure or subsequently subsequently.In embodiments, balloon can expand and have the coating from balloon free (at least partly) thereon in health, when being removed by balloon, stays in tube chamber or chamber.After balloon compacting is used for inserting, coating can be applied to balloon, cause part to cover the coating on surface of balloon, or can before compacting or period use.In embodiments, before and after compacting balloon, the two, be applied to balloon by coating.In embodiments, by such as rolling up or fold compacting balloon.In the method the following describing compacting balloon, such as, U.S. Patent number 7,308,748 " Method for compressing an intraluminal device (for suppressing the method for endoluminal device) " and U.S. Patent numbers 7,152,452 " Assembly for crimping an intraluminal device and method of use (assembly and using method for pipe crimping intracavitary unit) ", it relates to evenly rolls up balloon on conduit or other endoluminal device; With 5,350,361 " Tri-fold balloon for dilatation catheter and related method (three folding balloon and the relevant methods for dilating catheter) ", it relates to balloon method for folding and device, is attached to herein all by reference and in full.In some embodiments, by delivery apparatus, balloon delivery is delivered to intervention position.In some embodiments, delivery apparatus comprises conduit.In some embodiments, balloon is angioplasty balloons.Balloon can be sent, removes and be estimated between delivery period, and is removed by methods known in the art, such as, for inserting angioplasty balloons, support and other medical treatment device.For estimating the method for area for treatment and planning apparatus insertion at such as U.S. Patent number 7,171,255 " Virtual reality3D visualization for surgical procedures (the virtual reality 3D for surgical procedure estimates) " and U.S. Patent numbers 6,610, describe in 013 " 3D ultrasound-guided intraoperative prostate brachytherapy (in the art of 3D ultrasonic guidance prostate close-range treatment) ", they are attached to herein by reference and in full.

" being obedient to balloon " used herein refers to compared with being partly obedient to balloon, and relatively more multiple coincidence gets involved position, and compared with non-compliant balloon, still more multiple coincidence gets involved the balloon at position.When improving pressure in balloon, be obedient to balloon expansion and stretching, and be made up of the material of such as polyethylene or polyolefin copolymer.Exist in this area based on their dilatancy or " compliance " relative to each other the universal classification of balloon, as at such as U.S. Patent number 5, describe in " Block copolymer elastomer catheter balloons (elastomer block copolymer catheter balloon) " of 556,383.Generally speaking, " non-compliant " balloon is minimum is elastic, when by balloon from about 6 atmospheric the blowing pressures be forced into about 12 atmospheric pressure time, improve diameter and be about 2-7%, usually about 5%, namely, on this pressure limit, they have " expansion " of about 5%." be partly obedient to " balloon and there is expansion larger a little, on the pressurization scope that this is identical, be generally 7-16%, be typically 10-12%." be obedient to " balloon still more expansible, on the pressure limit that this is identical, expansion is generally 16-40%, is typically about 21%.Because wall intensity, the maximum extension (that is, from nominal diameter to the expansion of breaking) of various balloon material can be significantly higher than expansion percent discussed above, and therefore, fracture pressure varies widely between balloon material.These expansion scopes aim to provide general guidance, and as those skilled in the art recognize that, the compliance of balloon depends on size and/or the characteristic of chamber and/or wall of the lumen, and is not only the dilatancy of balloon.

Be obedient to the vascular system that balloon can be used for experimenter.Be obedient to balloon and also can be used for any pipe of vascular system outside or hole (no matter be natural existence or artificial, or produce during injuring).For limiting examples, be obedient to balloon and can be used for lumpectomy, coating to be placed on the position removing tumor, to treat abscess, treatment infection, prevention infection, auxiliary healing, to promote healing or the combination for these objects any.Coating in this embodiment can comprise somatomedin.

" non-compliant balloon " used herein refers to not meet intervention position, but tends to cause the balloon got involved position and meet balloon.When interior balloon pressure improve exceed make balloon inflate required pressure completely time, the balloon of the non-compliant usually prepared by the material of such as polyethylene glycol phthalate (PET) or polyamide keeps the diameter selected in advance.Non-compliant balloon is generally used for expansion space, such as, and vascular lumen.As described about being obedient to balloon, those skilled in the art recognize that, the compliance of balloon depends on size and/or the characteristic of chamber and/or wall of the lumen, and is not only the dilatancy of balloon.

" cutting balloon " used herein refers to the balloon being usually used in angioplasty, and it has has the special balloon of cutting element most advanced and sophisticated, such as, and small blade, tinsel, etc.When making balloon inflation, cutting element can activate.In angioplasty procedures, small blade can be used for speckle indentation, and balloon is for suppressing the fatty material facing to blood vessel wall.Cutting balloon may have nail or other wire elements, and in some embodiments, they contribute to coating and dissociate from balloon, and in some embodiments, can promote that coating and target tissue region adhere to or part adheres, or their some combinations.In some embodiments, cut balloon cutting element and also can make target tissue indentation, to promote that coating is introduced in target tissue.In some embodiments, cutting element does not cut and organize at intervention position.In some embodiments, cut balloon and comprise adhering element as cutting element.

" the blowing pressure " used herein instigates the pressure of balloon inflation.Nominal the blowing pressure used herein instigates balloon inflation to realize the pressure of specific balloon size (being generally the diameter of the balloon of design)." fracture pressure of evaluation " used herein or " RBP " refer to make balloon inflation and do not have the maximum statistics of failure to ensure pressure.For PTCA and PTA conduit, the fracture pressure of evaluation based on the result of the testing in vitro to PTCA and/or PTA conduit, and usually mean the balloon (there is 95% confidence level) of the test of at least 99.9% or lower than this pressure under can not break.

" adhering element " used herein refers to be transferred to for affecting coating the element on matrix surface getting involved position.Such as, on the surface of matrix, adhering element can comprise ledge, such as, and protuberance or nail.In embodiments, adhering element is suitable for making coating be fixed to cutting balloon, until cutting balloon inflation.In some embodiments, adhering element can comprise tinsel, and tinsel can adopt the wedge form molding referred to outwardly.In certain embodiments, adhering element does not cut and organize at intervention position.

" Surigical tool " used herein refers to any instrument for surgical procedure.The example of Surigical tool includes but not limited to: " Surigical tool " used herein refers to any instrument for surgical procedure.The example of Surigical tool includes but not limited to: blade, dissecting knife, seal wire, conduit, catheter, dilator, pin, syringe, cut sections for microscopic examination device, bone fracture device, add loti bone fracture device, osteotome, bone hammer, Ke Teer cartilage is hammered into shape, bone cutter, traction apparatus, bone external fixation device, tractizer in marrow, bone drill, bone dilator, bone file, crowbar, bone mallet, bastard file, bone saw, chock, clamping plate, hasp, slide calliper rule, sleeve pipe, conduit, cautery, clamp, coagulator, curet, settler, dilator, dissect and check cutter, traction apparatus, dermatome, tweezers, dissect inspection tweezers, gauze tweezers, sponge tweezers, bone tweezers, Carmalt tweezers, Cushing tweezers, red enlightening tweezers, dissection of aorta tweezers, Dewar poplar intestinal tweezers, hair pincers, Holstead tweezers, triumphant sharp tweezers, Cork that tweezers, mosquito pawl tweezers, mosquito forceps, hook, nerve hook, practise midwifery hook, skin hook, hypodermic needle, lancet, Wicresoft's pin, cut stone, rubble, mallet, handkerchief is very hammered into shape, dental stent, mouth-gag, Mai Motong, needle holder, dark slide, osteotome, Epker osteotome, periosteal raspatory, Joseph scrapes, depilation periosteal raspatory, the special periosteal raspatory of orthognathous, barrier film is scraped, the West periosteal raspatory, probe, retractor, gloomy retractor, Jie Er compares retractor, Weitlaner retractor, AUS/naval's specialty retractor, aokang Na-Ao Shaliwen retractor, Di Weiershi retractor, Bookwalter retractor, Sweetheart retractor, Joseph's skin hook, Lahey retractor, Blair (Rollet) retractor, rigidity inclination retractor, flexible inclination retractor, Ragnell retractor, Linde-Ragnell retractor, Davis retractor, Volkman retractor, Mathieu retractor, Jackson's trachea hook, Crile retractor, Meyer fourth finger retractor, Arthur D. Little retractor, Lip river husband's nerve retractor, Green retractor, Goelet retractor, Cushing vein retractor, bright Bake retractor, the gloomy retractor of Richard, Richard Sen-Yi Shiman retractor, triumphant sharp retractor, Parker's retractor, Parker-Mo Te retractor, Lu Shi retractor, Mayo-Collins's retractor, banded retractor, alm's retractor, self keeps retractor, Webster retractor, Beckman-Weitlaner retractor, Beckman-Eaton retractor, Beckman retractor, Adson retractor, rib retractor, rongeur, dissecting knife, ultrasound wave dissecting knife, laser scalpel, scissors, iris scissors, cut in base, dissecting scissors, Mei Shi dissecting scissors, cut tendon to cut, spatula, reflecting mirror, oral cavity sight glass, rectal eculum, Lyceum vaginal speculum, Cuzco vaginal speculum, chest bone saw, exhaust tube, surgery rises, ancistrum, surgery cutter, filler piece, operation needle, snare, art is with sponge, art spoon, art anastomat, stitching thread, syringe, spatula, tonsil knife, get tooth device, towel clip, towel forceps, Backhaus towel forceps, Lorna towel forceps, feed channel, tissue expander, subcutaneous inflation dilator, trepan, the trocar, tweezers and vein scissors.In some embodiments, Surigical tool also and/or alternatively can be called the instrument for implementing medical procedure.In some embodiments, Surigical tool can and/or be alternatively also for the instrument to intervention site delivery biologic medical implant.

" stimulation " used herein refers to affect, cause, cause and/or cause that coating and/or activating agent dissociate from matrix, any mechanical stimulus of dissociation and/or transfer, chemical stimulation, thermostimulation, electromagnetic stimulation and/or sound stimulation.

" mechanical stimulus " used herein refers to use affects coating and/or activating agent dissociates from matrix, the mechanical force of dissociation and/or transfer.Such as, mechanical stimulus can comprise shearing force, compression stress, the power applied in coating from the matrix side of coating, the power applied in coating by matrix, by outer member, translation, rotation, vibration or they be combined in the power that coating applies.In embodiments, mechanical stimulus comprises balloon expansion, stent expansion, etc.In embodiments, mechanical stimulus be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In embodiments, mechanical stimulus be suitable for causing that coating is free from matrix, dissociation and/or transfer.In embodiments, mechanical stimulus can be suitable for causing that coating is free from matrix, dissociation and/or transfer.In embodiments, outer member is an experimenter's part.In embodiments, outer member is not a part for device.In embodiments, outer member comprises liquid, such as, and saline or water.In certain embodiments, liquid is forced between coatings and substrate.In embodiments, mechanical stimulus comprises the geometric configuration making the maximized matrix of the shearing force in coating.

" chemical stimulation " used herein refers to use chemical force, and to affect, coating is free from matrix, dissociation and/or transfer.Such as, chemical stimulation can comprise bulk degradation, with the interaction of body fluid, with systemic interaction, with the chemical interaction of non-body fluid, react with the chemical interaction of chemicals, Acid-Base, enzyme reaction, hydrolysis or their combination.In embodiments, chemical stimulation be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In embodiments, chemical stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In embodiments, chemical stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In embodiments, comprising when getting involved position response original position enzyme reaction and be suitable for the coating of the material from matrix transfer, free and/or dissociation by using, realizing chemical stimulation, causing weak binding between coatings and substrate.

" thermostimulation " used herein refers to use thermostimulation, and to affect, coating is free from matrix, dissociation and/or transfer.Such as, thermostimulation can comprise at least one in thermostimulation and cold stimulation.In embodiments, thermostimulation comprise be suitable for expanding that coating is dissociated from matrix, at least one the thermostimulation of dissociation and/or transfer and cold stimulation.In embodiments, thermostimulation comprise be suitable for causing that coating is dissociated from matrix, at least one the thermostimulation of dissociation and/or transfer and cold stimulation.In embodiments, thermostimulation comprise be suitable for causing coating to dissociate from matrix, at least one the thermostimulation of dissociation and/or transfer and cold stimulation.

" electromagnetic stimulation " used herein refers to use electromagnetic stimulation, and to affect, coating is free from matrix, dissociation and/or transfer.Such as, electromagnetic stimulation is electromagnetic wave, its comprise such as following in one of at least: wireless wave, microwave, infrared waves, near-infrared ripple, visible light wave, ultraviolet waves, X-ray ripple and γ ripple.In embodiments, electromagnetic stimulation be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In embodiments, electromagnetic stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In embodiments, electromagnetic stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.

" sound stimulation " used herein refers to use sound stimulation, and to affect, coating is free from matrix, dissociation and/or transfer.Such as, sound stimulation can comprise sound wave, and wherein sound wave is at least one in ultrasound wave, acoustical sound waves and infrasonic wave.In embodiments, sound stimulation be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In embodiments, sound stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In embodiments, sound stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.

" releasing agent " used herein refers to affect material or the basal body structure of easy, speed that coating discharges from matrix or degree.Device is suitable for a part of coating and/or activating agent to be transferred to some embodiment getting involved position from matrix wherein, device is by following adjustment like this, such as, the surface modification of matrix characteristics and/or matrix is (for limiting examples: matrix forms, matrix material, base shape, matrix deployment characteristics, matrix delivery characteristics, substrate pattern and/or matrix quality), the delivery system of matrix and coating is (for limiting examples: control on matrix, delivery system is used to control on coating, the type of the delivery system provided, the material of delivery system and/or its combination), the physical characteristic of coating characteristic and/or coating is (for limiting examples: select activating agent and/or polymer and/or polymer-active agent to form, or by having specific pattern (such as, bar paten, veined surface, smooth surface and/or another pattern) coating, coating layer thickness, coating and/or another physics and/or component characteristic), releasing agent characteristic (for limiting examples: by select specific releasing agent and/or wherein releasing agent for transfer coated and/or the mode of activating agent and/or the releasing agent of use amount) and/or their combination.Releasing agent can comprise biocompatible releasing agent, with the releasing agent of biocompatible aggravated and/or response or incite inflammation are cured in induction in addition, powder releasing agent, lubricant (such as, ePTFE, sugar, other known lubricant), micronized medicine as releasing agent (with produce after coating is free from matrix disrupted beds, physics releasing agent (make matrix become pattern with free coating, other) and/or after inserting change character material (such as, the hydrogel of gel, lipid film, vitamin E, oil, mucoadhesive, adhesion, etc.).Matrix is made to become the method for pattern to be described in such as U.S. Patent number 7,537,610, " Method and system for creating a textured surface on an implantable medical device (for producing the method and system on veined surface on implantable medical treatment device) ".In embodiments, use more than a kind of releasing agent, such as, matrix can become pattern and also lubricate.In some embodiments, releasing agent comprises the fluid of thickness.

In some embodiments, releasing agent comprises the fluid of thickness.In some embodiments, the fluid of thickness comprises oil.In some embodiments, the fluid of thickness is the fluid of relative water thickness.In some embodiments, the fluid of thickness is the fluid of relative hyperlipidemia.In some embodiments, the fluid of thickness is the fluid relatively urinating thickness.In some embodiments, the fluid of thickness is the fluid of relative bile thickness.In some embodiments, the fluid of thickness is the fluid of relative counts of synovial fluid thickness.In some embodiments, the fluid of thickness is the fluid of alongside saline thickness.In some embodiments, the fluid of thickness is at the fluid getting involved the relative body fluid thickness in position.

In some embodiments, releasing agent comprises the physical characteristic of matrix.In some embodiments, the physical characteristic of matrix comprises at least one in the coating surface of pattern and strip coated surface.In some embodiments, the coating surface of pattern is become to comprise Support frame.In some embodiments, strip coated surface comprises the matrix surface of fluctuating.In some embodiments, strip coated surface comprises the bossed matrix surface of tool thereon.

In some embodiments, releasing agent comprises the physical characteristic of coating.In some embodiments, the physical characteristic of coating comprises pattern.In some embodiments, pattern is veined surface on the matrix side of coating, and the matrix side of its floating coat is a part for the coating on matrix.In some embodiments, pattern is the veined surface on the side, intervention position of coating, and the side, intervention position of its floating coat is be transferred to and/or be delivered to and/or in the part of coating getting involved site deposition.

" extruding " used herein and/or " extruding " and/or " extruding " refers to that moving matter is away from another material or object, especially after stimulation, such as, passes through mechanical force.Such as, in embodiments of the invention, from matrix extruding coating.

There is provided herein medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, wherein makes coating become pattern, and wherein after stimulation coating, coating is suitable for dissociating from matrix at least partially.

There is provided herein medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, wherein makes coating become pattern, and wherein after stimulation coating, coating is suitable for from matrix dissociation at least partially.

There is provided herein medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, wherein makes coating become pattern, and wherein after stimulation coating, coating is suitable for being transferred to from matrix getting involved position at least partially.

In some embodiments, the coating of pattern is become to comprise at least two kinds of different shapes.

Mention that coating " one-tenth pattern " used herein refers to have at least two kinds of difform coatings.Shape is formed by various method, comprises such as, etches, shelters, Electrostatic and/or by coating process described herein.Such as coating can have at least partly by the space of the thickness of coating.In some embodiments, space extends completely through coating.Space can be regular configuration or irregularly shaped.Space can form repeating pattern, to be formed into the coating of pattern.Space can remove from smooth or solid cladding, to be formed into the coating of pattern.In some embodiments, by have bar shaped, wavy or protuberance surface, coating can be made to become pattern.In some embodiments, by from the coating sheath of particular design and/or sheet material cutting and/or etching, coating can be made to become pattern.In such embodiments, use described herein for the manufacture of coating process, may form sheath and/or sheet material.Design can be selected to improve free, transfer from matrix and/or dissociation.Design can be selected to improve to getting involved the transfer at position and/or sending.

Use Method and Process described herein, the coating of pattern generation can be produced, for limiting examples, by providing the matrix of the design with pattern thereon, comprise such as, select with the material of selectivity trapping coating granule (no matter being activating agent, polymer or other coating granule), with the only required part of coated substrates.This part of coating can be the design of the one-tenth pattern of matrix.

Term used herein " polymer of image enhaucament " or " preparation " refer to the material that can use to observe at least one component of coating together with apparatus and method of the present invention, when coating is on matrix, or after, dissociation free at it and/or transfer.In embodiments, the polymer of image enhaucament is used as tracer, allows movement or the position of the device of qualification coating, such as, uses imaging system.In other embodiments, the polymer of image enhaucament allows doctor monitor sending of coating ingredients and move.In embodiments, the polymer of image enhaucament is used to make doctor can measure the dosage of the component (such as, activating agent) of the coating of free, dissociation and/or transfer.About the amount being transferred to the coating getting involved position, the information provided by polymer or the preparation of image enhaucament can allow doctor to measure the speed of release coat, thus allows to predict the administration along with the time.Preparation can comprise barium compound, such as, for limiting examples, and barium sulfate.Preparation can comprise iodine compound.Preparation can comprise any compound improving radiopacity.

In embodiments, the polymer of image enhaucament uses together with apparatus and method of the present invention, for following object, includes but not limited to following one or more: the position of monitoring matrix (such as, balloon or other device); Evaluation physiologic parameters, such as, flow and perfusion; Molecule specific with targeting.In embodiments, only under the target of their expection exists, " intelligence " agent of activation uses together with apparatus and method of the present invention.

There is provided herein a kind of method, described method comprises: provide medical treatment device, and wherein said device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent; Adhere with intervention position with making coating at least partially.In some embodiments, after use stimulation stimulates coating, coating layer portion (that is, a part of coating) is adhered with intervention position.

In some embodiments, matrix comprises balloon.In some embodiments, on it, the cated a part of balloon of tool comprises the outer surface of balloon.In some embodiments, outer surface is the surface of the balloon being exposed to coating before balloon folds.In some embodiments, outer surface is the surface of the balloon being exposed to coating after balloon folds.In some embodiments, outer surface is the surface of the balloon being exposed to coating after balloon is rolled.In some embodiments, coating experiences the material of plastic deformation under being included in the pressure that balloon inflation is provided.In some embodiments, coating comprise material be less than balloon evaluation fracture pressure pressure under experience the material of plastic deformation.

In some embodiments, coating experiences the material of plastic deformation under being included in the pressure of the nominal the blowing pressure being less than balloon.In some embodiments, coating comprises the material of use at least 8 atmospheric pressure experience plastic deformation.In some embodiments, coating comprises the material of use at least 6 atmospheric pressure experience plastic deformation.In some embodiments, coating comprises the material of use at least 4 atmospheric pressure experience plastic deformation.In some embodiments, coating comprises the material of use at least 2 atmospheric pressure experience plastic deformation.

In some embodiments, balloon is for being obedient to balloon.In some embodiments, balloon is partly be obedient to balloon.In some embodiments, balloon is non-compliant balloon.In some embodiments, balloon meets the shape getting involved position.

In some embodiments, balloon comprises cylindrical part.In some embodiments, balloon comprises spherical part substantially.In some embodiments, balloon comprises complicated shape.In some embodiments, complicated shape comprises at least one in binode shape, three node shapes, contraction shape, hourglass shape and bar shape.

Some embodiment generators, except delivery treatments, it can be used for getting involved object, such as, cut balloon.In some embodiments, matrix comprises cutting balloon.In some embodiments, cutting balloon comprises at least one adhering element, and it is suitable for coating is adhered with intervention position.In some embodiments, adhering element is suitable for making coating be fixed to cutting balloon, until cutting balloon inflation.In some embodiments, adhering element comprises tinsel.In some embodiments, tinsel is with the form molding of the wedge referred to outwardly.In some embodiments, adhering element does not cut and organize at intervention position.

A kind of illustrative apparatus provided herein comprises cutting balloon, is used for the treatment of vascular disease (such as, inaccessible in crown or peripheral vasculature infringement).In this embodiment, coating can preferentially be positioned in ' cutting metal wire ' part of device.After deployment, tinsel is pushed in speckle, act on to provide the treatment ' cutting ' of expectation.During this cutting, by effect compression on the metal filament and the combination of shearing force, tinsel is left in polymer and medication coat plastic deformation, leaves some or all of coating embedding specklees and/or arterial wall.Similar method can be applied to sends oncologic: (a) is directly delivered to tumor, and/or (b) is delivered to tremulous pulse blood being delivered to tumor, for site specific chemotherapy, and/or (c) is delivered to the space stayed after removing tumor (lumpectomy).These oncologys (and other non-vascular) application may not need ' cutting ' aspect, and by sheath on balloon or on balloon or form the embodiment of sheath on venting (pleating) balloon according to its floating coat, provide by direct coating.

Cutting balloon embodiment described herein provides some advantages.When balloon inflation, such embodiment allows to concentrate mechanical force on coating/tinsel, tinsel can be used for the point of the contact area of concentrated balloon expansion pressure, cause medicine and polymer coating for the much higher power of plastic deformation, the common balloon of relative non-cutting, this can on much bigger region distribution pressure (therefore, reducing the power proportional with the ratio of area).The embodiment relating to cutting balloon provides the use of polymer, they otherwise too rigidity (high modulus) and can not being out of shape from non-cutting balloon.

Other embodiment provided herein based on optimize distortion and coating to move from the body of device both the geometric configuration of device.Device is in an embodiment of cutting balloon wherein, makes (coating) tinsel molding of cutting balloon, as the wedge outwards referred to.

Another embodiment provides the device based on conduit, wherein via the inflation of balloon, by the therapentic part that medicine-delivery formulation is delivered in vascular system.

An embodiment provides the transcutaneous device of coating (such as, balloon, no matter be cutting balloon or other balloon types), in patients after specific position is launched, by some or all of medicines-delivery formulation (5-10%, 10-25%, 25-50%, 50-90%, 90-99%, 99-100%) be transferred to the therapentic part of needs.In certain embodiments, when expanding or formed, balloon is cylindrical at least partly.In certain embodiments, when expanding or formed, balloon is spherical at least partly.In certain embodiments, when expanding or formed, balloon is spherical at least partly.In certain embodiments, when expanding or formed, balloon has complicated shape (for limiting examples, such as binode shape, three node shapes, have contraction section and/or have hourglass shape).

In some embodiments, shifting activating agent at least partially comprises from matrix transfer at least about 3%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, be greater than 35%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% activating agent.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, transfer can be shifted and be less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, at the most about 35%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% the activating agent that there is not at least one stimulated in coatings and substrate.

Term " be suitable for by least partially " coating or activating agent are transferred to be got involved position and refers to be designed for the device coating of any part or activating agent being transferred to and getting involved position.

Term " be suitable for dissociating from matrix " a part of coating and/or activating agent refers to be designed for and to dissociate the device of the coating of some percent and/or activating agent, coating and/or matrix from matrix.Be designed for and be designed for do not suppress coating and/or activating agent from matrix from the dissociate device used herein of the coating of some percent and/or activating agent, coating and/or matrix of matrix, and/or removing coating may have with any blocking of matrix and/or be connected (no matter being direct or indirect).

In some embodiments, device is suitable for dissociating a part of coating and/or activating agent from matrix.For limiting examples, device is by following and so regulate: matrix characteristics is (for limiting examples: matrix forms, matrix material, shape, matrix deployment characteristics, matrix delivery characteristics, substrate pattern and/or matrix quality), the delivery system of matrix and coating is (for limiting examples: control on matrix, delivery system is used to control on coating, the type of the delivery system provided, the material of delivery system and/or its combination), coating characteristic is (for limiting examples: select activating agent and/or polymer and/or polymer-active agent to form, or by having specific pattern (such as, bar paten, veined surface, smooth surface and/or another pattern) coating, coating layer thickness, coating and/or another physics and/or component characteristic), releasing agent characteristic (for limiting examples: by select specific releasing agent and/or releasing agent how for transfer coated and/or activating agent and/or use how many releasing agents) and/or their combination.

In some embodiments, matrix is suitable for dissociating a part of coating and/or activating agent from matrix.For limiting examples, matrix is by following and so regulate: select matrix composition, matrix material, shape, matrix deployment characteristics, matrix delivery characteristics, substrate pattern and/or matrix quality and/or its combine.Such as, balloon can be designed for only partial inflation in the limit of intervention position.Partial inflation can prevent the part of the design of coating from dissociating.

In some embodiments, coating is suitable for dissociating a part of coating and/or activating agent from matrix.For limiting examples, coating is by following and so regulate: select activating agent and/or polymer and/or polymer-active agent composition, or by coating, coating layer thickness, coating and/or another physics with specific pattern (such as, bar paten, veined surface, smooth surface and/or another pattern) and/or component characteristic.

In some embodiments, matrix is suitable for dissociating a part of coating and/or activating agent to intervention position from matrix.For limiting examples, matrix is by following and so regulate: select matrix composition, matrix material, shape, matrix deployment characteristics, matrix delivery characteristics, substrate pattern and/or matrix quality and/or its combine.Such as, balloon can be designed for only partial inflation in the limit of intervention position.Partial inflation can prevent the part of the design of coating from dissociating.

In some embodiments, coating is suitable for dissociating a part of coating and/or activating agent to intervention position from matrix.For limiting examples, coating is by following and so regulate: select activating agent and/or polymer and/or polymer-active agent composition, or by coating, coating layer thickness, coating and/or another physics with specific pattern (such as, bar paten, veined surface, smooth surface and/or another pattern) and/or component characteristic.

In some embodiments, free coating at least partially comprises and at least about 20%, at least about 30%, is greater than 35% at least about 10% from matrix is free, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, free can dissociating is less than about 1%, is less than about 5%, is less than about 10%.Be less than about 15%, be less than about 25%, at the most about 35%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% the coating that there is not at least one stimulated in coatings and substrate.

Term " is suitable for from matrix dissociation " a part of coating and/or activating agent and refers to be designed for from the device of the coating of some percent of matrix dissociation and/or activating agent, coating and/or matrix.Be designed for and be designed for from the association removing between coating (and/or activating agent) and matrix from the device used herein of the coating of some percent of matrix dissociation and/or activating agent, coating and/or matrix.In addition and/or alternatively, be designed for be designed for by the device used herein of the coating of some percent of matrix dissociation and/or activating agent, coating and/or matrix and make coating (and/or activating agent) and Matrix separation.In some embodiments, this separation can be reversible.In some embodiments, this separation may not be reversible.

In some embodiments, device is suitable for from matrix dissociation part coating and/or activating agent.For limiting examples, device is by following and so regulate: matrix characteristics is (for limiting examples: matrix forms, matrix material, shape, matrix deployment characteristics, matrix delivery characteristics, substrate pattern and/or matrix quality), the delivery system of matrix and coating is (for limiting examples: control on matrix, delivery system is used to control on coating, the type of the delivery system provided, the material of delivery system and/or its combination), coating characteristic is (for limiting examples: select activating agent and/or polymer and/or polymer-active agent to form, or by having specific pattern (such as, bar paten, veined surface, smooth surface and/or another pattern) coating, coating layer thickness, coating and/or another physics and/or component characteristic), releasing agent characteristic (for limiting examples: by select specific releasing agent and/or releasing agent how for transfer coated and/or activating agent and/or use how many releasing agents) and/or their combination.

In some embodiments, matrix is suitable for from matrix dissociation part coating and/or activating agent.For limiting examples, matrix is by following and so regulate: select matrix composition, matrix material, shape, matrix deployment characteristics, matrix delivery characteristics, substrate pattern and/or matrix quality and/or its combine.Such as, balloon can be designed for only partial inflation in the limit of intervention position.Partial inflation can prevent the part of the design of coating from dissociating.

In some embodiments, coating is suitable for from matrix dissociation part coating and/or activating agent.For limiting examples, coating is by following and so regulate: select activating agent and/or polymer and/or polymer-active agent composition, or by coating, coating layer thickness, coating and/or another physics with specific pattern (such as, bar paten, veined surface, smooth surface and/or another pattern) and/or component characteristic.

In some embodiments, coating be suitable for from matrix dissociation a part coating and/or activating agent to intervention position.For limiting examples, coating is by following and so regulate: select activating agent and/or polymer and/or polymer-active agent composition, or by coating, coating layer thickness, coating and/or another physics with specific pattern (such as, bar paten, veined surface, smooth surface and/or another pattern) and/or component characteristic.

In some embodiments, dissociation at least partially coating comprises from matrix dissociation at least about 10%, at least about 20%, at least about 30%, is greater than 35%, at least about 50%, at least about 75%, at least about 85%, at least about 90%, at least about 95% and/or at least about 99% coating.In some embodiments, the contact reduced between coatings and substrate is stimulated.In some embodiments, dissociation energy dissociation is less than about 1%, is less than about 5%, be less than about 10%, be less than about 15%, be less than about 25%, at the most about 35%, be less than about 50%, be less than about 70%, be less than about 80% and/or be less than about 90% the coating that there is not at least one stimulated in coatings and substrate.

" plastic deformation " used herein coating physics change of shape for being caused by the power of inducing on device.Plastic deformation causes improving the contact area of coating organizationally and is reduced in the contact area of coating on device.The change of this contact area causes some or all of coatings to be preferentially exposed to tissue instead of device.In the context of coating, term used herein " plastic deformation " and " plastic deformation " are intended to comprise the elastic limit that expansion coating material exceedes material, make material permanent deformation." elastic deformation " used herein refers under stress or strain (such as, the blowing pressure of balloon matrix), the change of the form of object or the reversible of size.In the context of balloon or other matrix, term used herein " plastic deformation " and " plastic deformation " are intended to comprise the elastic limit that swollen matrix exceedes matrix material, make matrix material permanent deformation.Once plastic deformation, material becomes essentially no elasticity, and usually due to self, can not be back to the size and dimension before its expansion." remaining plastic deformation " refers to after removing inflation stress (such as, when balloon is exitted), the distortion that can keep at least partly." elastic deformation " used herein refers under stress or strain (such as, the blowing pressure), the form of object (no matter being coating or matrix) or the reversible change of size.

" shear transfer " used herein is and will coating is driven away from the vertical power (or component of power) of the device of device matrix.This induces on device by expansion, the pressure-response from surrounding tissue and/or the tissue ingrowth around coating.

" body migration " used herein for provided by removing device and/or by through time degrade that coating provides and/or by through time the coating hydration tissue that provides on/among mix coating.The degraded of coating and hydration can reduce the cohesion and tacky adhesion of coating and device, thus promote that coating is transferred to tissue.

An embodiment can be described as contact print product similarly, thus chemical-biological activities ' ink ' (polymer+medication coat) is from ' punch die ' (device) to ' bin ' (position health).

Based on the specific character that medicine-delivery formulation provides, in conjunction with embodiments more provided herein, described apparatus and method are favourable.Especially well suited in impermanent implant (such as ballon catheter, cutting balloon, etc.) a kind of such character be ' soft ' coating, its under the pressure by making balloon inflation provide (2-25 barometric pressure range, usual 10-18 atmospheric pressure) experiences plastic deformation.Especially the well suited character such in the another kind of Permanent implantation thing (such as support) is wherein by hydration or by degraded or the combination by hydration and degraded, after the implantation, becomes the coating of ' soft ' at some some polymer.

Some embodiments provide the device that can advantageously use with the methods combining of the transfer that can help/promote coating.These are included in health situ and introduce once stimulation (wherein of short duration or permanent delivery apparatus) to the device of coating.Such stimulation to may be provided in coating induced chemical response (light, heat, radiation, etc.) or mechanical force can be provided to shift in the tissue to expand coating (ultrasonic, translation, rotation, vibration and combination thereof).

In some embodiments, coating is free from matrix, dissociation and/or transfer to use mechanical stimulus to make.In some embodiments, use mechanical stimulus that coating is dissociated from matrix.In some embodiments, mechanical stimulus is used to make coating from matrix dissociation.In some embodiments, use mechanical stimulus that coating is shifted from matrix.In some embodiments, use mechanical stimulus that coating is transferred to and get involved position.In some embodiments, use mechanical stimulus that coating is delivered to and get involved position.In some embodiments, mechanical stimulus be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In some embodiments, mechanical stimulus be suitable for causing that coating is free from matrix, dissociation and/or transfer.In some embodiments, mechanical stimulus be suitable for causing that coating is free from matrix, dissociation and/or transfer.In some embodiments, mechanical stimulus comprise following at least one: compression stress, shearing force, tensile force, the power applied in coating from the matrix side of coating, the power applied in coating by matrix, the power applied in coating from outer member, translation, rotation, vibration and their combination.In some embodiments, outer member is an experimenter's part.In some embodiments, outer member is not a part for device.In some embodiments, outer member comprises liquid.In some embodiments, liquid exerts a force between coatings and substrate.In some embodiments, liquid comprises saline.In some embodiments, liquid comprises water.In some embodiments, mechanical stimulus comprises the geometric configuration making the maximized matrix of the shearing force in coating.In some embodiments, mechanical stimulus comprises the geometric configuration of the matrix of the shearing force improved in coating.In some embodiments, mechanical stimulus comprises the geometric configuration of the matrix of the shearing force strengthened in coating.

In some embodiments, coating is free from matrix, dissociation and/or transfer to use chemical stimulation to make.In some embodiments, use chemical stimulation that coating is dissociated from matrix.In some embodiments, chemical stimulation is used to make coating from matrix dissociation.In some embodiments, use chemical stimulation that coating is shifted from matrix.In some embodiments, use chemical stimulation that coating is transferred to and get involved position.In some embodiments, use chemical stimulation that coating is delivered to and get involved position.In some embodiments, chemical stimulation comprise following at least one: bulk degradation, with the interaction of body fluid, with systemic interaction, with the chemical interaction of non-body fluid, react with the chemical interaction of chemicals, Acid-Base, enzyme reaction, hydrolysis and combination thereof.In some embodiments, chemical stimulation comprises the bulk degradation of coating.In some embodiments, chemical stimulation comprises the interaction of coating or its part and body fluid.In some embodiments, chemical stimulation comprises coating or its part and systemic interaction.In some embodiments, chemical stimulation comprises the chemical interaction of coating or its part and non-body fluid.In some embodiments, chemical stimulation comprises the chemical interaction of coating or its part and chemicals.In some embodiments, chemical stimulation comprises Acid-Base reaction.In some embodiments, chemical stimulation comprises enzyme reaction.In some embodiments, chemical stimulation comprises hydrolysis.

In some embodiments, chemical stimulation be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In some embodiments, chemical stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In some embodiments, chemical stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In some embodiments, coating comprises when being suitable for, from the material of matrix transfer, free and/or dissociation, causing weak binding between coatings and substrate getting involved position response original position enzyme reaction.

In some embodiments, coating is free from matrix, dissociation and/or transfer to use thermostimulation to make.In some embodiments, use thermostimulation that coating is dissociated from matrix.In some embodiments, thermostimulation is used to make coating from matrix dissociation.In some embodiments, use thermostimulation that coating is shifted from matrix.In some embodiments, use thermostimulation that coating is transferred to and get involved position.In some embodiments, use thermostimulation that coating is delivered to and get involved position.In some embodiments, thermostimulation comprise be suitable for expanding that coating is dissociated from matrix, at least one the thermostimulation of dissociation and/or transfer and cold stimulation.In some embodiments, thermostimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In some embodiments, thermostimulation comprise be suitable for causing that coating is dissociated from matrix, at least one the thermostimulation of dissociation and/or transfer and cold stimulation.In some embodiments, thermostimulation comprise be suitable for causing that coating is dissociated from matrix, at least one the thermostimulation of dissociation and/or transfer and cold stimulation.

In some embodiments, make that coating is free from device by electromagnetic stimulation, dissociation and/or transfer.In some embodiments, use electromagnetic stimulation that coating is dissociated from matrix.In some embodiments, electromagnetic stimulation is used to make coating from matrix dissociation.In some embodiments, use electromagnetic stimulation that coating is shifted from matrix.In some embodiments, use electromagnetic stimulation that coating is transferred to and get involved position.In some embodiments, use electromagnetic stimulation that coating is delivered to and get involved position.In some embodiments, electromagnetic stimulation comprises electromagnetic wave, its comprise following in one of at least: wireless wave, microwave, infrared waves, near-infrared ripple, visible light wave, ultraviolet waves, X-ray ripple and γ ripple.In some embodiments, electromagnetic stimulation be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In some embodiments, electromagnetic stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In some embodiments, electromagnetic stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.

In some embodiments, make that coating is free from device by sound stimulation, dissociation and/or transfer.In some embodiments, use sound stimulation that coating is dissociated from matrix.In some embodiments, sound stimulation is used to make coating from matrix dissociation.In some embodiments, use sound stimulation that coating is shifted from matrix.In some embodiments, use sound stimulation that coating is transferred to and get involved position.In some embodiments, use sound stimulation that coating is delivered to and get involved position.In some embodiments, sound stimulation comprises sound wave, and wherein sound wave is at least one in ultrasound wave, acoustical sound waves and infrasonic wave.In some embodiments, sound stimulation be suitable for expanding that coating is free from matrix, dissociation and/or transfer.In some embodiments, sound stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.In some embodiments, sound stimulation be suitable for causing that coating is free from matrix, dissociation and/or transfer.

In some embodiments, by the combination of at least two kinds in mechanical stimulus, chemical stimulation, electromagnetic stimulation and sound stimulation, make that coating is free from device, dissociation and/or transfer.

In some embodiments, make that coating is free from matrix by extruding, dissociation and/or transfer.

There is provided herein and make the maximized device geometry of the shearing force in coating.Such geometry designs of device provides two advantages: (1) improves (concentrating) power with the adhesion strength making medicine and polymer coating plastic deformation (2) reduce coating.Such as, with directly compress relative, wedge-shape along shear plan arrangement distortion power.This embodiment provides: the effect that the coating that (1) shifts about % improves; (2) based on different situations, the precision of the amount of transfer is improved; (3) utilize under unfolding condition otherwise can not be out of shape and/or also can not body migration ' harder/more stiff ' material (biopolymer); (4) move via on purpose design shape and distortion and body both direction, the chance of particle detachment is minimized.Such as wedge, less may have granule, because use soft material, due to the shearing of the device from sheet-form, arrange coating in advance, this coating that can be used as silicone caulk illustrates, silicone caulk is extruded by the pressure of the rod of mat to be pushed.

Another embodiment provides the geometry arrangement of coating, thus providing layer in the coating, such as, laminate structures, with the plastic deformation in the tissue of regulation and control coating, shearing and body migration.

An embodiment provides the matrix of coating, and in patients after specific position is launched, some or all of coatings (5-10%, 10-25%, 25-50%, 50-90%, 90-99%, 99-100%) is transferred to the therapentic part of needs by it.

In some embodiments, device also comprises releasing agent.In some embodiments, releasing agent is biocompatible.In some embodiments, releasing agent is biocompatible.In some embodiments, releasing agent comprises powder.In some embodiments, releasing agent comprises lubricant.In some embodiments, releasing agent comprises the surface modification of matrix.

In some embodiments, releasing agent comprises gel.

In some embodiments, releasing agent comprises at least one in activating agent and another kind of activating agent.Before coating, can activating agent be placed on matrix, to be used as releasing agent.Activating agent can be the activating agent different from activating agent in the coating.Once coating is from matrix release (or from matrix transfer or free or dissociation), the activating agent for releasing agent can provide second-source medicine to get involved position or another position to be delivered to.

In some embodiments, releasing agent comprises the physical characteristic of matrix.In some embodiments, the physical characteristic of matrix comprises at least one in the coating surface of pattern and strip coated surface.In some embodiments, the coating surface of pattern is become to comprise Support frame.In some embodiments, strip coated surface comprises the matrix surface of fluctuating.In some embodiments, strip coated surface comprises the bossed matrix surface of tool on it.

In some embodiments, releasing agent comprises the character that can change at intervention position.In some embodiments, character comprises physical property.In some embodiments, character comprises chemical property.In some embodiments, when contacting with at least one in biofluid with biological tissue, releasing agent can change character.In some embodiments, when with liquid, aqueous contact, releasing agent can change character.

In some embodiments, releasing agent is between matrix and coating.

In some embodiments, single emulsifying/evaporation technique is used to encapsulate medicament at least partially.In some embodiments, this technology comprises at least following steps: (1) merges the first polymer (such as, PVA) and water, to form the first polymer solution; Merge the second polymer (such as, PLGA) and organic solvent (such as, dichloromethane), to form the second polymer solution; Merge the second polymer (such as, PLGA) and organic solvent (such as, dichloromethane), to form terpolymer solution; With merging medicament and polar non-solute (such as, DMSO), to form liquid medicine, (2) make the second polymer solution and liquid medicine mixing, and (3) add the first polymer solution, and the mixture that homogenize obtains; (4) terpolymer solution is added; (5) optional, allow organic solvent evaporation; (6) remaining solution is filtered.In some embodiments, centrifuge is used to complete filtration.In some embodiments, by making mixture by filter paper, filtration is completed.In some embodiments, by medicament settling flux and the lyophilizing in water further of encapsulating.

In some embodiments, the polymer concentration of the first polymer solution is about 1%-about 10%, about 1%-about 9%, about 1%-about 8%, about 1%-about 7%, about 1%-about 6%, about 1%-about 5%, about 1%-about 4%, about 1%-about 3%, about 1.5%-about 2.5% or about 2%.When mentioning polymer concentration as percent statement, term " about " used herein refers to the change of 0.05%, 0.1%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5%.Such as the polymer concentration of about 2% can be expressed as 2%+/-0.5% (that is, 1.5%-2.5%), or can be 1.95-2.05% (2%+/-0.05%), depend on embodiment.In some embodiments, the polymer concentration of the first polymer solution is 1%-10%, 1%-9%, 1%-8%, 1%-7%, 1%-6%, 1%-5%, 1%-4%, 1%-3%, 1.5%-2.5% or 2%.

In some embodiments, the polymer concentration of the second polymer solution is about 100mg/mL for about 10 mg/mL-, about 15 mg/mL-about 95 mg/mL, about 20 mg/mL-about 90 mg/mL, about 25 mg/mL-about 85 mg/mL, about 30 mg/mL-about 80 mg/mL, about 35 mg/mL-about 75 mg/mL, about 40 mg/mL-about 70 mg/mL, about 40 mg/mL-about 60 mg/mL, about 45 mg/mL-about 55 mg/mL or about 50 mg/mL.When mentioning polymer concentration with mg/mL statement, term " about " used herein refers to 1 mg/mL, 5 mg/mL, and the change of 10 mg/mL or 15 mg/mL, depends on embodiment.In some embodiments, the polymer concentration of the second polymer solution is 10 mg/mL-100mg/mL, 15 mg/mL-95 mg/mL, 20 mg/mL-90 mg/mL, 25 mg/mL-85 mg/mL, 30 mg/mL-80 mg/mL, 35 mg/mL-75 mg/mL, 40 mg/mL-70 mg/mL, 40 mg/mL-60 mg/mL, 45 mg/mL-55 mg/mL or 50 mg/mL.

In some embodiments, the polymer concentration of terpolymer solution is about 0.5%-about 5%, about 0.5%-about 4.5%, about 0.5%-about 4%, about 0.5%-about 3.5%, about 0.5%-about 3%, about 0.5%-about 2.5%, about 0.5%-about 2%, about 0.5%-about 1.5% or about 2%.When mentioning polymer concentration as percent statement, term " about " used herein refers to the change of 0.05%, 0.1%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5%.Such as the polymer concentration of about 2% can be expressed as 2%+/-0.5% (that is, 1.5%-2.5%) or can be 1.95-2.05% (2%+/-0.05%), depend on embodiment.In some embodiments, the polymer concentration of terpolymer solution is 0.5%-5%, 0.5%-4.5%, 0.5%-4%, 0.5%-3.5%, 0.5%-3%, 0.5%-2.5%, 0.5%-2%, 0.5%-1.5% or 2%.

In some embodiments, be about 1 mg/mL-about 50 mg/mL in the concentration of liquid medicine Chinese medicine, about 1 mg/mL-about 40 mg/mL, about 1 mg/mL-about 30 mg/mL, about 2 mg/mL-about 30 mg/mL, about 5 mg/mL-about 30 mg/mL, about 5 mg/mL-about 25 mg/mL, about 5 mg/mL-about 20 mg/mL, about 5 mg/mL-about 15 mg/mL, about 7 mg/mL-about 12 mg/mL or about 10 mg/mL.When mentioning polymer concentration with mg/mL statement, term " about " used herein refers to 0.5 mg/mL, 1 mg/mL, 5 mg/mL, and the change of 10 mg/mL or 15 mg/mL, depends on embodiment.In some embodiments, be 1 mg/mL-50 mg/mL in the concentration of liquid medicine Chinese medicine, 1 mg/mL-40 mg/mL, 1 mg/mL-30 mg/mL, 2 mg/mL-30 mg/mL, 5 mg/mL-30 mg/mL, 5 mg/mL-25 mg/mL, 5 mg/mL-20 mg/mL, 5 mg/mL-15 mg/mL, 7 mg/mL-12 mg/mL or 10 mg/mL.

In some embodiments, be at least 5%, at least 10% by the volume of organic solvent of evaporation removing, at least 15%, at least 20%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.In some embodiments, be 5%-95%, 5%-85%, 5%-50%, 5%-25% by the volume of organic solvent of evaporation removing, 5%-10%, 10%-95%, 10%-50%, 10%-30%, 20%-95%, 30%-75%, 40%-95%, 50%-95%, 70%-90%, 75%-95% or 80%-95%.

In some embodiments, by the encapsulation process based on emulsion, can encapsulation of crystalline medicament.In some embodiments, the technology comprising at least following steps is used to encapsulate medicament at least partially: (1) merges the first polymer (such as, and water PVA), to form the first polymer solution, merge the second polymer (such as, PLGA) and organic solvent (such as, dichloromethane), to form the second polymer solution, and merging second polymer and organic solvent, to form terpolymer solution; (2) make the first and second polymer solution mixing, allow organic solvent evaporation, to form emulsion; (3) confection is to terpolymer solution, to form suspension; (4) emulsion and suspension is made to merge, to form the mixture based on emulsion; (5) mixture based on emulsion is filtered.In some embodiments, centrifuge is used to complete filtration.In some embodiments, by pouring soln by filter paper, filtration is completed.In some embodiments, by medicament settling flux and the lyophilizing in water further of encapsulating.

In some embodiments, the polymer concentration of the first polymer solution is about 1%-about 10%, about 1%-about 9%, about 1%-about 8%, about 1%-about 7%, about 1%-about 6%, about 1%-about 5%, about 1%-about 4%, about 1%-about 3%, about 1.5%-about 2.5% or about 2%.When mentioning polymer concentration as percent statement, term " about " used herein refers to the variable of 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4% or 0.5%.Such as the polymer concentration of about 2% can be expressed as 2%+/-0.5% (that is, 1.5%-2.5%) or can be 1.95-2.05% (2%+/-0.05%), depend on embodiment.In some embodiments, the polymer concentration of the first polymer solution is 1%-10%, 1%-9%, 1%-8%, 1%-7%, 1%-6%, 1%-5%, 1%-4%, 1%-3%, 1.5%-2.5% or 2%.

In some embodiments, the polymer concentration of the second polymer solution is about 100mg/mL for about 10 mg/mL-, about 15 mg/mL-about 95 mg/mL, about 20 mg/mL-about 90 mg/mL, about 25 mg/mL-about 85 mg/mL, about 30 mg/mL-about 80 mg/mL, about 35 mg/mL-about 75 mg/mL, about 40 mg/mL-about 70 mg/mL, about 40 mg/mL-about 60 mg/mL, about 45 mg/mL-about 55 mg/mL or about 50 mg/mL.When mentioning polymer concentration with mg/mL statement, term " about " used herein refers to 0.5 mg/mL, 1 mg/mL, 5 mg/mL, and the variable of 10 mg/mL or 15 mg/mL, depends on embodiment.In some embodiments, the polymer concentration of the second polymer solution is 10 mg/mL-100mg/mL, 15 mg/mL-95 mg/mL, 20 mg/mL-90 mg/mL, 25 mg/mL-85 mg/mL, 30 mg/mL-80 mg/mL, 35 mg/mL-75 mg/mL, 40 mg/mL-70 mg/mL, 40 mg/mL-60 mg/mL, 45 mg/mL-55 mg/mL or 50 mg/mL.

In some embodiments, the polymer concentration of terpolymer solution is about 0.5%-about 5%, about 0.5%-about 4.5%, about 0.5%-about 4%, about 0.5%-about 3.5%, about 0.5%-about 3%, about 0.5%-about 2.5%, about 0.5%-about 2%, about 0.5%-about 1.5% or about 2%.When mentioning polymer concentration as percent statement, term " about " used herein refers to the variable of 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4% or 0.5%.Such as the polymer concentration of about 2% can be expressed as 2%+/-0.5% (that is, 1.5%-2.5%) or can be 1.95-2.05% (2%+/-0.05%), depend on embodiment.In some embodiments, the polymer concentration of terpolymer solution is 0.5%-5%, 0.5%-4.5%, 0.5%-4%, 0.5%-3.5%, 0.5%-3%, 0.5%-2.5%, 0.5%-2%, 0.5%-1.5% or 2%.

In some embodiments, the concentration of the medicament in medicament-terpolymer solution mixture is about 0.01 mg/mL-about 0.1 mg/mL, about 0.02 mg/mL-about 0.09 mg/mL, about 0.03 mg/mL-about 0.08 mg/mL, about 0.03 mg/mL-about 0.07 mg/mL, about 0.04 mg/mL-about 0.07 mg/mL, about 0.04 mg/mL-about 0.06 mg/mL or about 0.05 mg/mL.When mentioning drug concentration with mg/mL statement, term " about " used herein refers to 0.001 mg/mL, 0.005 mg/mL, 5 mg/mL, 0.002 mg/mL, and the variable of 0.0025 mg/mL or 0.1 mg/mL, depends on embodiment.In some embodiments, the concentration of the medicament in medicament-terpolymer solution mixture is 0.01 mg/mL-0.1 mg/mL, 0.02 mg/mL-0.09 mg/m, about 0.03 mg/mL-0.08 mg/mL, about 0.03 mg/mL-0.07 mg/mL, about 0.04 mg/mL-about 0.07 mg/mL, about 0.04 mg/mL-about 0.06 mg/mL or about 0.05 mg/mL.

In some embodiments, the volume passing through the organic solvent of evaporation removing during encapsulation process is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% and at least 95%.In some embodiments, be 5%-95%, 5%-85%, 5%-50%, 5%-25% by the volume of organic solvent of evaporation removing during encapsulation process, 5%-10%, 10%-95%, 10%-50%, 10%-30%, 20%-95%, 30%-75%, 40%-95%, 50%-95%, 70%-90%, 75%-95% or 80%-95%.

In some embodiments, the medicament of polymer-encapsulating is microsphere or microparticulate form.The example of the microsphere relevant to the disclosure comprises: Luzzi, L. A., J. Pharm. Psy. 59:1367 (1970); U.S. Patent number 4,530,840; Lewis, D. H., " Controlled Release of Bioactive Agents from Lactides/Glycolide Polymers (by lactide/glycolides polymer controlled release bioactivator) ", Biodegradable Polymers as Drug Delivery Systems, Chasin, M. and Langer, R. edit, Marcel Decker (1990); U.S. Patent number 4,675,189; The people such as Beck, " Poly (lactic acid) and Poly (lactic acid-co-glycolic acid) Contraceptive Delivery Systems (poly-(lactic acid) and lactic acid-ethanol copolymer contraceptive delivery systems) ", Long Acting Steroid Contraception, Mishell, D. R. edits, Raven Press (1983); U.S. Patent number 4,758,435; U.S. Patent number 3,773,919; U.S. Patent number 4,474,572.Example as the protein protective of microsphere preparation comprises: U.S. Patent number 6,458,387; U.S. Patent number 6,268,053; U.S. Patent number 6,090,925; U.S. Patent number 5,981,719; With U.S. Patent number 5,578,709, and be attached to by reference in the disclosure.

Microsphere has spherical form usually, but the microparticle of irregular-shape is also possible.The size of microsphere can be different, and diameter is at submicron to 1000 micrometer range.The microsphere being applicable to use together with medical treatment device coating disclosed herein is submicron to 250 micron diameter microsphere.Microsphere is prepared by any method producing the microsphere being used for the acceptable size range of coating process disclosed herein.

Suitable example for the microsphere of this paper or the polymeric material of microparticle comprises poly-(glycolic), poly-d, l-lactic acid, poly-l-lactic acid, aforesaid copolymer, poly-(aliphatic carboxylic acid), copolymerized oxalate, polycaprolactone, polydioxonene, poly-(orthocarbonic ester), poly-(acetal), poly-(lactic acid-caprol acton), poe, poly-(glycolic-caprolactone), polydioxonene, condensing model, poly-phosphazine and natural polymer comprise albumin, casein and some wax, such as, glycerol list-and distearate etc.Various commercially available PLGA material (PLGA) is optional for method disclosed herein.Such as, d, l-lactic acid-ethanol copolymer as RESOMER RG 503 H commercially from Boehringer-Ingelheim.This product has the mole percent composition of 50% lactide and 50% Acetic acid, hydroxy-, bimol. cyclic ester.These copolymers can obtain with wide in range molecular weight and lactic acid and glycolic ratio.An embodiment comprises use polymer d, l-PLGA.In such copolymer, the mol ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester comprises the scope that about 95:5-is about 50:50.

The molecular weight of polymeric material has some important.In some embodiments, molecular weight is enough high, and make it form gratifying polymer coating, that is, polymer should be good film former.Usually, gratifying molecular weight at 5,000-500,000 dalton's scope.From the angle of the biodegradation rate of molecular weight effects polymer, the molecular weight of polymer is also important.By polymeric material, the biodegradation by polymeric material or the combination by the two, by diffusion, from microparticle release medicine.By suitable selective polymerization material, prepare microspheres preparation, make obtained microsphere present dispersal events and biodegradation releasing properties.This can be used for obtaining heterogeneous release pattern.

Multiple method is known, is encapsulated in microsphere by compound by these methods.In these methods, use agitator, agitator or other dynamic hybrid technology, usually dispersion or emulsified agent in the solvent of the material containing formation wall.Remove desolventizing from microsphere subsequently, obtain microsphere product subsequently.

In one embodiment, by mixing medicament and/or other medicament in poly-(lactic acid-ethanol)-polyvinyl alcohol microspheres, the medicament of polymer-encapsulating used herein is prepared.In another embodiment, the cell modulator that ear is felt is encapsulated in alginate (ester) microsphere.(see U.S. Patent number 6,036,978, it is bonded to herein for the disclosure).For encapsulating the biocompatible polymer based on methacrylate of medicament optionally for preparation disclosed herein and method.The wide in range polymer system based on methacrylate is commercially available, the EUDRAGIT polymer such as sold by Evonik.The useful aspect of of methacrylate polymers is, by mixing various copolymer, changes the character of preparation.Such as, because the hydroxy-acid group in poly-(acrylic acid) and mucin form the hydrogen bond (people such as Park, Pharm. Res. (1987) 4 (6): 457-464), acryl acid-methyl methacrylate copolymer microparticle presents the viscosity adhesive property of enhancing.The change of the ratio of acrylic acid and methyl methacrylate monomer is for regulating the character of copolymer.Based on the microparticle of methacrylate also for protein therapeutic preparation (people such as Naha, Journal of Microencapsulation, on February 4th, 2008, (online publishing thing)).

An example for micro-encapsulation process of the routine of pharmaceutical preparation is shown in U.S. Patent number 3,737,337, and it is bonded to by reference herein for the disclosure.Use conventional blender, comprise (in preparation dispersion) vibrator and high speed agitator, etc., medicament that is to be encapsulated or embedding is dissolved or dispersion in the organic solution (phase A) of polymer.Containing in aqueous phase (B) phase (A) dispersion in solution or suspension carried out containing core material, the blender of same use routine, such as super mixer, vibromixer or even nozzle, in this case, not by means of only the concentration of phase (A), and measured the particle diameter of microsphere by emulsion or sized micro-spheres.Use the technology of the routine being used for the cell modulator that micro-encapsulating ear is felt, by stirring, stirring, vibration or some other dynamic hybrid technologies, when in immiscible solution, emulsifying or dispersion contain the solvent of activating agent and polymer, formation microsphere.

Method for building microsphere is also described in U.S. Patent number 4,389, and 330 and U.S. Patent number 4,530,840, it is bonded to by reference herein for the disclosure.Dissolve or dispersions in suitable solvent.Relative to active component with certain amount, add polymer matrix material to containing in the medium of medicament, obtain the product with the activating agent expecting load.Optionally, all the components of the cell modulator microsphere product of ear sensation can be blended together in solvent medium.Suitable solvent for medicament and polymer matrix material comprises organic solvent, and such as acetone, halogenated hydrocarbons are as chloroform, dichloromethane etc., compound aromatic hydrocarbon, halogenated aromatic hydrocarbon compound, cyclic ether, alcohol, ethyl acetate etc.

In continuous phase treatment media, the mixture of emulsified component in a solvent; Continuous phase medium makes the dispersion of the microlayer model formed in continuous phase medium containing instruction composition.Nature, continuous phase treatment media and the necessary unmixing of organic solvent, and comprise water, use non-aqueous medium, such as diformazan Benzene and Toluene and artificial oil and natural oil although optional.Optionally, surfactant is joined in continuous phase treatment media, to prevent the size of the solvent microlayer model in microparticle agglomeration and control emulsion.Preferred surfactant-disperse medium is combined as 1-10 % by weight poly-(vinyl alcohol), in aqueous mixtures.By the material that mechanical agitation mixes, form dispersion.Optionally through the droplet adding activating agent-wall-forming materials solution to continuous phase treatment media, form emulsion.Not especially critical forming the temperature during emulsion, but affect the size of microsphere and quality and the dissolubility of medicine in continuous phase.Be desirably in continuous phase and there is the least possible medicament.In addition, depend on solvent and the continuous phase treatment media of employing, temperature is necessary can not be too low, otherwise solvent and machining medium will solidify or will become too thickness for the object treatment media put into practice, or temperature is necessary can not be too high, makes treatment media that evaporation maybe can not be kept fluid handling media.In addition, the temperature of medium can not be too high, makes adversely to affect the stability of the concrete medicament mixing microsphere.Therefore, at any temperature keeping stable operating condition, carry out dispersive process, preferred temperature is about 15 DEG C-60 DEG C, depends on selected medicine and excipient.

The dispersion formed is stable emulsion, and in the first step of removal of solvents process, from the immiscible fluid of this dispersion optional part removing organic solvent.By various technology except desolventizing, such as, by evaporation, heating, administering reduced pressure or the combination of the two.Usually can not degrade for the temperature from microlayer model evaporating solvent and prepare the medicament adopted in given microparticle, also should too highly not make, with such speed evaporating solvent fast, to cause the defect of wall-forming materials.Generally speaking, in the first solvent removal step, remove the solvent of 5-95%.

After stage, by any separation means easily, the microparticle of the dispersion in the immiscible fluid media (medium) of solvent is separated from fluid media (medium).Therefore, such as, by fluid from microsphere decant, or microsphere suspension is filtered.Other, if expected, use the various combinations of isolation technics again.

After being separated microsphere from continuous phase treatment media, by optional extraction removing remaining solvent in microsphere.In this step, microactuator suspension spheroid in for the identical continuous phase treatment media of step 1, has or does not have surfactant, or in another kind of liquid.Spe medium removes desolventizing from microsphere but does not dissolve microsphere.During extracting, optional removing has the spe medium of the solvent of dissolving, and replaces with new spe medium.Be preferably based on and carry out continuously.For given process, the rate-compatible that spe medium is filled again, measures when implementation process, therefore, can not pre-determine the limit of accuracy of speed.At most of solvent from after microsphere removing, by being exposed to air or by the dry technology of other routine (such as vacuum drying, on desiccant dry etc.), microsphere is dry.Owing to obtaining maximum 80 % by weight, the preferably core load of maximum 60 % by weight, this process is effective to the cell modulator encapsulating ear sensation very much.

general manufacture method

In some embodiments, by e-RESS, e-SEDS or e-DPC process, by comprising the process of deposited polymer and/or activating agent, matrix forms coating.In some embodiments, before the expanding unit of intervention position, the process forming coating provides the adhesion of the improvement of coating and matrix, and promotes at intervention position from matrix dissociation coating.In some embodiments, by e-RESS, e-SEDS or e-DPC process, and not making matrix electrically charged, by comprising the process of position activity agent, matrix forming coating.In some embodiments, by e-RESS, e-SEDS or e-DPC process, and between matrix and the coating apparatus for position activity agent, not producing current potential, by being included in the process of substrate deposit activating agent, matrix forming coating.

For generation of have or do not have matrix device can the means of polymer+medication coat of bio-absorbable:

● use medicine and polymer spray-on coating-form, as carried out in Micell process (e-RESS, e-DPC, compression-gas sintered).

● implement multiple and sequential coating-sintering step, wherein can deposit different materials in each of the steps, therefore produce the structure with the lamination of the thin layer of numerous medicine, polymer or medicine+polymer, it builds final device.

● by device (tube chamber) comprise mask on the surface, implement deposited polymer+medicine laminated material.Such mask can simply as the non-conductive footstalk that the internal diameter by coating form inserts.Before adding any layer, can be there is this and shelter, or after whole coating-some layers of form successive sedimentation, on purpose insert.

In some embodiments, coating comprises micro structure.In some embodiments, the granule of activating agent chelating or encapsulating in micro structure.In some embodiments, micro structure comprises microchannel, micropore and/or microcavity.In some embodiments, select micro structure to allow lasting release bioactive agent.In some embodiments, select micro structure to allow controlled release activating agent.

Other method for the preparation of coating comprises the coating process based on solvent and the coating process based on plasma.In some embodiments, coating is prepared by the coating process based on solvent.In some embodiments, by preparing coating based on the coating process of solvent plasma.

Another advantage of the present invention is, uses controlled (with a scale) medicine-elution curve, can produce delivery apparatus.Via having different materials and the position of medicine can be controlled and independent of these layers, described method can obtain can discharging the device of medicine by very specific elution curve (sequencing sequential and/or parallel elution curve) in every one deck of laminate structures.In addition, the present invention allows a kind of medicine of controlled eluting and does not affect the eluting of the second medicine (or identical medicine of various dose).

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With at least one in e-RESS, e-SEDS and e-DPC process of passing through, by at substrate deposit activating agent, matrix at least partially forms coating, and wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for being transferred to from matrix getting involved position at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With at least one in e-RESS, e-SEDS and e-DPC process of passing through, and do not make matrix electrically charged, by at substrate deposit activating agent, matrix at least partially forms coating, wherein forming coating causes in use stimulation to after stimulating coating, and coating is suitable for being transferred to from matrix getting involved position at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With at least one in e-RESS, e-SEDS and e-DPC process of passing through, and between matrix and the coating apparatus at least one in e-RESS, e-SEDS and e-DPC process, do not produce current potential, by at substrate deposit activating agent, matrix at least partially forms coating, wherein forming coating causes in use stimulation to after stimulating coating, and coating is suitable for being transferred to from matrix getting involved position at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With at least one by flooding and/or in spray process, by at substrate deposit activating agent, matrix at least partially forms coating, and wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for being transferred to from matrix getting involved position at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With at least one in e-RESS, e-SEDS and e-DPC process of passing through, by at substrate deposit activating agent, matrix at least partially forms coating, and wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for dissociating from matrix at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With by least one in dipping and/or spray process, by substrate deposit activating agent, matrix at least partially forms coating, wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for dissociating from matrix at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With at least one in e-RESS, e-SEDS and e-DPC process of passing through, by at substrate deposit activating agent, matrix at least partially forms coating, and wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for from matrix dissociation at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With by least one in dipping and/or spray process, by substrate deposit activating agent, matrix at least partially forms coating, wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for from matrix dissociation at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With at least one in e-RESS, e-SEDS and e-DPC process of passing through, by at substrate deposit activating agent, matrix at least partially forms coating, and wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for being delivered to and gets involved position at least partially.

There is provided herein a kind of method forming medical treatment device, described device comprises matrix and the coating on matrix at least partially, and its floating coat comprises activating agent, and described method comprises: provide matrix; With by least one in dipping and/or spray process, by substrate deposit activating agent, matrix at least partially forms coating, wherein form coating and cause in use stimulation to after stimulating coating, coating is suitable for being delivered to and gets involved position at least partially.

In some embodiments, implement e-RESS, e-SEDS and/or e-DPC process for the formation of coating, and do not make matrix electrically charged.In some embodiments, implement e-RESS, e-SEDS and/or e-DPC process for the formation of coating, and between matrix and the coating apparatus for e-RESS, e-SEDS and/or e-DPC process, do not produce current potential.

In some embodiments, before matrix arrives intervention position, form coating and cause coating to adhere to matrix.

Some embodiments are also included on matrix and provide releasing agent.In some embodiments, before formation application step, implement the step that releasing agent is provided.In some embodiments, releasing agent comprise following one of at least: the physical characteristic of the surface modification of the releasing agent of biocompatible releasing agent, biocompatible, powder, lubricant, matrix, the fluid of thickness, gel, activating agent, the second activating agent, matrix.In some embodiments, the physical characteristic of matrix comprise following one of at least: the coating surface of the one-tenth pattern of matrix and the bar shaped surface of matrix.In some embodiments, releasing agent comprises the character that can change at intervention position.In some embodiments, character comprises physical property.In some embodiments, character comprises chemical property.In some embodiments, when contacting with at least one in biofluid with biological tissue, releasing agent can change character.In some embodiments, when with liquid, aqueous contact, releasing agent can change character.In some embodiments, coating causes promoting that coating is transferred to the coating performance getting involved position.In some embodiments, coating performance comprises the physical characteristic of coating.In some embodiments, physical characteristic comprises pattern.

In some embodiments, form coating and promote that coating is transferred to intervention position.

In some embodiments, shift, free, dissociation, deposition and/or adhesion step comprise and carry out soft polymer by hydration, degraded or the combination by hydration and degraded.In some embodiments, shift, free, dissociation, deposition and/or adhesion step comprise and carry out soft polymer by the hydrolysis of polymer.

In some embodiments, provide step to comprise and form coating by the coating process based on solvent.In some embodiments, provide step to comprise and form coating by the method based on solvent plasma.

In some embodiments, generator is included in the multiple layer of substrate deposit, and to form coating, wherein at least one layer comprises activating agent.In some embodiments, at least one layer comprises polymer.In some embodiments, polymer is can bio-absorbable.In some embodiments, activating agent and polymer in identical layer, in independent layer or formed overlapping layer.In some embodiments, multiple layer comprises the five layers: first polymeric layer of following deposition, the first active agent layer, the second polymer layer, the second active agent layer and trimerization nitride layer.

Embodiment

There is provided following examples so that selected embodiment to be described.They should not think to limit the scope of the invention, and are merely illustrative and representational.For each embodiment enumerated, multiple analytical technology can be provided herein.Any monotechnics of the multiple technology enumerated can be enough to the parameter and/or the characteristic that indicate test, or any combination of technology can be used for indicating these parameters and/or characteristic.Those skilled in the art are familiar with the wide in range analytical technology for drug characterization/polymer coating.The technology (but being not limited to these technology) presented herein can be used in addition and/or the specific character of alternatively characterizing coating, and having is the change and adjustment that significantly adopt to those skilled in the art.

Sample preparation

Generally speaking, the coating on support, on balloon, on sample, on other matrix or on the sample prepared for In vivo model is prepared in herein.But the amendment of given analytical method is presented in described embodiment and/or is obvious to those skilled in the art.Therefore, without deviating from the invention, it may occur to persons skilled in the art that numerous change, change and substitute.It should be understood that various alternative can be used for for the embodiment of the present invention described with the embodiment provided puts into practice the parameter described by the present invention and instruction and/or characteristic herein.

Coating on balloon

Preparation as described herein and/or the balloon of the coating prepared by method disclosed herein.In certain embodiments, the targeting coating layer thickness of the balloon of coating is about 15 microns (activating agents of about 5 microns).In certain embodiments, coating process is utilize the medicine of depositing dry powder end form and the PDPDP (polymer, sintering, medicine, polymer, sintering, medicine, polymer, sintering) by RESS method and equipment deposition polymerization composition granule described herein.In explanation herein, the balloon of the coating obtained can have 3-layer coating, be included in polymer in ground floor (such as, PLGA), medicine in the second layer (such as, rapamycin) and polymer in third layer, wherein a part of third layer is substantially free of medicine (such as, the subgrade in third layer, its thickness equals the sub-fraction of the thickness of third layer).As described layer, intermediate layer (or medicine layer) can be overlapping with one or two in first (polymer) and the 3rd (polymer) layer.Overlay defining between medicine layer and polymeric layer is that polymeric material extends in the physical space occupied in a large number by medicine.Overlap between medicine and polymeric layer can relate to part packaged pharmaceuticals granule during formation medicine layer.When deposited on top crystalline drug particles at the first polymeric layer, space and/or gap can be retained between dry crystalline particle.The granule that space and gap can be used for by depositing during formation the 3rd (polymer) layer occupies.Some granules from the 3rd (polymer) layer can rest near the drug particles in second (medicine) layer.When completing sintering step for the 3rd (polymer) layer, trimerization nitride layer particle fusion, to form continuous film, this continuous film forms the 3rd (polymer) layer.But in some embodiments, the 3rd (polymer) layer has a part along the longitudinal axis of support, thus this part is not at the Contact of polymeric material and drug particles.Substantially this part of the third layer contacted with drug particles can be as thin as 1 nanometer.

Had by method preparation disclosed herein and comprise polymer but the balloon of the not polymer-coating of the coating of drug containing, and make targeting coating layer thickness be such as about 0.5,1,2,3,4,5,10,15,20,25,30,35,40,45 or 50 microns, depend in part on coating after hydration whether to expand, and if expand, its whether hydration.In embodiments, coating layer thickness is 1-5 micron.In other embodiments, coating layer thickness is 1-10 micron.

Use RESS method and equipment described herein, a kind of embodiment coating process is PPP (PLGA, sintering, PLGA, sintering, PLGA, sintering).In following embodiments, the balloon of these polymer-coatings can be used as control sample.

In certain embodiments, balloon is made by being obedient to polymer.In certain embodiments, balloon is made up of non-compliant polymer.In certain embodiments, the length of balloon can be 5-50 mm, and preferred length is 10-20 mm.

Balloon can be coated with, and inflate and compacting afterwards, or they can be coated with, unaerated simultaneously simultaneously.If balloon coating is inflated and folding or compacting in addition afterwards simultaneously, then by until arrange in unexposed a part of balloon before inflation, a part of coating can be protected during inserting.As this area is inserted described by angioplasty balloons for promotion, by using sheath or other covering, also can protective finish.

The coating (such as, for analyzing coated tape and/or being coated with a part of balloon) from balloon release can be analyzed.Alternatively, in certain embodiments, direct analysis coating on balloon.This coating and/or coating and balloon can cut the part becoming turning 90 degree, and use the surface composition technology that presents or known other technology (or other characteristic, such as degree of crystallinity) of surface composition analysis field to estimate herein.Adopt in this way, when coating is on balloon or when removing from balloon, coating composition can be analyzed (namely by the degree of depth, once contact balloon or its part, the degree of depth from the surface, nearly chamber of coating to the surface of the coating of removing), become the surface analysis of coating, such as, it can indicate the layer in coated sheet, has much higher resolution.Also can analyze the coating of the remnants on the balloon extracted, and compared with the amount of the coating on untapped balloon, use, such as, HPLC, as described herein.Not not remove from balloon from the coating of balloon removing or analysis and/or the coating of release can be adopted and processed in a like fashion, and technology described by using and/or other technology well known by persons skilled in the art measure, estimate and/or characterize.

For the sample preparation of In vivo model

By the device comprising the balloon with coating disclosed herein pig (raise and train pig, childhood farm pig or the miniature pig of Yucatan) porcine coronary in launch.Develop porcine coronary angioplasty herein, due to such model obtain with in people experimenter, measure neointimal hyperplasia other study comparable result.Make balloon expansion to the balloon of 1:1.1: artery ratio.At multiple time point, make animal euthanasia (such as, t=1 days, 7 days, 14 days, 21 days and 28 days), extract around the tissue getting involved position and measure.

The device comprising the balloon with coating disclosed herein is alternatively implanted in the common iliac artery of New Zealand white rabbit.Make balloon expansion to the balloon of 1:1.1: artery ratio.At multiple time point, make animal euthanasia (such as, t=1 days, 7 days, 14 days, 21 days and 28 days), extract around the tissue getting involved position and measure.

embodiment 1: cutting balloon

cutting balloon (1)-mechanical stimulus is with free coating

Coating comprises the cutting balloon of polymer and activating agent.Getting involved the cutting balloon of position layout coating.By balloon inflation extremely lower than its nominal the blowing pressure at least 25%.After exitting and cutting balloon from the removing of intervention position, free from the surface of cutting balloon at least about the coating of 30% at least about 5%-, and at intervention site deposition.

In certain embodiments, launching at aeration period balloon, causing mechanical shear stress at least to expand coating from balloon to getting involved the transfer at position and/or free and/or deposition.

In certain embodiments, in the distortion of aeration period balloon, mechanical shear stress is caused at least to expand coating from balloon transfer and/or free and/or deposition.

In one embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is medicament, such as macrolide immunosuppressive drug.Adopt equipment similar to Example 1 and coating process.Getting involved position is vascular lumen wall.After making cutting balloon inflation, the coating at least about 50% is dissociated from device at intervention position.

In another embodiment, cutting balloon is coated with the preparation of PLGA+ sirolimus, and the full payload of its sirolimus is about 20 μ g, is preferentially coated with on the tinsel of cutting balloon.Adopt equipment similar to Example 1 and process.Intervention position is coronary artery.After making cutting balloon inflation, the coating of about 5 %-about 15 % is dissociated from device, causes sending the medicine that about 2.0 μ g are delivered to tremulous pulse.

In another embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is chemotherapeutics.Adopt equipment similar to Example 1 and coating process.Getting involved position is the chamber obtained owing to removing tumor.After making cutting balloon inflation, the coating at least about 75% is transferred to from device and gets involved position.

Body build-in test: the group of 27 New Zealand white rabbit prepares to be used for Seldinger program, (MW is about 19kD to 50:50 PLGA-ester end group to use coating to have an appointment, degradation rate is about 1-2 month) and the cutting balloon of preparation of sirolimus, the full payload of its sirolimus is about 20 μ g, is preferentially coated with on the tinsel of cutting balloon.Device is placed on Percutantnoeus coronary intervention position, secondary fluorescence inspection is to contribute in each experimenter at identical location arrangements device.Six animal vias, by this program, use the balloon in the coating without the coating of sirolimus.After expansion and removal device, 3 control animals were put to death in 1 hour after deployment, collect serum and tissue sample.Remaining 3 control animals were put to death in 56 days after deployment.During research process, within every five days, collect blood serum sample from contrast with through the animal of Drug therapy.Animal (each 3) through Drug therapy is put to death for 1 hour after deployment, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days.Blood serum sample and tissue sample is collected from expansion position.

Tissue and blood serum sample can experience the analysis of sirolimus concentration.In order to the percent of the total amount as the coating on matrix, measure amount that is that dissociate from device and/or that be delivered to the coating getting involved position, can be used in a hours point (or any time point in first day after the procedure) sirolimus tissue concentration and for coating expection total content (total content based on to manufacture batch) or and once the content of removing remaining coating on device, and calculate percent.This percent to dissociate from device, dissociation and/or transfer relevant with the percent that is delivered to the coating getting involved position.Alternatively, organize (described herein by various means, include but not limited to SEM, TEM, and wherein use the polymer of image enhaucament, the various imaging means of polymer that these strengthen can be detected) analyze, dissociate from matrix to detect, dissociation and/or transfer and the percent that is delivered to the coating getting involved position.Equally, based on manufacture batch properties and/or evaluate after experimenter's removal device, on device, remaining coating is (such as, wherein device is angioplasty catheter, and matrix is the balloon of conduit), the amount of known coating on matrix can be used for measuring dissociate from device, the percent of the coating of dissociation and/or transfer.In some cases, after independent program, evaluating apparatus is enough to evaluate and dissociates or the amount of dissociation from matrix, and need not measure the amount being delivered to and getting involved position.In addition, when expecting to measure improvement and/or disease treatment, such as, by testing the CRP (hsCRP) of hypersensitivity, interleukin-6 (IL-6), Interleukin-1β (IL-1 β) and/or monocyte chemoattractant protein-1 (MCP-1), the level of pro-inflammatory marker thing can be tested to indicate improvement and/or the treatment of disease and/or imbalance.By drawing sirolimus concentration at above-mentioned time point, the release dynamics of medicine can be indicated.

For the embodiment of the different pharmaceutical used beyond sirolimus, based on disease to be treated and the medicine that gives during therapeutic process, select biomarker, as those skilled in the art determine.These biomarkers can be used for indicating the therapeutic outcome for each experimenter.

Other body build-in test described herein can be used to replace this test and/or except this test, the particularity according to this device regulates, as is known to persons skilled in the art.

Testing in vitro a: sample of the cutting balloon of the coating prepared in embodiment 1 is fixed to ballon catheter.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, by balloon inflation to lower than the nominal pressure at least 25% of balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.Optical microscopy is implemented to pipe and/or balloon (it is inflated to the nominal pressure at least 25% lower than balloon to major general), with measure the existence of the coating being transferred to pipe and amount and/or dissociate from balloon, the amount of the coating of dissociation and/or transfer.Other testing in vitro described herein can be used to replace this test and/or except this test, the particularity according to this device regulates, as is known to persons skilled in the art.

cutting balloon (2)-mechanical stimulus is with free coating

Use the system based on solvent (spraying or dip-coating) the coating cutting balloon comprising polymer and activating agent.Getting involved the cutting balloon of position layout coating.By balloon inflation extremely lower than its nominal the blowing pressure at least 25%.Free from the surface of cutting balloon at least about the coating of 30% at least about 5%-, and at intervention site deposition.

In one embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is medicament, such as macrolide immunosuppressive drug.Adopt the equipment and coating process that use spraying and/or dip coating process.Getting involved position is vascular lumen wall.After making cutting balloon inflation, the coating at least about 50% is dissociated from device at intervention position.

In another embodiment, cutting balloon is coated with the preparation of PLGA+ sirolimus, and the full payload of its sirolimus is about 20 μ g, is preferentially coated with on the tinsel of cutting balloon.Adopt the equipment and coating process that use spraying and/or dip coating process.Intervention position is coronary artery.After making cutting balloon inflation, the coating of about 5 %-about 15 % is dissociated from device, causes sending the medicine that about 2.0 μ g are delivered to tremulous pulse.

In another embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is chemotherapeutics.Adopt the equipment and coating process that use spraying and/or dip coating process.Getting involved position is the chamber obtained owing to removing tumor.After making cutting balloon inflation, the coating at least about 75% is transferred to from device and gets involved position.

Body build-in test: the group of 27 New Zealand white rabbit prepares to be used for Seldinger program, (MW is about 19kD to 50:50 PLGA-ester end group to use coating to have an appointment, degradation rate is about 1-2 month) and the cutting balloon of preparation of sirolimus, the full payload of its sirolimus is about 20 μ g, is preferentially coated with on the tinsel of cutting balloon.Device is placed on Percutantnoeus coronary intervention position, secondary fluorescence inspection is to contribute in each experimenter at identical location arrangements device.Six animal vias, by this program, use the balloon in the coating without the coating of sirolimus.After expansion and removal device, 3 control animals were put to death in 1 hour after deployment, collect serum and tissue sample.Remaining 3 control animals were put to death in 56 days after deployment.During research process, within every five days, collect blood serum sample from contrast with through the animal of Drug therapy.Animal (each 3) through Drug therapy is put to death for 1 hour after deployment, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days.

Tissue and blood serum sample can experience the analysis of sirolimus concentration.In order to the percent of the total amount as the coating on matrix, measure amount that is that dissociate from device and/or that be delivered to the coating getting involved position, can be used in a hours point (or any time point in first day after the procedure) sirolimus tissue concentration and for coating expection total content (total content based on to manufacture batch) or and once the content of removing remaining coating on device, and calculate percent.This percent to dissociate from device, dissociation and/or transfer relevant with the percent that is delivered to the coating getting involved position.Alternatively, organize (described herein by various means, include but not limited to SEM, TEM, and wherein use the polymer of image enhaucament, the various imaging means of polymer that these strengthen can be detected) analyze, dissociate from matrix to detect, dissociation and/or transfer and the percent that is delivered to the coating getting involved position.Equally, based on manufacture batch properties and/or evaluate after experimenter's removal device, on device, remaining coating is (such as, wherein device is angioplasty catheter, and matrix is the balloon of conduit), the amount of known coating on matrix can be used for measuring dissociate from device, the percent of the coating of dissociation and/or transfer.In some cases, after independent program, evaluating apparatus is enough to evaluate and dissociates or the amount of dissociation from matrix, need not measure the amount being delivered to and getting involved position.In addition, when expecting to measure improvement and/or disease treatment, the level of pro-inflammatory marker thing can be tested to indicate improvement and/or the treatment of disease and/or imbalance, such as, by testing the CRP (hsCRP) of hypersensitivity, interleukin-6 (IL-6), Interleukin-1β (IL-1 β) and/or monocyte chemoattractant protein-1 (MCP-1).By drawing sirolimus concentration at above-mentioned time point, the release dynamics of medicine can be indicated.

Testing in vitro a: sample at the cutting balloon using the coating prepared in spraying and/or dip coating process is fixed to ballon catheter.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, by balloon inflation to lower than the nominal pressure at least 25% of balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.Optical microscopy is implemented to pipe and/or balloon (it is inflated to the nominal pressure at least 25% lower than balloon to major general), with measure the existence of the coating being transferred to pipe and amount and/or dissociate from balloon, the amount of the coating of dissociation and/or transfer.Other testing in vitro described herein can be used to replace this test and/or except this test, the particularity according to this device regulates, as is known to persons skilled in the art.

cutting balloon (3)-mechanical stimulus is with free coating

Coating comprises the cutting balloon of releasing agent, polymer and activating agent.Getting involved the cutting balloon of position layout coating.By balloon inflation extremely lower than its nominal the blowing pressure at least 25%.Free from the surface of cutting balloon at least about the coating of 50% at least about 5%-, and at intervention site deposition.

In one embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is medicament, such as macrolide immunosuppressive drug.Adopt equipment similar to Example 2 and coating process.Getting involved position is vascular lumen wall.After making cutting balloon inflation, the coating at least about 50% is dissociated from device at intervention position.

In another embodiment, cutting balloon is coated with the preparation of PLGA+ sirolimus, and the full payload of its sirolimus is about 20 μ g, is preferentially coated with on the tinsel of cutting balloon.Adopt equipment similar to Example 2 and process.Intervention position is coronary artery.Releasing agent is ePTFE powder.After making cutting balloon inflation, the coating of about 5 %-about 15 % is dissociated from device, causes sending the medicine that about 2.0 μ g are delivered to tremulous pulse.

In another embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is chemotherapeutics.Adopt equipment similar to Example 2 and coating process.Releasing agent is the another kind of activating agent of micronized activating agent or Micronised form.Getting involved position is the chamber obtained owing to removing tumor.After making cutting balloon inflation, the coating at least about 75% is transferred to from device and gets involved position.

Body build-in test: the group of 27 New Zealand white rabbit prepares to be used for Seldinger program, (MW is about 19kD to 50:50 PLGA-ester end group to use coating to have an appointment, degradation rate is about 1-2 month) and the cutting balloon of preparation of sirolimus, the full payload of its sirolimus is about 20 μ g, is preferentially coated with on the tinsel of cutting balloon.Device is placed on Percutantnoeus coronary intervention position, secondary fluorescence inspection is to contribute in each experimenter at identical location arrangements device.Six animal vias, by this program, use the balloon in the coating without the coating of sirolimus.After expansion and removal device, 3 control animals were put to death in 1 hour after deployment, collect serum and tissue sample.Remaining 3 control animals were put to death in 56 days after deployment.During research process, within every five days, collect blood serum sample from contrast with through the animal of Drug therapy.Animal (each 3) through Drug therapy is put to death for 1 hour after deployment, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days.Tissue and blood serum sample can experience the analysis of sirolimus concentration.

In order to the percent of the total amount as the coating on matrix, measure amount that is that dissociate from device and/or that be delivered to the coating getting involved position, can be used in a hours point (or any time point in first day after the procedure) sirolimus tissue concentration and for coating expection total content (total content based on to manufacture batch) or and once the content of removing remaining coating on device, and calculate percent.This percent to dissociate from device, dissociation and/or transfer relevant with the percent that is delivered to the coating getting involved position.Alternatively, organize (described herein by various means, include but not limited to SEM, TEM, and wherein use the polymer of image enhaucament, the various imaging means of polymer that these strengthen can be detected) analyze, dissociate from matrix to detect, dissociation and/or transfer and the percent that is delivered to the coating getting involved position.Equally, based on manufacture batch properties and/or evaluate after experimenter's removal device, on device, remaining coating is (such as, wherein device is angioplasty catheter, and matrix is the balloon of conduit), the amount of known coating on matrix can be used for measuring dissociate from device, the percent of the coating of dissociation and/or transfer.In some cases, after independent program, evaluating apparatus is enough to evaluate and dissociates or the amount of dissociation from matrix, need not measure the amount being delivered to and getting involved position.In addition, when expecting to measure improvement and/or disease treatment, the level of pro-inflammatory marker thing can be tested to indicate improvement and/or the treatment of disease and/or imbalance, such as, by testing the CRP (hsCRP) of hypersensitivity, interleukin-6 (IL-6), Interleukin-1β (IL-1 β) and/or monocyte chemoattractant protein-1 (MCP-1).By drawing sirolimus concentration at above-mentioned time point, the release dynamics of medicine can be indicated.

Testing in vitro a: sample of the cutting balloon of the coating prepared in example 2 is fixed to ballon catheter.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, by balloon inflation to lower than the nominal pressure at least 25% of balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.Optical microscopy implemented by pipe and/or balloon (it is inflated to the nominal pressure at least 25% lower than balloon to major general), with the amount of the existence and amount and/or the coating from balloon transfer that measure the coating being transferred to pipe.Other testing in vitro described herein can be used to replace this test and/or except this test, the particularity according to this device regulates, as is known to persons skilled in the art.

cutting balloon (4)-mechanical stimulus is with free coating

Coating comprises the cutting balloon of polymer and activating agent.Getting involved the cutting balloon of position layout coating.By balloon inflation extremely lower than its nominal the blowing pressure at least 25%.Free from the surface of cutting balloon at least about the coating of 50% at least about 10%-, and at intervention site deposition.

In one embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is medicament, such as macrolide immunosuppressive drug.Adopt equipment similar to Example 3 and coating process.Getting involved position is vascular lumen wall.After making cutting balloon inflation, the coating at least about 50% is dissociated from device at intervention position.

In another embodiment, cutting balloon is coated with the preparation of PLGA+ sirolimus, and the full payload of its sirolimus is about 20 μ g, is preferentially coated with on the tinsel of cutting balloon.Adopt equipment similar to Example 3 and process.Intervention position is coronary artery.After making cutting balloon inflation, the coating of about 5 %-about 15 % is dissociated from device, causes sending the medicine that about 2.0 μ g are delivered to tremulous pulse.

In another embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is chemotherapeutics.Adopt equipment similar to Example 3 and coating process.Getting involved position is the chamber obtained owing to removing tumor.After making cutting balloon inflation, the coating at least about 75% is transferred to from device and gets involved position.

Tissue and blood serum sample can experience the analysis of sirolimus concentration.In order to the percent of the total amount as the coating on matrix, measure amount that is that dissociate from device and/or that be delivered to the coating getting involved position, can be used in a hours point (or any time point in first day after the procedure) sirolimus tissue concentration and for coating expection total content (total content based on to manufacture batch) or and once the content of removing remaining coating on device, and calculate percent.This percent to dissociate from device, dissociation and/or transfer relevant with the percent that is delivered to the coating getting involved position.Alternatively, organize (described herein by various means, include but not limited to SEM, TEM, and wherein use the polymer of image enhaucament, the various imaging means of polymer that these strengthen can be detected) analyze, dissociate from matrix to detect, dissociation and/or transfer and the percent that is delivered to the coating getting involved position.Equally, and/or can evaluate after experimenter's removal device, on device, remaining coating is (such as based on manufacture batch properties, wherein device is cutting vessel plasty conduit, and matrix is the cutting balloon of conduit), use the amount of known coating on matrix, dissociate from device to measure, the percent of the coating of dissociation and/or transfer.In some cases, after independent program, evaluating apparatus is enough to evaluate and dissociates or the amount of dissociation from matrix, need not measure the amount being delivered to and getting involved position.In addition, when expecting to measure improvement and/or disease treatment, the level of pro-inflammatory marker thing can be tested to indicate improvement and/or the treatment of disease and/or imbalance, such as, by testing the CRP (hsCRP) of hypersensitivity, interleukin-6 (IL-6), Interleukin-1β (IL-1 β) and/or monocyte chemoattractant protein-1 (MCP-1).By drawing sirolimus concentration at above-mentioned time point, the release dynamics of medicine can be indicated.

Testing in vitro a: sample of the cutting balloon of the coating prepared in embodiment 3 is fixed to ballon catheter.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, by balloon inflation to lower than the nominal pressure at least 25% of balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.Optical microscopy is implemented to pipe and/or balloon (it is inflated to the nominal pressure at least 25% lower than balloon to major general), with measure the existence of the coating being transferred to pipe and amount and/or dissociate from balloon, the amount of the coating of dissociation and/or transfer.Other testing in vitro described herein can be used to replace this test and/or except this test, the particularity according to this device regulates, as is known to persons skilled in the art.

cutting balloon (5)-machinery and chemical stimulation are with free coating

Cutting balloon is coated with the preparation of the other layer of basal layer and the PLGA+ paclitaxel comprising acrylic acid methyl ester .-methacrylic acid copolymer, and wherein the total amount of paclitaxel is about 0.5 μ g/mm ²tinsel.Coating and sintering process and describe in embodiment 1 similar.Balloon is made up of semipermeable polymers.Pressure medium is pH 8 phosphate buffer.Getting involved the cutting balloon of position layout coating.By balloon pressurization extremely at least lower than its nominal the blowing pressure at least 25%.Make cutting balloon pressurization in ill tremulous pulse after, at least about 10%-at least about 30% coating be released into get involved position, after the pressurizing, removal device, this material intervention site deposition.

In certain embodiments, launch at aeration period balloon, the coating causing mechanical shear stress at least to expand pH mediation is released into from balloon and gets involved position.

In certain embodiments, in the distortion of aeration period balloon, the coating causing mechanical shear stress at least to expand pH mediation discharges from balloon.

In one embodiment, form the basal layer of acrylic acid methyl ester .-methacrylic acid copolymer, and the other layer of coating is that (MW is about 19kD to about 50:50 PLGA-ester end group, degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is medicament, such as macrolide immunosuppressive drug.Adopt equipment similar to Example 1 and coating process.Balloon is made up of semipermeable polymers.Pressure medium is pH 8 phosphate buffer.Getting involved position is vascular lumen wall.After making cutting balloon inflation, the coating at least about 50% is dissociated from device at intervention position.

In another embodiment, cutting balloon is coated with the basal layer of acrylic acid methyl ester .-methacrylic acid copolymer and the other layer of PLGA+ sirolimus, and the full payload of its sirolimus is about 20 μ.Adopt equipment similar to Example 1 and process.Intervention position is coronary artery.Balloon is made up of semipermeable polymers.Pressure medium is pH 8 phosphate buffer.After making cutting balloon inflation, the coating of about 5 %-about 15 % is dissociated from device, causes sending the medicine that about 2.0 μ g are delivered to tremulous pulse.

embodiment 2: medicine-send ballon catheter

medicine-send balloon (1): be obedient to balloon

Be obedient to balloon and be coated with the material comprising polymer and activating agent.The balloon of being obedient to of coating is arranged at intervention position.By balloon inflation extremely lower than its nominal the blowing pressure at least 25%.In venting with after being obedient to balloon from the removing of intervention position, free from the surface of being obedient to balloon at least about the coating of 30% at least about 5%-, and at intervention site deposition.

In one embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is medicament, such as macrolide immunosuppressive drug.Adopt equipment similar to Example 1 and coating process.Getting involved position is vascular lumen wall.After making to be obedient to balloon inflation, the coating at least about 50% is dissociated from device at intervention position.

In another embodiment, be obedient to the preparation that balloon is coated with PLGA+ sirolimus, the full payload of its sirolimus is about 20 μ g.Adopt equipment similar to Example 1 and process.Intervention position is coronary artery.After making to be obedient to balloon inflation, the coating of about 5 %-about 15 % is dissociated from device, causes sending the medicine that about 2.0 μ g are delivered to tremulous pulse.

In another embodiment, the polymer of coating is 50:50 PLGA-ester end group, and MW is about 19kD, and degradation rate is about 1-2 month or 50:50 PLGA-carboxylate end group, and MW is about 10kD, degradation rate about 28 days.Activating agent is chemotherapeutics.Adopt equipment similar to Example 1 and coating process.Getting involved position is the chamber obtained owing to removing tumor.After making to be obedient to balloon inflation, the coating at least about 75% is transferred to from device and gets involved position.

Body build-in test: the group of 27 New Zealand white rabbit prepares to be used for Seldinger program, (MW is about 19kD to 50:50 PLGA-ester end group to use coating to have an appointment, degradation rate is about 1-2 month) and sirolimus preparation be obedient to balloon, the full payload of its sirolimus is about 20 μ g.Device is placed on Percutantnoeus coronary intervention position, secondary fluorescence inspection is to contribute in each experimenter at identical location arrangements device.Six animal vias, by this program, use the balloon in the coating without the coating of sirolimus.After expansion and removal device, 3 control animals were put to death in 1 hour after deployment, collect serum and tissue sample.Remaining 3 control animals were put to death in 56 days after deployment.During research process, within every five days, collect blood serum sample from contrast with through the animal of Drug therapy.Animal (each 3) through Drug therapy is put to death for 1 hour after deployment, 24 hours, 7 days, 14 days, 28 days, 42 days and 56 days.Tissue and blood serum sample can experience the analysis of sirolimus concentration.

In order to the percent of the total amount as the coating on matrix, measure amount that is that dissociate from device and/or that be delivered to the coating getting involved position, can be used in a hours point (or any time point in first day after the procedure) sirolimus tissue concentration and for coating expection total content (total content based on to manufacture batch) or and once the content of removing remaining coating on device, and calculate percent.This percent to dissociate from device, dissociation and/or transfer relevant with the percent that is delivered to the coating getting involved position.Alternatively, organize (described herein by various means, include but not limited to SEM, TEM, and wherein use the polymer of image enhaucament, the various imaging means of polymer that these strengthen can be detected) analyze, dissociate from matrix to detect, dissociation and/or transfer and the percent that is delivered to the coating getting involved position.Equally, and/or can evaluate after experimenter's removal device, on device, remaining coating is (such as based on manufacture batch properties, wherein device is cutting vessel plasty conduit, and matrix is the balloon of conduit), use the amount of known coating on matrix, dissociate from device to measure, the percent of the coating of dissociation and/or transfer.In some cases, after independent program, evaluating apparatus is enough to evaluate and dissociates or the amount of dissociation from matrix, need not measure the amount being delivered to and getting involved position.In addition, when expecting to measure improvement and/or disease treatment, the level of pro-inflammatory marker thing can be tested to indicate improvement and/or the treatment of disease and/or imbalance, such as, by testing the CRP (hsCRP) of hypersensitivity, interleukin-6 (IL-6), Interleukin-1β (IL-1 β) and/or monocyte chemoattractant protein-1 (MCP-1).By drawing sirolimus concentration at above-mentioned time point, the release dynamics of medicine can be indicated.

Testing in vitro a: sample of being obedient to balloon of the coating prepared in embodiment 1 is fixed to ballon catheter.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, by balloon inflation to lower than the nominal pressure at least 25% of balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.Optical microscopy is implemented to pipe and/or balloon (it is inflated to the nominal pressure at least 25% lower than balloon to major general), with measure the existence of the coating being transferred to pipe and amount and/or dissociate from balloon, the amount of the coating of dissociation and/or transfer.

For measuring the method for sirolimus level: HPLC can be used to measure the sirolimus content of medium.The calibration criterion product of the medicine containing known quantity are for measuring the amount of the medicine of eluting.Add multiple peaks (being also present in calibration criterion product) that sirolimus exists, to obtain the amount (absolute magnitude and as the cumulant of eluting) of the medicine at this time period eluting.Use Waters HPLC system implementation HPLC to analyze, arrange as provided with following table 1 and each sample is run, using the volume injected of 100 L.

Table 1

Time point (minute)	% acetonitrile	% ammonium acetate (0.5%), pH 7.4	Flow velocity (mL/ minute)
				0.00	10	90	1.2
1.00	10	90	1.2
				12.5	95	5	1.2
13.5	100	0	1.2
				14.0	100	0	3
16.0	100	0	3
				17.0	10	90	2
20.0	10	90	0

External mass loss test a: sample of being obedient to balloon of the coating prepared in embodiment 1 is weighed on microbalance, is fixed to ballon catheter subsequently.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, by balloon inflation to lower than the nominal pressure at least 25% of balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.After drying, remove balloon from wire, further dry and weigh on microbalance.Before launching and after launching the comparison instruction of weight have that how many coatings are free from balloon, dissociation and/or transfer.This analysis can change into and/or alternatively comprise the test of pipe, to dissociate from device during being determined at this testing in vitro, the amount of the coating of dissociation and/or transfer.

External coating test a: sample of being obedient to balloon of the coating prepared in embodiment 1 is fixed to ballon catheter.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, by balloon inflation to lower than the nominal pressure at least 25% of balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.The part being exposed to the pipe of the balloon of expansion cut open from the remainder of pipe, inside a small amount of ethanol and a certain amount of dichloromethane of the pipe of excision, to form total rinsing volume of 25 mL, collect in flask, for analyzing.Implement above-mentioned HPLC to analyze, dissociate from balloon to measure, the amount of the material of dissociation and/or transfer.This analysis can change into and/or alternatively comprise the test of matrix itself, to dissociate from device during being determined at this testing in vitro, the amount of the coating of dissociation and/or transfer.

Testing in vitro a: sample of being obedient to balloon of the coating prepared in embodiment 1 is fixed to ballon catheter.Part layout coronarius from the excision of the miniature pig of Yucatan is fixed and is filled with the saline solution of phosphate-buffered, and immerses in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.The balloon of coating is inserted in tremulous pulse, by balloon inflation to the nominal pressure at least 25% lower than balloon, with by coating from balloon mechanical transfer to arterial wall.Balloon is exitted, and removes from tremulous pulse.The part being exposed to the tremulous pulse of the balloon of expansion is cut open from the remainder of arterial portions, is placed in tissue homogenizer, the material dichloromethane extraction of homogenize, to form total rinsing volume of 25 mL, collect in flask and be used for analyzing.Implement above-mentioned HPLC to analyze, dissociate from balloon to measure, the amount of the material of dissociation and/or transfer.This analysis can change into and/or alternatively comprise test base itself, to dissociate from device during being determined at this testing in vitro, the amount of the coating of dissociation and/or transfer.

For the embodiment about non-vascular or the application of non-tube chamber, such as, the position of tumor locus or other chamber or sleeve pipe insertion, adopts identical technology, and amendment part is that tissue to be determined is excised in the chamber adjoined from the tissue accepting Drug therapy.

Testing in vitro a: sample of being obedient to balloon of the coating prepared in embodiment 1 is fixed to ballon catheter.Part layout coronarius from the excision of the miniature pig of Yucatan is fixed and is filled with the saline solution of phosphate-buffered, and immerses in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.The balloon of coating is inserted in tremulous pulse, by balloon inflation to the nominal pressure at least 25% lower than balloon, with by coating from balloon mechanical transfer to arterial wall.Balloon is exitted, and removes from tremulous pulse.The part being exposed to the tremulous pulse of the balloon of expansion cut open from the remainder of arterial portions, longitudinally cutting, opens tremulous pulse to sprawl.Optical microscopy is implemented in the inside of tremulous pulse, with the amount of the existence and amount and/or the coating from balloon transfer that measure the coating being transferred to tremulous pulse.Tissue sample also stands TEM-SEM and analyzes.

The testing in vitro of release dynamics a: sample of being obedient to balloon of the coating prepared in embodiment 1 is fixed to ballon catheter, the full payload of its sirolimus is about 20 μ g.Be equipped with magnetic agitation, prepare accurately to contain the flask of 25 mL balances to the pH 7.4 water-bearing phosphate salt buffer of 37 DEG C.The balloon of coating is placed in this flask, and the conduit portion of fixing device, make balloon not contact the side of flask.Use sterilized water by balloon inflation to 120 psi.Before adding balloon, after placement balloon but before making balloon inflation, and with the interval of the rule of 2,4,6,8,10,12 and 14 minutes, remove the aliquot of 100 μ L.After each aliquot of removing, adding the water-containing buffering liquid of same volume, is 25 mL to keep volume.As analyzed the sirolimus concentration of aliquot above by HPLC.

The testing in vitro of distally flow particles a: wire sample of being obedient to balloon of the coating prepared in embodiment 1 being fixed to the porous filter in conjunction with 100 micron hole size, such as Cordis AngioGuard embolus trapping wire.External diameter=0.125 "; internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter.By in the balloon insertion tube of coating, the adjacent end epoxide around the pipe of wire seals, in the pipe of the hypodermic needle insertion be connected the reservoir of the saline solution with infusion pump and 37 DEG C of phosphate-buffered and balloon assembly vicinity.Start the flowing of saline, launch distally filter, and by balloon inflation to the nominal pressure at least 25% lower than balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.After removing balloon, filter is launched 5 minutes, stop the flowing of saline, adjacent loops oxide seal cutting pipe, filter is retracted, and removes from pipe.The inclusions of analysis and filter device.

Testing in vitro for distally flow particles a: sample of being obedient to balloon of the coating prepared in embodiment 1 is fixed to wire.External diameter=0.125 ", internal diameter=0.0625 " the optically transparent TYGON B-44-3 part of managing (McMaster-Carr Part can be derived from number: 5114K11 (www.mcmaster.com)) be filled with the saline solution of phosphate-buffered, and immerse in 37 DEG C of water-baths, to simulate the physiological conditions launched in experimenter, the distal end of pipe is connected with turbidity light scattering detector, as what describe in Analytical Ultracentrifugation of Polymers and Nanoparticles (analytical ultracentrifugation of polymer and nano-particle), W. Machtle and L. Borger, (Springer) 2006, 41st page.By in the adjacent end of the balloon insertion tube of coating, the adjacent end epoxide around the pipe of wire seals, in the pipe of the hypodermic needle insertion be connected the reservoir of the saline solution with infusion pump and 37 DEG C of phosphate-buffered and balloon assembly vicinity.Start the flowing of saline, set up the light transmissive baseline by detector, by balloon inflation to the nominal pressure at least 25% lower than balloon, with by coating from balloon mechanical transfer to tube wall.Balloon is exitted and removes from pipe.After removing balloon, by stream maintenance 10 minutes, based on detector response, the existence of granule in analysis stream.

medicine-send balloon (2): non-compliant balloon

Non-compliant balloon is coated with the material comprising polymer and activating agent.The non-compliant balloon of coating is arranged at intervention position.By balloon inflation extremely lower than its nominal the blowing pressure at least 25%.In venting with after intervention position removing non-compliant balloon, free from the surface of non-compliant balloon at least about the coating of 30% at least about 5%-, and at intervention site deposition.

In one embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is medicament, such as macrolide immunosuppressive drug.Adopt equipment similar to Example 1 and coating process.Getting involved position is vascular lumen wall.After making non-compliant balloon inflation, the coating at least about 50% is dissociated from device at intervention position.

In another embodiment, non-compliant balloon is coated with the preparation of PLGA+ sirolimus, and the full payload of its sirolimus is about 20 μ g.Adopt equipment similar to Example 1 and process.Intervention position is coronary artery.After making non-compliant balloon inflation, the coating of about 5 %-about 15 % is dissociated from device, causes sending the medicine that about 2.0 μ g are delivered to tremulous pulse.

In another embodiment, the polymer of coating is about 50:50 PLGA-ester end group (MW is about 19kD, and degradation rate is about 1-2 month) or about 50:50 PLGA-carboxylate end group (MW is about 10kD, degradation rate about 28 days).Activating agent is chemotherapeutics.Adopt equipment similar to Example 1 and coating process.Getting involved position is the chamber obtained owing to removing tumor.After making non-compliant balloon inflation, the coating at least about 75% is transferred to from device and gets involved position.

Can according in method embodiment described herein and/or testing in vitro.

embodiment 3: send rapamycin in the balloon body of coating

the balloon preparation of the sirolimus coating tested in rabbit

GHOST is used to exchange (Rx) conduit fast in this embodiment.Coating GHOST 3.0 × 18 mm Rx catheter balloon, and for zooscopy.Study according to following design.Run some tests, to measure the vivo drug delivery characteristic of rapamycin from the balloon of coating.

First test is included in rabbit iliac artery the balloon of coating of expanding.Manufacture the balloon of 8 coatings, and test in 4 rabbits.4 balloons be coated with are inflated 60 seconds in the tremulous pulse (ILR) expanded in advance, 4 balloons be coated with are inflated 60 seconds in the tremulous pulse (left ilium) of on-expansible.Be determined at the amount of the medicine (sirolimus) that expansion position finds in arterial tissue.Following table indicates the test result of the sirolimus concentration of these tremulous pulsies in arterial tissue and the total amount at each tremulous pulse sirolimus.By the balloon inflation of the coated with drug in ILR tremulous pulse/exit about 10-20 minute before execution.By the balloon inflation of the coated with drug in left ilium tremulous pulse/exit about 5-15 minute before execution.

Iliac artery	Average sirolimus (ng/mg)	SD	The average total sirolimus (μ g) of each tremulous pulse	SD
					ILR (exposed) (n=4)	178.3	32.1	5.4	1.1
Left ilium (unharmed) (n=4)	216.1	122.4	3.9	1.7
					The right side+left ilium the tremulous pulse (n=8) of combination	197.2	85.3	4.7	1.6

These identical tremulous pulsies of following table instruction test are at the initial data of the total amount of each tremulous pulse sirolimus.It also indicates sirolimus to be exposed to the time of the estimation of blood flow to the transfer effect of the calculating of rabbit iliac artery and tremulous pulse.The total being used in the estimation of sirolimus on balloon is transferred to the percent (%) of the sirolimus of tremulous pulse.The total amount of the estimation of sirolimus on balloon, is tested by the UV-viscosimetric analysis of balloon as batch average total amount of the sirolimus that test sample balloon is coated with based on the balloon in same batch.The time that tremulous pulse is exposed to the estimation of blood flow is time quantum between balloon inflation and balloon test and/or at balloon inflation with until by the time between sacrifice of animal, is extracted by tremulous pulse, for the content by HPLC testing drug.

Rabbit #	Balloon #	Total sirolimus (μ g) of each tremulous pulse	Be transferred to the % sirolimus of tremulous pulse	Tremulous pulse is exposed to the time (minute) of the estimation of blood flow
					#1 ILR tremulous pulse	N185	5.0	7.76%	20
#1 left ilium tremulous pulse	N157	3.2	5.58%	15
					#2 ILR tremulous pulse	N164	7.0	12.62%	10
#2 left ilium tremulous pulse	N167	5.0	8.98%	5
					#3 ILR tremulous pulse	N175	5.1	9.17%	10
#3 left ilium tremulous pulse	N178	1.8	2.88%	5
					#4 ILR tremulous pulse	N191	4.5	7.59%	15
#4 left ilium tremulous pulse	N117	5.7	7.95%	10
					Follow the tracks of average	-	4.7	7.8%	-
SD	-	1.6	2.8%	-

The haemoconcentration (whole blood) of the sirolimus that following table instruction is taken out from the animal for this test.For each animal, before being exposed to the balloon of coating (namely, before making balloon inflation), get the baseline concentrations of sirolimus.In each animal, because the balloon delivery of two coatings in this test delivers to each animal, within 5-15 minute after second balloon inflation, get whole blood sample.Therefore, the result instruction indicated in the following table is for the accumulation whole blood sirolimus concentration of each animal from the inflation of the balloon of 2 coated with drug.Total sirolimus in blood is based on 56mL blood/kg (that is, the weight of the rabbit of every kilogram of test).

Rabbit #	Extraction concentration (ng/mL)	The total sirolimus (μ g) estimated in blood
			#1 baseline	Lower than level of quality	-
#2 baseline	Lower than level of quality	-
			#3 baseline	Lower than level of quality	-
#4 baseline	Lower than level of quality	-
			#1 (15 minutes)	11.4	2.7
#2 (5 minutes)	30.8	8.2
			#3 (5 minutes)	22.2	5.9
#4 (10 minutes)	19.3	4.8
			On average (5-15 minute)	20.9	5.4
SD	8.0	2.3

Following table indicates the concentration of sirolimus after test itself on each balloon for this test, to indicate the percent (%) of the sirolimus lost after test program.As mentioned above, follow the tracks of the corresponding tremulous pulse of each balloon, and inflate 60 seconds (1 minute), exit subsequently, from animal removing, and the percent of test remaining sirolimus on balloon.The percent (%) of the sirolimus of loss, based on the amount of remaining sirolimus and the total amount of sirolimus that is coated with on balloon on balloon after a test, by balloon batch averaged power spectrum, uses the test of UV-viscosity measurement.The variable contributing to the amount (or percent) of the sirolimus lost comprises following: balloon inserts ilium (via jugular vein+aorta); Blood flow; Pleating/folding/sheath method and program; About 10% loss during shipping; And/or balloon inflation/with arterial wall contact.

Balloon ID	Total sirolimus (μ g) of each balloon	The sirolimus % of loss
			Rabbit #1 RIA balloon N185	13.2	79.3%
Rabbit #1 LIA balloon N157	17.3	69.9%
			Rabbit #2 RIA balloon N164	4.8	91.5%
Rabbit #2 LIA balloon N167	11.7	79.1%
			Rabbit #3 RIA balloon N175	16.0	71.4%
Rabbit #3 LIA balloon N178	14.7	77.0%
			Rabbit #4 RIA balloon N191	9.6	83.6%
Rabbit #4 LIA balloon N117	14.9	79.1%
			Follow the tracks of average	12.8	78.9%
SD	4.0	6.8%

In another test, carry out follow-up study.Test pack contains the aorta of balloon to rabbit of tracking 4 coating.Insert each in the balloons of 4 coatings, track to the aorta of rabbit, and stay in aorta and reach 2 minutes, and do not make balloon inflation.After such insertion, follow the tracks of and keep balloon in aorta, reach 2 minutes, comprising the conduit of the balloon of coating from animal removing.

The concentration of the sirolimus of following table instruction after test itself on each balloon for this test, to indicate the percent (%) of the sirolimus lost after test program.The percent (%) of the sirolimus of loss, based on the amount of remaining sirolimus and the total amount of sirolimus that is coated with on balloon on balloon after a test, by balloon batch averaged power spectrum, uses the test of UV-viscosity measurement.The variable contributing to the amount (or percent) of the sirolimus lost comprises following: balloon inserts ilium (via jugular vein+aorta); Blood flow; Pleating/folding/sheath method and program; And/or about 10% loss during shipping.

Balloon ID	Total sirolimus (μ g) of each balloon	The sirolimus % of loss
			Follow the tracks of #1 balloon (N120)	23.6	66.9%
Follow the tracks of #2 balloon (N160)	20.8	63.9%
			Follow the tracks of #3 balloon (N166)	19.0	66.0%
Follow the tracks of #4 balloon (N176)	22.0	65.5%
			Follow the tracks of average	21.3	65.6%
SD	2.0	1.3%

Balloon and blood sample (as in the first two table indicated by " total sirolimus (ug) of each balloon " hurdle, and as the instruction of haemoconcentration table generality) the upper enforcement sirolimus from two tests above quantitative.Namely, measure sirolimus content from 8 balloons inflated rabbit iliac artery, follow the tracks of 4 balloons, but do not inflate in rabbit aorta, have 8 whole blood samples (2 sample/rabbits).Store liver,kidney,spleen, the heart and lung (80 DEG C) for pharmaceutical analysis afterwards.

In a word, below the test instruction implemented in this embodiment: the sirolimus of 197.2 ± 85.3 ng/mg is embedded in arterial wall.The effect that sirolimus is transferred to arterial wall from balloon is 7.8 ± 2.8 %.The amount of the sirolimus washed off is in the circulating cycle 5.4 ± 2.3 μ g.In the artery after inflation, from the sirolimus be coated with at balloon of balloon removing 78.9 ± 6.8%.In the artery before inflation, from the sirolimus be coated with at balloon of balloon removing 65.6 ± 1.3%.In order to reference, each balloon is coated with 50-100 μ g sirolimus.The medicine (sirolimus) of 1%-5% is transferred to tremulous pulse.At test period, find 1 ng sirolimus/mg tissue, as described in this embodiment.

embodiment 4: send rapamycin in the balloon body of coating

Can binding agent be incorporated in coating, retain with the activating agent improved in the artery.Embodiment binding agent comprises cationics and/or positively charged molecule.An embodiment of binding agent can be surfactant.Also and/or can alternatively use other binding agent.For non-limiting example, binding agent can comprise following one of at least: poly arginine, poly arginine 9-L-pArg, DEAE-dextran (DEAE-cellulose-dextran), DMAB (two (dodecyl) ditallowdimethyl ammonium bromide), PEI (polymine), TAB (four (dodecyl) ammonium bromide) and DMTAB (dimethyl two (myristyl) ammonium bromide).In some embodiments of device provided herein, coating and/or method, arranging the surface of the coating for contact treatment position, coating comprises positive surface charge.

In some embodiments, surfactant comprises at least one in the primary amine of pH < 10 and the secondary amine of pH <4.In some embodiments, surfactant comprises octenidine dihydrochloride.In some embodiments, surfactant comprises permanent charged quaternary ammonium cation.In some embodiments, permanent charged quaternary ammonium cation comprise following one of at least: alkyl trimethyl ammonium salt, such as cetyl trimethyl ammonium bromide (CTAB), cetyl trimethyl ammonium bromide, hexadecyltrimethylammonium chloride (CTAC); Cetylpyridinium chloride (CPC); The beef tallow amine (POEA) of polyethoxylated; Benzalkonium chloride (BAC); Benzethonium chloride (BZT); 5-bromo-5-nitro-1,3-dioxane; Dimethyl dioctadecyl ammonium chloride; With two (octadecyl) ditallowdimethyl ammonium bromide (DODAB).In some embodiments, surfactant comprise following one of at least: two (dodecyl) ditallowdimethyl ammonium bromide (DMAB), linear isotype (isoform) polymine (linear PEI), the low MW polymine (PEI) (about <25KDa) of branching, the low MW polymine (PEI) (about <15KDa) of branching, the low MW polymine (PEI) (about <10KDa) of branching, the high MW polymine (about >/=25 KDa) of branching, pR (average or nominal MW is about 70,000 Da), pR (average or nominal MW > about 50,000 Da), pR (average or nominal MW is about 5,000-about 15,000 Da), poly-L-Lysine (average or nominal MW is about 28,200 Da), poly-L-Lysine (average or nominal MW is about 67,000 Da), polyhistidyl, ethylhexadecyl ditallowdimethyl ammonium bromide, Dodecyl trimethyl ammonium chloride, four (dodecyl) ammonium bromide, dimethyl two (myristyl) ammonium bromide, tetrabutylammonium iodide, DEAE-dextran hydrochlorate and hexadimethrine bromide.In some embodiments, the molecular weight of binding agent is controlled.In some embodiments, the average-size of binding agent is controlled.

In some embodiments of device provided herein, coating and/or method, by binding agent and activating agent mixing, and be deposited on together on device.In some embodiments, on device before deposition, by activating agent and binding agent lyophilizing.In some embodiments, adopt the another kind of mode that those skilled in the art are familiar with, produce the dry granule of activating agent and binding agent, be coated with on balloon or other medical treatment device described herein subsequently, such as, by eSTAT coating process.In some embodiments of device provided herein, coating and/or method, after activating agent deposits thereon, deposition surface activating agent on balloon.

The positive surface charge of coating can be about 20 mV-and is about 40mV.Positive surface charge can be following one of at least: at least about 1 mV, exceed about 1 mV, at least about 5 mV, at least about 10 mV, about 10 mV-about 50 mV, about 20 mV-about 50 mV, about 10 mV-about 40 mV, about 30 mV-about 40 mV, about 20 mV-about 30 mV and about 25 mV-about 35 mV.

In some embodiments, the mean molecule quantity of binding agent is controlled.Such as, the mean molecule quantity of poly arginine can be 70kDa, 5-15 kDa, another kind of controlled molecular weight, or their combination.In some embodiments, the molecular weight of binding agent is controlled.Such as, in some embodiments, poly arginine is binding agent, and the poly arginine ortho states of at least 75% is 70kDa, 5-15 kDa or another kind of controlled molecular weight.In some embodiments, poly arginine is binding agent, and the poly arginine ortho states of at least 50% is 70kDa, 5-15 kDa or another kind of controlled molecular weight.In some embodiments, poly arginine is binding agent, and the poly arginine ortho states of at least 90% is 70kDa, 5-15 kDa or another kind of controlled molecular weight.In some embodiments, poly arginine is binding agent, and the poly arginine ortho states of at least 95% is 70kDa, 5-15 kDa or another kind of controlled molecular weight.In some embodiments, poly arginine is binding agent, and the poly arginine ortho states of at least 98% is 70kDa, 5-15 kDa or another kind of controlled molecular weight.In some embodiments, poly arginine is binding agent, and the poly arginine ortho states of at least 99% is 70kDa, 5-15 kDa or another kind of controlled molecular weight.

In some embodiments, control the size of activating agent in the coating, retain with the medicine improved in the artery.For non-limiting example, when sirolimus is as activating agent, the average-size (average diameter) of sirolimus can be following one of at least: 1.5 μm, 2.5 μm, 645nm, 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the median size of its sirolimus be following one of at least: 1.5 μm, 2.5 μm, 645nm, 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the average-size of its sirolimus (average diameter) for following one of at least: about 1.5 μm, about 2.5 μm, about 645nm, about 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the median size of its sirolimus be following one of at least: about 1.5 μm, about 2.5 μm, about 645nm, about 100-200 nm, another kind of controlled size, or their combination.In some embodiments, the size of activating agent is controlled.Such as, in some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 75% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 50% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 90% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 95% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 98% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 99% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.Activating agent on average can be following one of at least: 5 microns at the most, more than 1 micron, 1 micron-5 microns, on average about 1.5 microns and average about 2.5 microns.

In some embodiments, the ratio of activating agent and binding agent is controlled.In some embodiments, the ratio of activating agent and binding agent is 1:1,1:2,1:3,1:4,1:5,1:10,1:20,2:1,3:1,4:1,5:1,10:1,15:1,20:1,3:2,2:3,5:2,5:3,2:5,3:5, or another kind of controlled rate.

In some embodiments, coating can comprise nano-particle, and nano-particle can comprise activating agent and polymer.

The balloon exchanging 3.0 × 18 or 3.0 × 17 balloons of (Rx) conduit at GHOST is fast coated with multiple coating agent, and in rabbit, is delivered to their iliac artery.The arterial tissue of rabbit is extracted at some time point (maximum 72 hours), and the amount of the medicine found in arterial tissue is determined at by method known to those skilled in the art, such as by HPLC method test arterial tissue or the loss being found coating or medicament during program by UV-viscosity measurement, organize statement with ng medicine (sirolimus)/mg, indicate (sample size wherein indicated) in the following table.In most of the cases, postmortem time point is 5 minutes +/-, 5%, 24 hours +/-5% and 72 hours +/-5%.Such as, for each animal, the performing an autopsy on sb. for about 5 minutes, 24 hours or 72 hours of (time point of +/-5%) after the balloon venting of second coated with drug, wherein two blood vessels are used for research.

* two kinds of researchs are carried out, and herein by data assemblies, research 1:n=2,8.1+/-5.2, research 2:n=4,17.0+/-13.5.

As the amount of the total sirolimus extracted in the artery, result of calculation, as indicated in the following table:

* an overflow value is removed

* notes being divided into two kinds of modes for analyzing from the data of F3, by study and by manufacture batch, therefore, represents identical result (research 1,2 and batch 1,2) in two groups.

Select some preparation for other analysis, and their test result normalization is used for the tremulous pulse part size of balloon length and extraction.For the preparation selected by these, find following result:

Select some preparation to analyze for another, and concentration results normalization is used for tremulous pulse weight (being normalized to 0.025g).For the preparation selected by these, find following result.

In the rabbit tremulous pulse mentioned in this embodiment and blood testing, use following coating details and preparation.

-F1 (preparation 1) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the sirolimus being on average of a size of 2.5 μm.

-F2 (preparation 2) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 1:1 ratio is the sirolimus of 2.5 μm: poly arginine 70kDa.

-F3 (preparation 3) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 1.5 μm or 2.5 μm: poly arginine 70kDa.

-F4 (preparation 4) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 2.5 μm: DEAE-dextran (DEAE-cellulose-dextran).

-F5 (preparation 5) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 1:1 ratio is sirolimus and the DMAB (two (dodecyl) ditallowdimethyl ammonium bromide) of 2.5 μm.

-F6 (preparation 6) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is sirolimus and the DMAB (two (dodecyl) ditallowdimethyl ammonium bromide) of 2.5 μm.

-F7 (preparation 7) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is sirolimus and the PEI (polymine) of 2.5 μm.

-F8 (preparation 8) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is sirolimus and the TAB (four (dodecyl) ammonium bromide) of 2.5 μm.

-F9 (preparation 9) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is sirolimus and the DMTAB (dimethyl two (myristyl) ammonium bromide) of 2.5 μm.

-F10 (preparation 10) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 1:1:1 ratio is the sirolimus of 2.5 μm: poly arginine 70kDa:PEI (polymine).

-F11 (preparation 11) comprises PLGA, namely, about 50:50 lactic acid: glycolic, and the average-size of 10:1:1 ratio is the sirolimus of 2.5 μm: TAB (four (dodecyl) ammonium bromide): DEAE-dextran (DEAE-cellulose-dextran).

-F12 (preparation 12) comprises PLGA nanosphere body (130nm), and wherein PLGA is 50:50 lactic acid: glycolic, and 6.3% sirolimus.

-F13A (preparation 13A) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the sirolimus being on average of a size of 645nm.

-F13B (preparation 13B) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 645nm: poly arginine 70 kDa.

-F13C (preparation 13C) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 1:1 ratio is the sirolimus of 645nm: DMAB (two (dodecyl) ditallowdimethyl ammonium bromide).

-F13D (preparation 13D) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus-PEI (polymine) of 645nm.

-F14A (preparation 14A) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the sirolimus being on average of a size of 100-200 nm.

-F14B (preparation 14B) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 100-200 nm: poly arginine 70 kDa.

-F14C (preparation 14C) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 1:1 ratio is the sirolimus of 100-200 nm: DMAB (two (dodecyl) ditallowdimethyl ammonium bromide).Notice that said preparation can not be prepared, therefore, zooscopy result can not be obtained.

-F14D (preparation 14D) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 100-200 nm: PEI (polymine).

-F15 (preparation 15) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 1.5 μm: poly arginine 5-15 kDa.

-F16 (preparation 16) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and 10:1 ratio average-size is the sirolimus of 1.5 μm: poly arginine 9-L-pArg.

-F17 (preparation 17) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 645nm: poly arginine 5-15 kDa.

-F18 (preparation 18) comprises PLGA, that is, about 50:50 lactic acid: glycolic, and the average-size of 10:1 ratio is the sirolimus of 645nm: poly arginine 9-L-pArg.

F12 makes an exception, and all methods comprise use RESS process for being coated with PLGA and using eSTAT process for being coated with sirolimus and positively charged molecule to balloon on balloon.Universal process for being coated with is: polymer-coated 1) by RESS process, 2) by the sirolimus of eSTAT process and adhesive coated (or independent sirolimus, if do not use binding agent in the formulation, such as, 14A), the 3) balloon of sinter coating.The part that binding agent (that is, charged granule, surfactant and/or cationic particle) is sirolimus application step, wherein use eSTAT process, balloon is coated with both sirolimus and binding agent.Only use eSTAT or RESS process and sintering step, painting preparation 12 on balloon.

In the following ways, sirolimus and binding agent (if existing in concrete preparation) (such as, for non-limiting example, surfactant, cationic particle, charged molecule) is made to mix.This process can be suitable for different binding agents and different activating agents, but use as described about sirolimus and binding agent in this article, the binding agent in the preparation wherein mentioned in this embodiment is surfactant.Lyophilizing or " lyophilization " process produce the dry powder of medicine and the binding agent (such as, surfactant) associated, and it is applicable to deposit on balloon via eSTAT method.Other process that those skilled in the art are familiar with can be used as the alternative of lyophilizing, to be applicable to the form deposited on balloon via method described herein, with associated drug and binding agent.In this embodiment, rapamycin (sirolimus) suspends in water together with binding agent, to use adhesive coated sirolimus.By the sirolimus of well suspended and binder solution freezing, retain sirolimus and binding agent assembly, by distillation except anhydrating, to produce dry sirolimus and adhesive material.

The prior lyophilizing setting of step can be used for producing dry sirolimus and the process of binder solution, for eSTAT coating process.Thus the solution produced can be used for freeze dryer.The medicine (such as, sirolimus) of desired amount of weighing in 100mL Schott bottle and binding agent.Adding 50mL water subsequently in Schott bottle, take 10mL as increment.During each increment, use stirring rod mixed solution, to guarantee that sirolimus is wetted.After adding 50mL, solution is being bathed the middle supersound process of ultrasonoscope (Branson 1510) 1 hour.In final prior step of freeze drying, use plastic suction pipet that the solution of well suspended is carefully transferred to 50mL conical centrifuge tube; The sirolimus do not suspended and/or adhesive particle (usually finding to swim on the surface of suspension) do not shift.Attention: the sirolimus of the solution of effect impact transfer sirolimus being suspended by binding agent and the reality of the powder of final recovery and surfactant ratio, change it from the initial sirolimus of weighing and binder ratio usually.

Step of freeze drying can be as follows: be immersed in liquid nitrogen by the suspension reclaimed in 50mL centrifuge tube, until solution is completely freezing.Parafilm is for covering the opening of the pipe containing freezing suspension, and preparation perforation in film simultaneously, escapes to allow vapor phase water.Pipe containing freezing sample is carried on freeze dryer to preserve in container, container is connected with a freeze dryer station.Activate the switch on the nozzle at the station for load, to start this process.When seeing that all freezing moisture does not exist in pipe, complete step of freeze drying.When the process is finalised, by vibrating or stirring, the sample that can be used as xerogel existence after lyophilizing is easily converted into free-pouring dry powder.For the sample of preparation as mentioned above, usual 1-2 consuming time days to complete step of freeze drying.Attention: freeze-dried device may need periodically defrosting, with the moisture from sample removing accumulation, effectively to work.

In the eSTAT coating process (having used RESS process to be coated with PLGA in advance, as other places describe in this article) of balloon, following steps are adopted to prepare sirolimus and the dry solution of binding agent.Sirolimus and the binding agent of aequum is measured in 100mL Schott bottle.In Schott bottle, add 50mL water, take 10mL as increment.During each increment, use stirring rod to mix sirolimus and binder solution.After adding 50mL water, From Solution Under Ultrasound Treatment reaches 1 hour.After supersound process, use plastic suction pipet that the solution of suspension is transferred to 50mL centrifuge tube.Avoid shifting any sirolimus of not suspending and adhesive particle.50mL conical tube (not lid) is placed in liquid nitrogen, until solution is completely freezing.Cover the top of conical tube with Parafilm, in film, do hole, water can be passed.In lyophilizing container, seal the conical bottle of 50mL, container is connected with freeze dryer nozzle station.Open the switch on nozzle, with from container evacuate air.Keeping sample is on freeze-dried device, until all water is removed (usual 1-2 days).

Rabbit haemoconcentration result is as follows.For some preparations, measure the amount of medicine, as the concentration of every mL blood, as indicated in the following table.BQL refers to lower than determination limit (whole blood about sirolimus is quantitative, 1-2ng/ml) herein.

* note being divided into two kinds of modes for analyzing from the data of F3, by studying and by manufacture batch, therefore, representing identical result (research 1,2, relative batch 1,2) in two groups.

These data of * represent the balloon of the coating of two batches, and for one batch, sirolimus (ng/mL) result in whole blood is: (n=2), 0.7+/-1.0

For some preparations, the amount being determined at the medicine found in arterial tissue as total amount, as indicated in the following table.

Various preparation has the average magnitude of the following sirolimus be coated with on each balloon tested in rabbit tremulous pulse.These are the average magnitude according to the medicine that the sample balloon of identical program described herein coating finds, and from identical batch and batch of material, test in rabbit just as described above those.The amount of the sirolimus that balloon is coated with for before pleating at balloon, folding and sterilizing, based on the average sirolimus concentration that UV-Vis analyzes.

Preparation	The sirolimus (μ g) that balloon is coated with
		F1	64.52±8.73
F1 (second batch)	63.40±2.89
		F2	41.05±7.17
F3	89.54±19.61
		F3 (second batch)	128.71±26.86
F4	115.12±16.92
		F5	68.49±4.73
F6	316.95±82.66
		F7	165.25±17.47
F8	97.19±16.46
		F9	218.86±26.73
F10	65.38±24.45
		F11	170.66±14.30
F12	74.20±15.77
		F13A	134.23±17.03
F13B	144.63±51.84
		F13C	55.46±13.14
F13D	105.31±16.02
		F14A	83.10±15.19
F14B	175.96±78.30
		F14D	77.50±31.02
F15	106.53±22.55
		F16	75.84±5.98
F17	197.64±15.89
		F18	196.43±45.89

In rabbit tremulous pulse after expanding baloon, remove each balloon from animal, be determined at the sirolimus of the remnants on each balloon.Use 5-minute data as be transferred to tremulous pulse sirolimus amount (therefore, percent) instruction, after being used in program on balloon the amount of remaining medicine, and the estimation of the total amount as medicine in initial installation, the average magnitude (table see above) of medicine on the balloon being used in same batch, measures the total percentage of the percent being transferred to the sirolimus of rabbit tremulous pulse and the sirolimus discharged during whole program.Following table gathers the result of the preparation adopting which test.

Preparation	Sirolimus (μ g) after deployment on balloon	The sirolimus discharged from corresponding balloon is transferred to the sirolimus % (5 minutes) of tremulous pulse	The sirolimus % of release
				F1	12.8±4.0 (n=8)	9.8±3.1% (n=8)	78.9±6.8% (n=8)
F1 (second batch)	45.7±7.3 (n=36)	23.0±8.5% (n=12)	35.9±10.2% (n=36)
				F2	6.1±2.7 (n=2)	N/A	85.1±3.6% (n=2)
F3 studies 1*	25.8±9.6 (n=12)	N/A	68.8±16.2% (n=12)
				F3 studies 2* (2.5 μm)	28.1±4.9 (n=6)	N/A	73.1±7.6% (n=6)
F3 (first batch) *	27.6±9.1 (n=20)	4.8±1.4% (n=6)	68.4±15.4% (n=20)
				F3 (second batch-1.5 μm) *	56.8±15.6 (n=6)	1.2±0.6% (n=2)	59.0±8.6% (n=6)
F4	16.0±2.9 (n=6)	5.1±3.5% (n=4)	84.9±2.5% (n=6)
				F5	5.0±2.7 (n=14)	0.6±0.2% (n=4)	92.8±3.7% (n=14)
F6	49.4±6.9 (n=4)	3.5±0.2% (n=2)	84.4±3.7% (n=4)
				F7	7.1±3.0 (n=14)	3.9±2.4% (n=4)	95.7±1.7% (n=14)
F8	20.5±0.1 (n=2)	N/A	78.1±3.8% (n=2)
				F9	37.0±4.1 (n=2)	N/A	82.6±0.3% (n=2)
F10	1.4±0.8 (n=14)	4.0±0.3% (n=4)	98.1±0.8% (n=14)
				F11	43.6±11.2 (n=14)	1.7±0.4% (n=4)	74.4±6.9% (n=14)
F12	2.3±0.8 (n=2)	N/A	97.1±1.0% (n=2)
				F13A	21.6±1.0 (n=2)	N/A	85.0±0.8% (n=2)
F13B	30.4±7.4 (n=14)	3.8±0.6% (n=4)	76.5±7.2% (n=14)
				F13C	2.1±0.1 (n=2)	N/A	96.6±0.0% (n=2)
F13D	9.2±2.6 (n=2)	N/A	92.1±2.3% (n=2)
				F14A	11.6±0.8 (n=2)	N/A	87.5±0.3% (n=2)
F14B	16.4±0.6 (n=2)	N/A	91.9±0.8% (n=2)
				F14D	1.7±0.1 (n=2)	N/A	98.5±0.1% (n=2)
F15	24.9±5.6 (n=12)	5.3±0.7% (n=4)	76.4±6.3% (n=12)
				F16	21.4±3.9 (n=12)	4.2±1.6% (n=4)	72.0±4.6% (n=12)
F17	49.3±6.9 (n=12)	6.6±1.9% (n=4)	74.6±3.6% (n=12)
				F18	44.5±8.7 (n=12)	2.5±0.8% (n=4)	76.4±3.3% (n=12)

* note the balloon of the coating of Computer-Assisted Design, Manufacture And Test some batches in some research, the representative of the data that present is from two kinds of researchs with from the data of two batches.Therefore, in a research and one batch that also lifts at upper tabular present some data again (namely in the two, from the balloon test in both research 1 and research 2 of coating manufacturing batch 1, therefore, present in the group that result studies 1, F3 research 2 and F3 first batch at above F3).

About the rabbit tremulous pulse mentioned in this embodiment and blood testing, the observation of following summary can be carried out.72 hours places of what its preparation in office, preparation 15 has maximum medicine and retains.Preparation 3 is left 3.9+/-3.4 ng/mg (combinations of two batches) at the sirolimus of 72 hours, and balloon expands latter five minutes in the artery, and 3.2 % retain in the artery from the medicine (combinations of two batches) of balloon release.Preparation 13B is left 0.9+/-1.7 ng/mg at the sirolimus of 72 hours, and balloon expands latter five minutes in the artery, and 3.8 % retain in the artery from the medicine of balloon release.Preparation 15 is left 46.5+/-46.1 ng/mg at the sirolimus of 72 hours, and balloon expands latter five minutes in the artery, and 5.3 % retain in the artery from the medicine of balloon release.

Discovery is in addition as follows, and this proves for some preparation, the sirolimus total amount of the relatively each tremulous pulse of tissue concentration.In the tissue of the specified quantitative gathered in the crops in postmortem program, sirolimus organizes level to replace concentration removing experimental variable as absolute magnitude.

* the overflow value at 72 hours total μ g of 137 ng/mg or 4.99 is got rid of.

In some embodiments of method provided herein, coating or device, coating comprises the activating agent of 10:1 ratio: binding agent, and wherein activating agent comprises sirolimus, and wherein binding agent comprises poly arginine.In some embodiments, the average-size of sirolimus is 1.5 μm or 2.5 μm.In some embodiments, poly arginine mean molecule quantity is 70kDa.In some embodiments, poly arginine mean molecule quantity is 5-15kDa.In some embodiments, eSTAT coating process is used, together with being deposited on balloon with binding agent by activating agent.In some embodiments, on balloon before deposition, by activating agent and binding agent lyophilizing.In some embodiments, make balloon inflation after 72 hours in the artery, in arterial tissue, find the activating agent at least about 2 ng/mg.In some embodiments, make balloon inflation after 72 hours in the artery, in arterial tissue, find the activating agent at least about 3 ng/mg.In some embodiments, make balloon inflation after 72 hours in the artery, in arterial tissue, find the activating agent at least about 5 ng/mg.In some embodiments, make balloon inflation after 72 hours in the artery, in arterial tissue, find the activating agent at least about 10 ng/mg.In some embodiments, make balloon inflation after 72 hours in the artery, in arterial tissue, find the activating agent at least about 20 ng/mg.In some embodiments, make balloon inflation after 72 hours in the artery, in arterial tissue, find the activating agent at least about 30 ng/mg.In some embodiments, make balloon inflation after 72 hours in the artery, in arterial tissue, find the activating agent at least about 40 ng/mg.

In some embodiments of method provided herein, coating or device, the intra-arterial that in-vivo measurement is included in pig makes balloon inflation about 1 minute, and wherein evaluated the remaining coating on balloon making balloon inflation measure after about five minutes in the artery by UV-Vis, measure the amount being transferred to the activating agent of tremulous pulse.In some embodiments of method provided herein, coating or device, the intra-arterial that in-vivo measurement is included in pig makes balloon inflation about 1 minute, and wherein use standard method described herein and/or well known by persons skilled in the art, extract tremulous pulse after about five minutes by making balloon inflation in the artery and in the tremulous pulse extracted, measure the amount of medicine, measuring the amount being transferred to the activating agent of tremulous pulse.In some embodiments of method provided herein, coating or device, the intra-arterial that in-vivo measurement is included in rabbit makes balloon inflation about 1 minute, and wherein evaluated the remaining coating on balloon making balloon inflation measure after about five minutes in the artery by UV-Vis, measure the amount being transferred to the activating agent of tremulous pulse.In some embodiments of method provided herein, coating or device, the intra-arterial that in-vivo measurement is included in rabbit makes balloon inflation about 1 minute, and wherein use standard method described herein and/or well known by persons skilled in the art, extract tremulous pulse after about five minutes by making balloon inflation in the artery and in the tremulous pulse extracted, measure the amount of medicine, measuring the amount being transferred to the activating agent of tremulous pulse.

There is provided herein a kind of method forming coating on medical treatment device, described method comprises use RESS process deposited polymer on medical treatment device, make binding agent and activating agent mixing, to produce activating agent-binder combination, freeze drying activity agent-binder combination, use eSTAT process, position activity agent-binder combination on medical treatment device.In some embodiments, binding agent comprises surfactant.

Pharmacokinetic in pig model:

According to said procedure, painting preparation 3 (F3) on the balloon exchanging (Rx) conduit at 3.0 × 17 Ghost fast, is delivered to the crown of them and mammary arteries in pig.By sacrifice of animal, extract arterial tissue at some time point.Be determined at the amount of the medicine found in coronary artery arterial tissue, organize statement with ng medicine (sirolimus)/mg, and state with normalized form, that is, normalized/mg tissue, and use microgram (μ g) to state in the following table.

time point	tremulous pulse sirolimus concentration (ng/mg)	sD	total sirolimus (μ g) of each tremulous pulse	sD
					1st day: coronary artery (n=5)	5.528	4.806	0.3647	0.3056
3rd day: coronary artery (n=6)	2.559	2.927	0.1436	0.1402
					7th day: coronary artery (n=5)	1.141	1.324	0.0948	0.1375
14th day: coronary artery (n=5)	0.764	0.858	0.0645	0.0940
					30th day: coronary artery (n=5)	0.038	0.085	0.0013	0.0029.

Be determined at the amount of the medicine found in mammary arteries tissue, organize statement with ng medicine (sirolimus)/mg, and state with normalized form, that is, normalized/mg tissue, and use microgram (μ g) to state in the following table.

Time point	Tremulous pulse sirolimus concentration (ng/mg)	SD	Total sirolimus (μ g) of each tremulous pulse	SD
					1st day: mammary gland (n=5)	2.722	2.931	0.1303	0.1285
3rd day: mammary gland (n=4)	0.243	0.386	0.0129	0.0200
					7th day: mammary gland (n=9)	0.277	0.648	0.0100	0.0225
14th day: mammary gland (n=4)	0.105	0.066	0.0058	0.0037
					30th day: mammary gland (n=9)	0.030	0.090	0.0014	0.0043

Implement the contrast that the artery medicine in rabbit between relative pig model retains, use above-mentioned F3 preparation.Contrast instruction, at the 1st day, the rabbit iliac artery concentration of sirolimus was 25.20+/-20.20, in ng sirolimus/mg tissue, maybe when passing through the amount normalization of tissue in sample (n=7-10), 0.901 μ g+/-0.684 μ g.The time point identical at the 1st day, the porcine coronary concentration of sirolimus is 5.528+/-4.806, in ng sirolimus/mg tissue, maybe when passing through the amount normalization of tissue in sample (n=5-6), 0.365 μ g+/-0.306 μ g.At the 3rd day, the rabbit iliac artery concentration of sirolimus was 4.66+/-3.65, in ng sirolimus/mg tissue, maybe when passing through the amount normalization organized in the sample to which, and 0.319 μ g+/-0.338 μ g.The time point identical at the 3rd day, the porcine coronary concentration of sirolimus is 2.559+/-2.927, in ng sirolimus/mg tissue, maybe when passing through the amount normalization organized in the sample to which, 0.144 μ g+/-0.144 μ g.

Using standard elution method, standing eluting test by selecting the some preparations being used for test in 72 hours in rabbit ilium model.Fig. 1 indicates for preparation F3, F5 and F7, at different time points, from the average percentage of the sirolimus of balloon eluting.The 0th day time, F5 was the highest percent eluting, was about 60%, and at the 0th day, F3 eluting was next the maximum data point, be about 45% eluting, and at whole all time points, F7 was the minimum rate of accumulation, is about 30% eluting at the 0th day.The line of F5 is the top line of figure, and in the three kinds of preparations indicated in the drawings, eluting is the fastest, and F3 is the intermediate line of figure, and F7 eluting is the slowest, reaches 100% eluting the about the 13rd talent.

Through following one of at least, coating can in therapentic part release bioactive agent: about 3 days, about 5 days, about 1 week, about 1.5 weeks, about 2 weeks, about 14 days, about 3 weeks, about 21 days, about 4 weeks, about 28 days, about 1 month, about 1.5 months, about 2 months, at least about 3 days, at least about 5 days, at least about 1 week, at least about 1.5 weeks, at least about 2 weeks, at least about 14 days, at least about 3 weeks, at least about 21 days, at least about 4 weeks, at least about 28 days, at least about 1 month, at least about 1.5 months, at least about 2 months, about 7-about 14 days, about 14-about 21 days, about 14-about 28 days, about 21-about 28 days and about 7-about 28 days.

There is provided herein a kind of medical treatment device of coating, described device comprises: for the bioactive agent delivery of encapsulating being delivered to the medical treatment device of therapentic part; With the coating on the medical treatment device of activating agent comprising encapsulating, the activating agent wherein encapsulated comprises the activating agent encapsulated in the polymer, and the activating agent wherein encapsulated has positive surface charge.

There is provided herein a kind of medical treatment device of coating, described device comprises: for the bioactive agent delivery of encapsulating being delivered to the medical treatment device of therapentic part; With the coating on the medical treatment device of activating agent comprising encapsulating, the activating agent wherein encapsulated comprises the polymer encapsulating activating agent at least partially, and the activating agent wherein encapsulated has positive surface charge.

In some embodiments, activating agent is not exclusively encapsulated.Activating agent (or its part) does not need completely around with by polymeric encapsulate.In some embodiments, at least 10% activating agent surface area encapsulating in the polymer.In some embodiments, at least 20% activating agent surface area encapsulating in the polymer.In some embodiments, at least 25% activating agent surface area encapsulating in the polymer.In some embodiments, at least 30% activating agent surface area encapsulating in the polymer.In some embodiments, at least 40% activating agent surface area encapsulating in the polymer.In some embodiments, at least 50% activating agent surface area encapsulating in the polymer.In some embodiments, at least 60% activating agent surface area encapsulating in the polymer.In some embodiments, at least 70% activating agent surface area encapsulating in the polymer.In some embodiments, at least 75% activating agent surface area encapsulating in the polymer.In some embodiments, at least 80% activating agent surface area encapsulating in the polymer.In some embodiments, at least 90% activating agent surface area encapsulating in the polymer.In some embodiments, at least 95% activating agent surface area encapsulating in the polymer.In some embodiments, below one of at least: the surface area of the activating agent of at least 5% by polymer at least partly around, the surface area of the activating agent of at least 10% by polymer at least partly around, the surface area of the activating agent of at least 15% by polymer at least partly around, the surface area of the activating agent of at least 20% by polymer at least partly around, the surface area of the activating agent of at least 25% by polymer at least partly around, the surface area of the activating agent of at least 30% by polymer at least partly around, the surface area of the activating agent of at least 40% by polymer at least partly around, the surface area of the activating agent of at least 50% by polymer at least partly around, the surface area of the activating agent of at least 60% by polymer at least partly around, the surface area of the activating agent of at least 70% by polymer at least partly around, the surface area of the activating agent of at least 75% by polymer at least partly around, the surface area of the activating agent of at least 80% by polymer at least partly around, the surface area of the activating agent of at least 90% by polymer at least partly around with at least 95% activating agent surface area by polymer at least partly around.

There is provided herein a kind of coating of medical treatment device of the activating agent for comprising encapsulating, described activating agent comprises the activating agent encapsulated in the polymer, the activating agent wherein encapsulated has positive surface charge, and wherein warp was at least about 1 day, and bioactive agent delivery is delivered to therapentic part by coating.

There is provided herein a kind of method forming coating on medical treatment device, described method comprises the activating agent that providing package contains the encapsulating of polymer and activating agent, and the activating agent wherein encapsulated has positive surface charge, and on medical treatment device, deposit the activating agent of encapsulating.In some embodiments, warp was at least about 1 day, and bioactive agent delivery is delivered to therapentic part by coating.

There is provided herein a kind of method forming coating on medical treatment device, described method comprises the activating agent that providing package contains the encapsulating of the polymer encapsulating activating agent at least partially at least partly, the activating agent wherein encapsulated has positive surface charge, and on medical treatment device, deposit the activating agent of encapsulating.In some embodiments, warp was at least about 1 day, and bioactive agent delivery is delivered to therapentic part by coating.

There is provided herein a kind of medical treatment device of coating, described device comprises: for bioactive agent delivery being delivered to the medical treatment device of therapentic part; With the coating on the device comprising activating agent, the medical treatment device be wherein coated with coating will be delivered to therapentic part at least partially, through at least about 1 day, and this part release bioactive agent in therapentic part.

There is provided herein a kind of coating of the medical treatment device for comprising activating agent, wherein warp was at least about 1 day, and coating is sent in therapentic part.

There is provided herein a kind of method using activating agent to form coating on medical treatment device, described method comprises use eSTAT process, position activity agent on medical treatment device.

In some embodiments of device provided herein, coating and/or method, polymer comprises PLGA.PLGA can have following one of at least: MW is for about 30KDa and Mn be about 15KDa, and Mn is about 10KDa-about 25 Kda and MW is about 40KDa for about 15 KDa-.

In some embodiments of method provided herein and/or device, coating comprises can the polymer of bio-absorbable.In some embodiments, comprise can the polymer of bio-absorbable for activating agent.In some embodiments, can the polymer of bio-absorbable comprise following one of at least: polylactide (PLA); PLGA (PLGA); Condensing model; Poe; Poly-(N-(2-hydroxypropyl) Methacrylamide); DLPLA-poly-(dl-lactide); LPLA-poly-(l-lactide); PGA-PGA; PDO-poly-(dioxanone); PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester copolymer; PGA-LPLA-l-PLGA; PGA-DLPLA-dl-PLGA; LPLA-DLPLA-l-lactide-dl-lactide copolymer; With PDO-PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester-dioxanone terpolymer and combination, copolymer and derivant.In some embodiments, the polymer of bio-absorbable the polymer based on PLGA of 1%-95% glycolic content can be comprised.

In some embodiments of method provided herein and/or device, polymer comprise following at least one: polycarboxylic acids, cellulosic polymer, protein, polypeptide, polyvinyl pyrrolidone, maleic anhydride polymer, polyamide, polyvinyl alcohol, poly(ethylene oxide), glucosaminoglycan, polysaccharide, polyester, aliphatic polyester, polyurethane, polystyrene, copolymer, silicone, containing silicone polymer, poly-alkylsiloxane, poe, condensing model, the copolymer of vinyl monomer, Merlon, polyethylene, polypropytenes, polylactic acid, polylactide, polyglycolic acid, PGA, PLGA, polycaprolactone, poly-(6-caprolactone), polyhydroxybutyrate valerate, polyacrylamide, polyethers, dispersions of polyurethanes, polyacrylate, acrylic latex dispersions, polyacrylic acid, polyalkyl methacrylate, alkene-vinyl acetate copolymer, polyene, aliphatic polycarbonate, polyhydroxyalkanoatefrom, poly-four haloalkene, poly (phosphasones), poly-four haloalkene, poly (phosphasones) and composition thereof, combination and copolymer.Polymer of the present invention can be natural or synthesis origin, comprise gelatin, chitosan, dextrin, cyclodextrin, poly-(ammonia ester), poly-(siloxanes) or silicone, poly-(acrylate) be poly-(methyl methacrylate) such as, poly-(butyl methacrylate) and poly-(2-hydroxyethyl methacrylate), poly-(vinyl alcohol), poly-(alkene) is poly-(ethylene) such as, poly-(isoprene), halogenated polymer such as poly-(tetrafluoroethene) and derivant and copolymers are as usually used as those of Teflon (R) production marketing, poly-(vinylidene fluoride), poly-(vinyl acetate), PVP, poly-(acrylic acid), polyacrylamide, vinyl-vinyl acetate copolymer, PEG, poly-(propylene glycol), poly-(methacrylic acid), etc..Suitable polymer also comprises absorbable and/or can resorbent polymer, comprise following, following combination, copolymer and derivant: polylactide (PLA), PGA (PGA), PLGA (PLGA), condensing model, poe, poly-(N-(2-hydroxypropyl) Methacrylamide), poly-(l-agedoite), comprise derivant DLPLA-poly-(dl-lactide); LPLA-poly-(l-lactide); PDO-poly-(dioxanone); PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester copolymer; PGA-LPLA-l-PLGA; PGA-DLPLA-dl-PLGA; LPLA-DLPLA-l-lactide-dl-lactide copolymer; With PDO-PGA-TMC-Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester-dioxanone terpolymer and combination thereof.

In some embodiments of method provided herein and/or device, the dry modulus of polymer is 3,000-12,000 KPa.In some embodiments, after the implantation, polymer energy deliquescing.In some embodiments, after the implantation, by hydration, degraded or the combination by hydration and degraded, the deliquescing of polymer energy.In some embodiments, when getting involved the hydrolysis of position due to polymer, polymer is being suitable for from matrix transfer, free and/or dissociation.

In some embodiments of method provided herein and/or device, can bio-absorbable polymer can following at least again and again absorb: about 1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about 180 days, about 6 months, about 9 months, about 1 year, about 1-about 2 days, about 1-about 5 days, about 1-about 2 weeks, about 2-about 4 weeks, about 45-about 60 days, about 45-about 90 days, about 30-about 90 days, about 60-about 90 days, about 90-about 180 days, about 60-about 180 days, about 180-about 365 days, about 6 months-Yue 9 months, about 9 months-Yue 12 months, about 9 months-Yue 15 months and about 1 year-Yue 2 years.

In some embodiments of method provided herein and/or device, coating comprises microstructure.In some embodiments, activating agent granule chelating or be encapsulated in microstructure.In some embodiments, microstructure comprises microchannel, micropore and/or microcavity.In some embodiments, microstructure is selected to discharge lastingly to allow activating agent.In some embodiments, select microstructure to allow activating agent controlled release.

In some embodiments of device provided herein, coating and/or method, coating comprises positive surface charge.Reducible 20 mV-of positive surface charge are about 40mV.Positive surface charge can be following one of at least: at least about 1 mV, exceed about 1 mV, at least about 5 mV, at least about 10 mV, about 10 mV-about 50 mV, about 20 mV-about 50 mV, about 10 mV-about 40 mV, about 30 mV-about 40 mV, about 20 mV-about 30 mV and about 25 mV-about 35 mV.

In some embodiments of device provided herein, coating and/or method, in the activating agent of encapsulating, the w/w percent of activating agent is about 5%.In some embodiments of device provided herein, coating and/or method, in the activating agent of encapsulating, the w/w percent of activating agent is about 10-25%.

In some embodiments, the activating agent of encapsulating comprises the polymer encapsulating activating agent at least partially at least partly, and the activating agent wherein encapsulated has positive surface charge.In some embodiments, activating agent is not exclusively encapsulated.Activating agent (or its part) does not need completely around with by polymeric encapsulate.In some embodiments, at least 10% activating agent surface area encapsulating in the polymer.In some embodiments, at least 20% activating agent surface area encapsulating in the polymer.In some embodiments, at least 25% activating agent surface area encapsulating in the polymer.In some embodiments, at least 30% activating agent surface area encapsulating in the polymer.In some embodiments, at least 40% activating agent surface area encapsulating in the polymer.In some embodiments, at least 50% activating agent surface area encapsulating in the polymer.In some embodiments, at least 60% activating agent surface area encapsulating in the polymer.In some embodiments, at least 70% activating agent surface area encapsulating in the polymer.In some embodiments, at least 75% activating agent surface area encapsulating in the polymer.In some embodiments, at least 80% activating agent surface area encapsulating in the polymer.In some embodiments, at least 90% activating agent surface area encapsulating in the polymer.In some embodiments, at least 95% activating agent surface area encapsulating in the polymer.In some embodiments, below one of at least: the surface area of the activating agent of at least 5% by polymer at least partly around, the surface area of the activating agent of at least 10% by polymer at least partly around, the surface area of the activating agent of at least 15% by polymer at least partly around, the surface area of the activating agent of at least 20% by polymer at least partly around, the surface area of the activating agent of at least 25% by polymer at least partly around, the surface area of the activating agent of at least 30% by polymer at least partly around, the surface area of the activating agent of at least 40% by polymer at least partly around, the surface area of the activating agent of at least 50% by polymer at least partly around, the surface area of the activating agent of at least 60% by polymer at least partly around, the surface area of the activating agent of at least 70% by polymer at least partly around, the surface area of the activating agent of at least 75% by polymer at least partly around, the surface area of the activating agent of at least 80% by polymer at least partly around, the surface area of the activating agent of at least 90% by polymer at least partly around with at least 95% activating agent surface area by polymer at least partly around.

In some embodiments of device provided herein, coating and/or method, the activating agent encapsulated at least partially is nano-particle.The activating agent encapsulated at least partially can be following one of at least: spherical form, disc-shape, hemispherical shape, cylinder form, cone shape, nanometer reef shape, nanometer box shape, bunch shape, nanotube shape, palpiform shape, rod shape, fiber shape, cup-shape, jack shape, hexagonal shape, elliptical shape, oblate elliptical shape, the elliptical shape of prolate, annular shape, spherical form, Mexico's folder cake sample shape, bullet shape, drum, lens shape, pod membrane shape, pulley shape, round disk shape, rectangle disc-shape, hexagon disc-shape, flying saucer sample shape, anthelmintic shape, band sample shape and won ton stew sample shape.

In some embodiments of device provided herein, coating and/or method, activating agent comprises macrolide immunosuppressive drug.Activating agent is optional from sirolimus, its prodrug, hydrate, ester, salt, polymorphic, derivant and analog.Part activating agent can be crystal form.

Activating agent on average can be following one of at least: 5 microns at the most, more than 1 micron, 1 micron-5 microns, on average about 1.5 microns and average about 2.5 microns.In some embodiments, control the size of activating agent in the coating, retain with the medicine improved in the artery.For non-limiting example, when sirolimus is as activating agent, the average-size (average diameter) of sirolimus can be following one of at least: 1.5 μm, 2.5 μm, 645nm, 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the median size of its sirolimus be following one of at least: 1.5 μm, 2.5 μm, 645nm, 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the average-size of its sirolimus (average diameter) for following one of at least: about 1.5 μm, about 2.5 μm, about 645nm, about 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and the median size of its sirolimus be following one of at least: about 1.5 μm, about 2.5 μm, about 645nm, about 100-200 nm, another kind of controlled size, or their combination.In some embodiments, the size of activating agent is controlled.Such as, in some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 75% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 50% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 90% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 95% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 98% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, sirolimus is activating agent, and the sirolimus ortho states of at least 99% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.

In some embodiments of device provided herein, coating and/or method, warp was at least about 1 day, and bioactive agent delivery is delivered to therapentic part by coating.At device provided herein, in some embodiments of coating and/or method, through following one of at least, bioactive agent delivery is delivered to therapentic part by coating: about 3 days, about 5 days, about 1 week, about 1.5 weeks, about 2 weeks, about 14 days, about 3 weeks, about 21 days, about 4 weeks, about 28 days, about 1 month, about 1.5 months, about 2 months, at least about 3 days, at least about 5 days, at least about 1 week, at least about 1.5 weeks, at least about 2 weeks, at least about 14 days, at least about 3 weeks, at least about 21 days, at least about 4 weeks, at least about 28 days, at least about 1 month, at least about 1.5 months, at least about 2 months, about 7-about 14 days, about 14-about 21 days, about 14-about 28 days, about 21-about 28 days and about 7-about 28 days.

In some embodiments of device provided herein, coating and/or method, therapentic part is blood vessel wall.In some embodiments of device provided herein, coating and/or method, therapentic part is coronary artery.In some embodiments of device provided herein, coating and/or method, therapentic part is bypass graft.In some embodiments of device provided herein, coating and/or method, therapentic part is the infringement of bifurcated.In some embodiments of device provided herein, coating and/or method, therapentic part is small coronary artery infringement (such as, reference diameter <2.5mm).In some embodiments of device provided herein, coating and/or method, therapentic part is peripheral arterial.In some embodiments of device provided herein, coating and/or method, therapentic part is vein.In some embodiments of device provided herein, coating and/or method, therapentic part is AV graft.In some embodiments of device provided herein, coating and/or method, therapentic part is AV fistula.In some embodiments of device provided herein, coating and/or method, therapentic part is biliary tract.In some embodiments of device provided herein, coating and/or method, therapentic part is bile duct.In some embodiments of device provided herein, coating and/or method, therapentic part is hole.In some embodiments of device provided herein, coating and/or method, therapentic part is vein grafts.

In some embodiments of device provided herein, coating and/or method, arranging the surface of the coating for contact treatment position, coating comprises positive surface charge.

In some embodiments of device provided herein, coating and/or method, the activating agent of encapsulating is micelle.

In some embodiments of device provided herein, coating and/or method, medical treatment device comprises balloon.In some embodiments, medical treatment device is the balloon of ballon catheter.

In some embodiments of device provided herein, coating and/or method, the activating agent of deposition encapsulating comprises use eSTAT process.In some embodiments of device provided herein, coating and/or method, after medical treatment device deposits the activating agent of encapsulating, medical treatment device deposits the second polymer.

Method provided herein, coating or and/or device some embodiments in, on matrix, form coating by a kind of process, described process comprises by RESS, e-RESS, e-SEDS or e-DPC process, deposited polymer and/or activating agent.In some embodiments of method provided herein and/or device, wherein on matrix, form coating by a kind of process, described process comprise following one of at least: by RESS, e-RESS, e-SEDS or e-DPC process deposited polymer, with by e-RESS, e-SEDS, eSTAT or e-DPC process deposition medicament.In some embodiments of method provided herein and/or device, on matrix, coating is formed by a kind of process, described process comprise following one of at least: by RESS, e-RESS, e-SEDS or e-DPC process deposited polymer, with by the agent of eSTAT, e-RESS, e-SEDS or e-DPC process position activity.In some embodiments, before the expanding unit of intervention position, the adhesion that the process forming coating provides coating and matrix to improve, and promote in intervention position coating from matrix dissociation.In some embodiments, form coating by a kind of process on matrix, described process comprises by the agent of eSTAT, e-RESS, e-SEDS or e-DPC process position activity, and does not make matrix electrically charged.In some embodiments, form coating by a kind of process on matrix, described process comprises by e-RESS, e-SEDS or e-DPC process at substrate deposit activating agent, and between matrix and the coating apparatus for deposited coatings, does not produce current potential.

In some embodiments of device provided herein, coating and/or method, the second polymer comprises PLGA.PLGA can have following one of at least: MW is for about 30KDa and Mn be about 15KDa, and Mn is about 10KDa-about 25 KDa and MW is about 40KDa for about 15 KDa-.Medical treatment device deposits the second polymer and can use at least one in RESS coating process, eSTAT coating process, dip coating process and spraying process.

In some embodiments of method provided herein, coating and/or device, get involved position in the health of experimenter or on the health of experimenter.In some embodiments, getting involved position is blood vessel wall.In some embodiments, getting involved position is non-vascular wall of the lumen.In some embodiments, getting involved position is vessel lumen wall.In some embodiments of method provided herein and/or device, getting involved position is the wall of bodily cavity.In some embodiments, bodily cavity is the result of lumpectomy.In some embodiments, getting involved position is the position of inserting at experimenter's inner sleeve.In some embodiments of method provided herein and/or device, intervention position is Dou Bi.In some embodiments, getting involved position is Dou Qiangbi.In some embodiments, activating agent comprises corticosteroid.

In some embodiments of method provided herein, coating and/or device, coating can have following one of at least: postpone to cure, delay to cure and prevent to cure.In some embodiments, coating can have following one of at least: postpone, delay and prevent the inflammatory stage of curing.In some embodiments, coating can have following one of at least: postpone, delay and prevent the multiplicative stage of curing.In some embodiments, coating can have following one of at least: postpone, delay and prevent the suppuration stage of curing.In some embodiments, coating can have following one of at least: postpone, delay and prevent the remodelling phase of curing.In some embodiments, activating agent comprises anti-angiogenic agent.

There is provided herein a kind of method, described method comprises provides medical treatment device, wherein said medical treatment device comprises matrix and the coating on matrix at least partially, and its floating coat comprises multiple layer, wherein at least one deck comprises the morphologic medicament for the treatment of expectation, and after use stimulation stimulates coating, coating will be transferred to intervention position from matrix at least partially.

Other compound that sirolimus (or in addition) can be replaced to use, comprises for non-limiting example: FKBP12 bonding (nM) is for 0.4-2.3 nM and antiproliferative effect (nM) sirolimus that is 0.1-3.5 nM; FKBP12 bonding (nM) is for 1.8-2.6 nM and antiproliferative effect (nM) everolimus that is 0.9-3.6 nM; FKBP12 bonding (nM) is for 2.0-3.2 nM and antiproliferative effect (nM) Zotarolimus that is 0.2-2.7 nM; The Biolimus of antiproliferative effect (nM) about 10 nM; The Temsirolimus that FKBP12 bonding (nM) is roughly the same with sirolimus with antiproliferative effect (nM); FKBP12 bonding (nM) is for 0.2-0.4 nM and the tacrolimus of antiproliferative effect (nM) about 350 nM; FKBP12 bonding (nM) is about 1.2 nM and the pimecrolimus of antiproliferative effect (nM) about 1 μM.

The compound candidate that sirolimus (or in addition) can be replaced to use comprises enough ineffective in the medicine effectively sent from drug stent platform, when sending from the balloon of coating, may more effectively (if medicine height lipotropy), for non-limiting example: comprise Dipyradamole, cerivastatin, troglitazone and/or cilostazol.Dipyradamole can be the suitable medicine used in the coating of balloon, such as, because it suppresses VSMC (vascular smooth muscle cell) propagation, for antiinflammatory, improve endothelial function and provide local to discharge t-PA (tissue plasminogen activator).Cerivastatin can be the suitable medicine used in the coating of balloon, such as, because it suppresses VSMC propagation, for antiinflammatory, improve endothelial function, and the speckle of Absorbable organic halogens rapid wear.Troglitazone can be the suitable medicine used in the coating of balloon, such as, because it suppresses VSMC propagation, for antiinflammatory, improve endothelial function and vascular lipid can be provided to reduce.Cilostazol can be the suitable medicine used in the coating of balloon, such as, because it suppresses VSMC propagation, Anhydroalkannin, improve endothelial function and discharge for vasodilation and/or raising NO (nitric oxide) and/or produce NO.

Can be suitable for use on medicine balloon as thus the other medicines of coating of release comprise following: prevent the medicine that elasticity is rebounded, such as smooth muscle cell relaxation agent and/or the medicament in conjunction with elastin laminin; The medicine injured for preventing Reperfu-sion, such as ANP, atorvastatin, erythropoietin and/or glucagon-like peptide 1; For stimulating the medicine of subsidiary blood flow, such as vasodilation and/or somatomedin (GF) and GF activator.The balloon of coated with drug can be used for reducing extreme and periphery instruction, such as, in PTA (Percutaneous Transluminal Angioplasty) neutralization and exposed holder combination, when stent restenosis, after atherectomy.The balloon of coated with drug is particularly useful for some coronary artery indication, such as, after stent restenosis, in vasculum angioplasty situation, combines in bifurcated and with exposed metal rack.Other application is included in AV fistula and graft (dialysis), in nasal sinuses, neural with blood vessel vascular, in Renal vascular or application, in anti-cancer applications with in urology application.A) fistula and graft (dialysis) fistula and graft (dialysis) fistula and graft (dialysis).

In some embodiments, the activating agent of at least 3% is discharged in apparatus body to tremulous pulse.In some embodiments, the activating agent of at least 5% is discharged in apparatus body to tremulous pulse.In some embodiments, the activating agent of release at least 10% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 5% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 7% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 10% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 15% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 20% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 25% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 30% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 40% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 2%-50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 5%-50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-30% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-25% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-20% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-15% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 1%-15% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 1%-10% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-10% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 1%-5% in apparatus body.

Depend on embodiment, " when after inflation " used herein refers to after treatment site removing device as far as possible reasonably fast.This can comprise timing, such as distance treatment site removing device about 1 minute, about 5 minutes, in distance treatment site removing device 1-15 minute, in distance treatment site removing device 1-15 minute, in distance treatment site removing device 1-20 minute, in distance treatment site removing device 1 minute-1 hour, in distance treatment site removing device 1 minute-2 hours and/or in distance treatment site removing device 1 minute-3 hours.

embodiment 5: send rapamycin from the turnover balloon of coating

There is provided herein a kind of device, this device comprises turnover balloon, coating on the side, nearly chamber of turnover balloon, and its floating coat comprises activating agent and binding agent.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 3% in apparatus body.

In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 5% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 7% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 10% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 15% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 20% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 25% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 30% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 40% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 2%-50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 5%-50% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-30% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-25% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-20% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-15% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 1%-15% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 1%-10% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 3%-10% in apparatus body.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release 1%-5% in apparatus body.

The turnover balloon of embodiment (it also and/or can alternatively be called turnover balloon) includes but not limited to the United States Patent (USP) 6039721 of December in 1997 submission on the 3rd; With describe in the United States Patent (USP) 4606347 that on August 8th, 1985 submits to those, these patents are attached to herein by reference and in full.In some embodiments; before inversion; the surface, nearly chamber of coating balloon; and once coating; balloon is overturn, makes in tracking or follow the tracks of and to contact with blood vessel wall or during the two, to protect the surface, nearly chamber of balloon to avoid blood flow; until ballon catheter is arranged near therapentic part, usually just contiguous with this position." side, nearly chamber " used herein or " surface, nearly chamber " refers to the cated a part of balloon of tool on it, and is intended to coating (medicament) to be delivered to therapentic part or position, that is, when therapentic part is vascular, and the tube chamber of vascular.Subsequently balloon is reversed, make in therapentic part, arrange surface, nearly chamber.

In the embodiment that balloon overturns in conduit wherein, utilize the balloon from the pressure of gas charge and discharge device (indeflator) or the non-inversion of another kind of form, conduit can be released, such as, for non-limiting example, by balloon itself by the far-end moving balloon in distally, in therapentic part, substantially untie balloon, make the part of the coating of balloon adjacent with therapentic part.In some embodiment that balloon overturns on the outside of conduit wherein, the far-end of balloon can be moved from the similar movement of gas charge and discharge device and/or pressure in distally, thus near therapentic part, untie the side of the coating of balloon.In some embodiments, balloon can partly reverse, and makes can control to treat length.Make balloon inflation subsequently, make the nearly chamber surface contact that is coated with and/or expansion therapentic part, thus by coating or one partial delivery to therapentic part.

Any device described herein, coating and/or method can combine with the balloon of turning type, to reduce and/or substantially to eliminate the mode delivery coating of coating loss, device is located (namely at therapentic part, device is delivered to therapentic part) before, owing to following the tracks of and/or blood flow and/or other is at coating loss in transit.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 1% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 3% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 5% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 10% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 15% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 20% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 25% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 30% removes from balloon at the most.

embodiment 6: send rapamycin from the balloon of the coating having sheath

There is provided herein a kind of device, this device comprises balloon, the coating on the side, nearly chamber of balloon and the sheath on balloon, and its floating coat comprises activating agent and binding agent.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 3% in apparatus body.In some embodiments, sheath regracting.In some embodiments, sheath regracting, to be exposed to therapentic part by coating.In some embodiments, sheath covers the balloon of coating, until balloon arrives therapentic part.In some embodiments, once the balloon of coating is arranged near therapentic part and/or in treatment site, sheath regracting.In some embodiments, sheath covers the balloon of coating, until the contiguous therapentic part of balloon.In some embodiments, sheath covers the balloon of coating, until balloon is in therapentic part distally.In some embodiments, sheath covers the balloon of coating, until balloon is in therapentic part.In some embodiments, after coating (or its part) has been released into tremulous pulse, after balloon venting, sheath can move on balloon, and can remove conduit, makes to be capped at the balloon of coating during experimenter's removing.In some embodiments, after coating (or its part) has been released into tremulous pulse, after balloon venting, sheath can remain retracted mode, and can remove conduit, makes to be exposed at the balloon of coating during experimenter's removing to send track.

Any device described herein, coating and/or method can combine with sheath, to reduce and/or substantially to eliminate the mode delivery coating of coating loss, device is located (namely at therapentic part, device is delivered to therapentic part) before, owing to following the tracks of and/or blood flow and/or other is at coating loss in transit.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 1% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 3% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 5% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 10% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 15% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 20% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 25% removes from balloon at the most.In some embodiments, owing to following the tracks of the balloon of coating to therapentic part, the coating of 30% removes from balloon at the most.

embodiment 7: send rapamycin from the balloon of the coating with closer

There is provided herein a kind of device, this device comprises balloon, coating on balloon and closer, and its floating coat comprises activating agent and binding agent.In some embodiments, closer is used for during coating is exposed to therapentic part for arranging, and blocks the flowing closer of body fluid (such as, blood) in the flowing of therapentic part.In some embodiments, after making balloon inflation, to the activating agent of tremulous pulse release at least 3% in apparatus body.In some embodiments, closer comprises second balloon of closed blood in the flowing of therapentic part.In some embodiments, balloon comprises closer, makes balloon have two parts: the part of flowing closer and coating, and the closer that wherein flows closes the flowing of blood at therapentic part.In some embodiments, balloon is binode, is wherein coated with distal node, and wherein adjacent node is closer.In some embodiments, closer be positioned at its on the cated balloon of tool and/or its part contiguous.In some embodiments, balloon is binode, is wherein coated with adjacent node, and wherein distal node is closer.In some embodiments, closer is positioned at away from the cated balloon of tool on it and/or its part.In some embodiments, balloon is the shape of applicable therapentic part, makes the closer part of balloon be suitable shape, with the flowing of closed blood at therapentic part.In some embodiments, near therapentic part, closer meets the shape of area for treatment substantially, thus closes at the blood flow of therapentic part.In some embodiments, balloon only part coating, make the distally and adjacent end one or both of of balloon uncoated, and the distally of balloon and/or adjacent end is closer.

There is provided herein a kind of device, this device comprises the first balloon, coating on the first balloon and can close second balloon of blood in the flowing of therapentic part at therapentic part during the first balloon expansion.In some embodiments, closer is the second balloon, and it is not the cated balloon of tool on it.In some embodiments, closer be positioned at its on the cated balloon of tool and/or its part contiguous.In some embodiments, closer is positioned at away from the cated balloon of tool on it and/or its part.

There is provided herein a kind of device, this device comprises the first balloon, coating on the first balloon and is arranged so that the second balloon that the second balloon expanded before the first balloon expansion.In some embodiments, before a part of balloon expansion, closer closes the flowing of blood at therapentic part.In some embodiments, closer be positioned at its on the cated balloon of tool and/or its part contiguous.In some embodiments, closer is positioned at away from the cated balloon of tool on it and/or its part.

In some embodiments, closer is not balloon, but arranges for the closer of closed blood in the another kind of form of the flowing of therapentic part.In some embodiments, deployable and the regracting of closer, to make before making the cated balloon inflation of tool on it it deployable, and balloon inflation and by drug delivery to therapentic part after, by removing balloon or after treatment site removing balloon, closer regracting and removing.

In some embodiments, it has the second coating with closer, has the second medicament and/or polymer that are coated with thereon, as described elsewhere herein, according to any Method and Process described herein.In some embodiments, the second coating comprises binding agent.In some embodiments, the second coating does not comprise binding agent.

embodiment 8: the coating using and do not use shear-mixed to prepare

Production F15 (preparation 15) as described in example 4 in multiple batches, and there is various rapamycin: poly arginine ratio.No matter rapamycin: poly arginine ratio, but instruction F15 comprises PLGA, that is, about 50:50 lactic acid: glycolic, and average-size is sirolimus and the poly arginine 5-15 kDa of 1.5 μm.Sirolimus is crystal form.Following rapamycin is produced for this embodiment: poly arginine ratio: 1:1,5:1,10:1 and 50:1.

In some batches (being commonly referred to F15 batch of 3 1:1,5:1,10:1 or 50:1), the production method of preparation is as described in the diagram.The method of these batches is as follows: in 100ml bottle, 25mg pR hydrochlorate (Aldrich P4663) (herein also referred to as poly arginine) (cas 26982-20-7 is dissolved in 50ml deionized water, 5-15kDa), add the rapamycin (1.5 micron grain sizes, crystal form) (step 46) of 250mg encapsulating.Supersound process (the desk-top ultrasonic cleaner of Branson 1510) reaches 2 hours (step 48).Use the liquid part that pipet makes well suspended and the solid manual separation (step 50) do not suspended.With 10,000 rpm centrifugal about 50ml suspension reaches 30 minutes (ThermoElectronCorp. IEC Multi RF centrifuge) (step 52).Supernatant decanted liquid, does not allow to be deposited into dry (step 54).After centrifugation step 52, there is a certain amount of fraction 64 do not suspended.Add the aqueous solution of pR hydrochlorate concentrate, to produce sirolimus/pR hydrochlorate ratio (step 56) of the encapsulating of expectation.By vibration and 10 minutes supersound process, settling flux deposit.Lyophilizing suspension, to produce the rapamycin/poly arginine powder solid lyophilized products 66 (Flexi-Dry MP) (step 58) of uncongealed encapsulating.This step 2-3 consuming time days to have realized.Using the solid 66 of this lyophilizing, as powder, on the balloon of balloon or PLGA-coating, eSTAT coating is (as described herein, dry-coated) (step 60), to produce the balloon 62 comprising the coating of PLGA, rapamycin and poly arginine, wherein rapamycin is crystal form.

For ratio-forming step, following output ratio: the 95ml masterbatch (combination of " well suspended " part of 4 kinds of From Solution Under Ultrasound Treatments) being estimated as about 5mg/ml solid is divided into 5 parts.Sirolimus for 50:1 ratio: poly arginine, adds 20ml water to Part I 18ml, by its supersound process, with settling flux and lyophilizing, to produce 50.3 mg solid lyophilized products.Sirolimus for 10:1 ratio: poly arginine, dissolves 9 mg poly arginines in 20ml water, joins in Part II 18ml, by its supersound process, with settling flux and lyophilizing, to produce 116.6 mg solid lyophilized products.Sirolimus for 5:1 ratio: poly arginine, dissolves 18mg poly arginine in 20ml water, joins in Part III 18ml, by its supersound process, with settling flux and lyophilizing, to produce 127.4 mg solid lyophilized products.Sirolimus for 1:1 ratio: poly arginine, dissolves 90mg poly arginine in 20ml water, joins in Part IV 18ml, by its supersound process, with settling flux and lyophilizing, to produce 142.4 mg solid lyophilized products.

In some batches (being commonly referred to F15 batch of 4 5:1 or 10:1), there is the rapamycin of 5:1 ratio: the F15 preparation of poly arginine batch and there is the rapamycin of 10:1 ratio: the production method of the F15 preparation of poly arginine batch is as follows.In 20ml bottle, in 25ml deionized water, dissolve 25mg (10:1) or 50 mg (5:1) pR hydrochlorate (Aldrich P4663) (cas 26982-20-7) (5-15kDa) (also referred to as poly arginine).Add 250mg sirolimus (1.5 micron grain sizes, crystal form).Use micro-mixer head adnexa, in laboratory blender (Silverson L4RT), with 10,000 rpm mixes 10 minutes, to form suspension (this mixing stays and seldom or not leaves deposition).Laboratory blender is have the high-shear mixer of impeller for mechanical mixture.Blender is run, to reclaim remaining material (washings) with 25ml pure water.Merge suspension and washings.Lyophilizing suspension, to produce the sirolimus/poly arginine powder (Flexi-Dry MP) of non-agglomeration, its 2-3 consuming time days to have realized.ESTAT coating (as described herein, dry-coated) on the balloon be coated with the solid 66 of this lyophilizing as powder at PLGA, to produce the balloon of the coating comprising PLGA, rapamycin and poly arginine, wherein rapamycin is crystal form.

Also be determined at the amount of the rapamycin found in the balloon of actual coating, and can be used for measuring actual rapamycin: poly arginine ratio (relative with the target ratio that other place of this paper provides).In order to measure the amount of the sirolimus on single balloon, adopt ultraviolet-visible spectrum (UV-Vis).After sintering, from the balloon (removing stylet before cutting) of conduit metal wire cutting coating, leave only about 1/4 " tinsel retain and be connected with balloon.Balloon is placed in the single 5 ml scintillation vial containing 4 ml ethanol or methanol (sirolimus dissolves in ethanol, maximum 50 mg/ml).Supersound process 3 hours, from balloon removing sirolimus.After supersound process, implement UV-Vis.Because sirolimus is triolefin (containing three double bonds), it produces UV absorbance under 3 wavelength: under 277 nm 1 main peak and under 267 nm and 288 nm two less peaks.Uncoated GHOST exchanges nylon balloon and PLGA single supersound process 3 hours in ethanol fast, and display is not disturbed extract to be used for sirolimus to measure.The absorbance deducting sirolimus from the absorbance of balloon uncoated under 277 nm is combined with standard curve, for calculating the balloon for each coating, and the amount of sirolimus.From 12 coatings balloons batch in the standard substance experience UV-Vis of 3 analyze, to obtain batch average (the measuring with μ g) for each balloon sirolimus.UV-Vis analysis also can be used for measuring the existence of polymer (in this embodiment, PLGA) in the coating and/or quantitatively it is measured.There is both poly arginine and rapamycin in the balloon that the UV-Vis test batch both 3 and 4 is disclosed in coating.For batches 3, measure following actual ratio: be about 1.3:1 for batch 3 1:1 (desirable) reality, be about 7.1:1 for batch 3 5:1 (desirable) reality, batch 3 10:1 (desirable) reality is about 14.3:1, is about 43.1:1 for batch 3 50:1 (desirable) reality.Equally, be about 6.1:1 for batch 4 5:1 (desirable) reality.

The balloon deliveries of F15 batches 3 coating are delivered to the tremulous pulse of the animal of rabbit research, reach 72 hours whether to evaluate and to have how many rapamycins to be retained in rabbit iliac artery.The balloon preparation be below coated with is as following table 18.

Table 18

Sirolimus: poly arginine ratio	Sirolimus/balloon (μ g) (n=6) *	Appearance of coat
			1:1	65.37±3.84	Transparent, spotted
5:1	79.02±9.83	Translucent, very thick
			10:1	89.71±5.27	Translucent, very thick
50:1	81.28±4.61	Translucent, very thick

* average sirolimus concentration is analyzed based on the UV-Vis before and sterilizing pleating/folding at balloon.

For this research research design as in table 19 describe.

Table 19

Analyze the sirolimus level of balloon, blood sample and the exposed iliac artery launched.

Measure following result, as shown in table 20,21,22.Maximum reservation is from F15 batch of 3 (1.8 ± 1.2 ng/mg) of 10:1 ratio.End 3 days, sirolimus blood level is lower than 1 ng/ml.

Table 20

F15 ratio	Tremulous pulse sirolimus concentration (ng/mg)	SD	Total sirolimus (μ g) of each tremulous pulse	SD
					F15 1:1 batches 3, n=6	1.52	2.63	0.022	0.035
F15 5:1 batches 3, n=6	0.67	0.53	0.013	0.011
					F15 10:1 batches 3, n=6	1.77	1.18	0.041	0.030
F15 50:1 batches 3, n=6	0.63	0.18	0.010	0.003

Table 21:

F15 ratio	After deployment, the sirolimus concentration (ug) on balloon	The * of the sirolimus %/loss of release
			1:1 batches 3	20.6±9.8 (n=6)	68.9±14.0% (n=6)
5:1 batches 3	37.9±6.3 (n=6)	52.0±7.8% (n=6)
			10:1 batches 3	41.3±7.2 (n=6)	53.7±9.1% (n=6)
50:1 batches 3	45.4±6.9 (n=6)	44.2±8.6% (n=6)

* based on the balloon batch average of sirolimus

The amount of the sirolimus that balloon is coated with is as follows: sirolimus=65.37 ± 3.84 that F15 (1:1, batch 3) is coated with on balloon; Sirolimus=79.02 ± 9.83 that F15 (5:1, batch 3) is coated with on balloon; Sirolimus=89.71 ± 5.27 that F15 (10:1, batch 3) is coated with on balloon; Sirolimus=81.28 ± 4.61 that F15 (50:1, batch 3) is coated with on balloon.

Table 22

F15 ratio	In whole blood sirolimus concentration (ng/mL)	Total sirolimus (μ g) * estimated in blood
			1:1 batches 3	0.29±0.03 (n=3)	0.054±0.01 (n=3)
5:1 batches 3	0.50±0.15 (n=3)	0.096±0.03 (n=3)
			10:1 batches 3	0.43±0.12 (n=3)	0.081±0.02 (n=3)
50:1 batches 3	0.38±0.08 (n=3)	0.064±0.01 (n=3)

* based on 56 mL blood/kg; BQL=is lower than determination limit (0.1 ng/ml)

The balloon deliveries of F15 batches 4 coating are delivered to the tremulous pulse of the animal of rabbit research, reach 72 hours whether to evaluate and to have how many rapamycins to be retained in rabbit iliac artery.

There is provided herein the medical treatment device that a kind of coating comprises balloon at least partially, thus on the balloon comprising activating agent and binding agent, medical treatment device is formed the method for coating, wherein the method comprises: dissolved adhesive is to form binder solution, merge binder solution and activating agent, the binding agent using high-shear mixer mixing to merge and activating agent, formed and comprise the activating agent of the mixing of merging and the suspension of binding agent, lyophilizing suspension, to form the lyophilized products of activating agent and binding agent, use eSTAT process, use the lyophilized products coating balloon of powder type, the activating agent be wherein coated with on balloon comprises the activating agent of crystal form.

In some embodiments, high-shear mixer is mechanical mixer.In some embodiments, mechanical mixer comprises impeller, propeller and/or high speed sawtooth disperser.In some embodiments, mechanical mixer comprises high-pressure pump.In some embodiments, high-shear mixer comprises sonic mixers.In some embodiments, sonic mixers comprises ultrasonoscope.In some embodiments, sonic mixers comprises the ultrasonoscope based on desk-top bath.In some embodiments, sonic mixers comprises ultrasonic mixer.In some embodiments, sonic mixers comprises million sound mixers.

In some embodiments, mechanical mixer comprises high-pressure pump (maximum 40,000 psi (2578 bar)), forces granule in interaction room with the speed of maximum 400 m/s.Interaction room can comprise the microchannel of design.In room, product can be exposed to consistent impact and shearing force, cools subsequently.

High-shear mixer disperses or carries a phase or composition (liquid, solid, gas) in dominant continuous phase (liquid), it typically is immiscible.In some embodiments of the mechanical mixer for high-shear mixer, rotor or impeller are together with fixed part (being called stator) or the array of rotor and stator, for the groove containing solution to be mixed or in pipe, solution passes through this pipe, to produce shearing.High-shear mixer can be used for producing emulsion, suspension, the hydrosol (gas disperseed in a liquid) and pelletized product.

When advancing with different speed relative to adjacent region in a region of fluid, fluid undergoes shear.In some embodiments of the mechanical mixer for high-shear mixer, high-shear mixer uses rotary blade or high speed rotor or a series of such impeller or online rotor, usually provide power by motor, make fluid " work ", produce flowing and shear.In the outer radius of rotor, the tip speed of fluid or speed higher than the speed of the heart in the rotor, and are that this speed difference produces and shears.

Fixed part can with Usage of rotor combine, and be called stator.Stator produces and closely removes gap between rotor and itself, and forms high shearing area when material leaves rotor.The rotor combined and stator are commonly referred to mixing head or generator.Large high shear Rotor-stator mixers can contain multiple generator.

In some embodiments, mechanical mixer comprises interval high-shear mixer.In interval high-shear mixer, component (no matter being immiscible liquid or powder in a liquid) the to be mixed mixing channel from its top feed to the bottom at groove on the rotary shaft containing blender.The material that interval high-shear mixer can process given volume is that about 2 times of the online Rotor-stator mixers of identical rated power are fast; When volume be faster treated to major requirement and the non-restricted quarter time, continue to use such blender.When mixing cohesive solution, some products can be stayed in groove, need clean.But, the design of the interval high-shear mixer of the part that cleaning slot runs as operation can be there is.Some high-shear mixers are designed for dry operation, are limited in clean amount required in groove like this.

In some embodiments, mechanical mixer comprises online high shear Rotor-stator mixers.Generally speaking, this pattern adopts identical rotor and stator in interval high-shear mixer, and installs in the shell with entrance and exit connection.Rotor is driven by sealing subsequently, therefore, causes the behavior of Rotor-stator mixers as centrifugal pumping device.Namely, in online high shear Rotor-stator mixers, rotor-stator array is included in shell, and this shell has entrance at an end and has outlet at another end, and rotor is driven by sealing.Component to be mixed is by the generator array sucking-off in Continuous Flow, whole as centrifugal pumping device.Online high-shear mixer provides more controlled hybird environment, takies less space, and can be used as a part for continuous process.By making product by online high-shear mixer more than once, balance mixing can be realized.Because online blender can be arranged in flowing stream, compared with intermittent structure, mixing can be more controlled, therefore can monitor the quantity of the passage by high shear area.

The online Rotor-stator mixers being equipped with powder induction provides motility, ability and portability to serve multiple mixers of in fact any size.It directly operates and convenience makes equipment utility maximization further, simplifies material processed simultaneously.

When using together with feed hopper with vacuum pump, online shear mixer can be very effective mode to mix powder in liquid stream.Be called high shear powder induction apparatus in addition, these systems have retention process in floor level instead of the advantage using the work of heavy bag on mezzanine.High shear powder induction system also provides the easy interchangeability with multiple groove.

High shear granulator is by online or interval high-shear mixer and the process array that forms of fluidized bed dryer.In granulation process, only need the solid constituent of mixture.Fluid is only used as processing aid.The particle diameter of expectation is down to by high-shear mixer process solid material, subsequently mixture is pumped to the drying bed wherein removing fluid, leaves pelletized product.

In the online blender of super-high shear, by rotor-stator array, in single or multiple passage, there is high shear mixing.Compared with the online Rotor-stator mixers of standard, mixer design makes product stand the shear event of higher shear and larger amt, produces the particle size distribution that exception is narrow.Use ultra-high shear technology, submicron particle diameter is possible.In order to realize this point, machine configuration has the stator of precision machined hole or slit, forces product by hole or slit by rotor.Rotor-stator array can also comprise such frame for movement, and wherein the momentum of fluid changes (such as by forcing it to pass through stator from the side), allows more processing in single path.

High-shear mixer can be used for the correct mixture producing the composition that can not naturally mix.When whole fluid is made up of two or more liquid, final result is emulsion; When being made up of solid and liquid, it is called suspension, and when in whole liquid during gas dispersion, result is the hydrosol.Each class may homogenize or may not homogenize, depends on the amount of input energy.

In order to realize standard mixing, can balance hybrid technology.Qualification target characteristic, makes, once blended product has obtained this characteristic, can not significantly change subsequently, no matter processes how long product.For dispersion, it is balance particle diameter.For emulsion, it is balance drop size.The material measuring the amount-certain volume of the mixing realized needed for balance mixing in groove upset must by the time quantum in high shear area.

In some embodiments, sonic mixers comprises ultrasonoscope.In some embodiments, sonic mixers comprises the desk-top ultrasonoscope based on bath.In some embodiments, sonic mixers comprises ultrasonic mixer.Ultrasonic mixer can adopt following in any one or multiple ultrasonic frequency: at least about 18kHz, at least about 20kHz, be less than 400 kHz, be less than 500 kHz, about 18kHz-is about 400kHz, about 20kHz-about 500 kHz, about 400kHz and at the most about 500 kHz at the most.In some embodiments, sonic mixers comprises million sound mixers.Million sound mixers can adopt following in any one or million multiple acoustic frequencies: at least about 500kHz, at least about 700kHz, at least about 800kHz, be less than about 5MHz, be less than about 4MHz, about 500kHz-is about 5MHz, about 700kHz-is about 4MHz, about 5MHz at the most, at the most about 4MHz, at least about 1MHz and any frequency in MHz scope.

In some embodiments, the ratio of activating agent and binding agent is that 1:1,1:2,1:3,1:4,1:5,1:10,1:20,2:1,3:1,4:1,5:1,10:1,15:1,20:1,3:2,2:3,5:2,5:3,2:5 or 3:5 are as target ratio.In some embodiments, actual activating agent and the ratio of binding agent are +/-10%, the +/-20% of ideal ratio, the +/-25% of ideal ratio or the +/-30% of target ratio of ideal ratio.In some embodiments, the UV-Vis based on medical treatment device tests, and calculates actual ratio.

In some embodiments, when by when being delivered to tremulous pulse in the balloon body of device, the activating agent of at least 3% is transferred to the tissue of tremulous pulse.In some embodiments, the activating agent of at least 5% is transferred to the tissue of tremulous pulse.In some embodiments, the activating agent of at least 10% is transferred to the tissue of tremulous pulse.

In some embodiments, binding agent comprise following one of at least: poly arginine, poly arginine 9-L-pArg, DEAE-dextran (DEAE-cellulose-dextran), DMAB (two (dodecyl) ditallowdimethyl ammonium bromide), PEI (polymine), TAB (four (dodecyl) ammonium bromide) and DMTAB (dimethyl two (myristyl) ammonium bromide).

In some embodiments, the mean molecule quantity of binding agent is controlled.In some embodiments, the size of activating agent is in the coating controlled.

In some embodiments, activating agent is sirolimus, and the average-size of its sirolimus be following one of at least: about 1.5 μm, about 2.5 μm, about 645nm, about 100-200 nm, another kind of controlled size, or their combination.In some embodiments, activating agent is sirolimus, and wherein the sirolimus ortho states of at least 75% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, activating agent is sirolimus, and wherein the sirolimus ortho states of at least 50% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, activating agent is sirolimus, and wherein the sirolimus ortho states of at least 90% is 1.5 μm, 2.5 μm, 645nm, 100-200 nm, or another kind of controlled size.In some embodiments, coating can comprise nano-particle, and nano-particle can comprise activating agent and polymer.

In some embodiments, coating comprises PLGA, and it comprises about 50:50 lactic acid: glycolic.In some embodiments, coating comprises the activating agent of about 10:1 ratio: binding agent, and wherein activating agent comprises sirolimus, and wherein binding agent comprises poly arginine.In some embodiments, the average-size of sirolimus is 1.5 μm or 2.5 μm.In some embodiments, poly arginine mean molecule quantity is 70kDa.In some embodiments, poly arginine mean molecule quantity is 5-15kDa.In some embodiments, on balloon before deposition, by activating agent and binding agent lyophilizing.In some embodiments, make balloon inflation after 72 hours in the artery, the activating agent at least about 2 ng/mg is found in arterial tissue, at least about the activating agent of 3 ng/mg, at least about the activating agent of 5 ng/mg, at least about the activating agent of 10 ng/mg, at least about the activating agent of 20 ng/mg, at least about the activating agent of 30 ng/mg and/or the activating agent at least about 40 ng/mg.

In some embodiments, the intra-arterial that in-vivo measurement is included in pig makes balloon inflation about 1 minute, is evaluated make balloon inflation be determined at remaining coating on balloon after five minutes in the artery by UV-Vis, measures the amount being transferred to the activating agent of tremulous pulse.In some embodiments, the intra-arterial that in-vivo measurement is included in rabbit makes balloon inflation about 1 minute, evaluates five and is determined at remaining coating on balloon, measure the amount being transferred to the activating agent of tremulous pulse by UV-Vis.

In some embodiments, device release is following one of at least: after making balloon inflation in body, the activating agent of at least 5% is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 7% is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 10 % is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 15 % is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 20 % is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 25 % is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 25 % is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 30 % is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 40 % is to tremulous pulse, after making balloon inflation in body, the activating agent of at least 50 % is to tremulous pulse, after making balloon inflation in body, the activating agent of 2%-50% is to tremulous pulse, after making balloon inflation in body, the activating agent of 3%-50% is to tremulous pulse, after making balloon inflation in body, the activating agent of 5%-50% is to tremulous pulse, after making balloon inflation in body, the activating agent of 3%-30% is to tremulous pulse, after making balloon inflation in body, the activating agent of 3%-25% is to tremulous pulse, after making balloon inflation in body, the activating agent of 3%-20% is to tremulous pulse, after making balloon inflation in body, the activating agent of 3%-15% is to tremulous pulse, after making balloon inflation in body, the activating agent of 1%-15% is to tremulous pulse, after making balloon inflation in body, the activating agent of 1%-10% is to tremulous pulse, when make in body the activating agent of 3%-10% after balloon inflation to tremulous pulse and after making balloon inflation in body the activating agent of 1%-5% to tremulous pulse.

In some embodiments, below one of at least: due to the balloon of following the tracks of coating to therapentic part at the most 1% coating remove from balloon, due to follow the tracks of coating balloon to therapentic part at the most 5% coating remove from balloon, due to follow the tracks of coating balloon to therapentic part at the most 10% coating remove from balloon, due to follow the tracks of coating balloon to therapentic part at the most 15% coating remove from balloon, due to follow the tracks of coating balloon to therapentic part at the most 20% coating remove from balloon, due to follow the tracks of coating balloon to therapentic part at the most 25% coating from balloon remove and due to follow the tracks of coating balloon to therapentic part at the most 30% coating remove from balloon.

There is provided herein the device prepared according to any method provided herein and there is feature described herein.

embodiment 9: balloon animal (rabbit) research of sirolimus coating

Painting preparation 3,19,20,21,22,23 on balloon, makes balloon inflation in rabbit iliac artery, 5 minutes after inflation, 72 hours and 14 days, research tremulous pulse.Object is whether the sirolimus of balloon evaluated from the coated with drug with the preparation 3,19,20,21,22 or 23 that it is coated with is retained in rabbit iliac artery maximum 72 hours and 14 days.Preparation, coating composition, the amount (in microgram) of sirolimus of each balloon coating, sample size (n) and the appearance of coat on balloon are described in table 23.Descriptive study general introduction in table 24.

Table 23

* for all preparations, sirolimus: poly arginine ratio is 10:1.

* sirolimus/balloon is based on UV-Vis before and sterilizing pleating/folding at balloon.

Table 24

* only medicine detected at the 3rd day in blood sample, within the 14th day, blood sample is by sent for analysis.

*, based on the artery medicine level of the 3rd day, at time point afterwards, can put to death animal at the 14th day.

As result of study, find preparation 3 and 20 maximum reservation in the artery at 3 days.All the other preparations do not provide high-caliber tremulous pulse to retain.Within 5 minutes, retain result display, compared with F3 (w/PLGA), F19 (not containing PLGA) retains more than about 2 times.Within 3 days, retain result display, F3 with F20 is in identical reservation level (about 4 ng/mg).Exist in all preparations and retain variable.In whole blood, result shows, and end 3 days, sirolimus blood level is lower than 1 ng/ml.Show 70 %-97% sirolimus releases from the drug effects of balloon release, depend on preparation.

In table 25, show tremulous pulse sirolimus retain, as concentration, in ng/mg, or as total sirolimus of each tremulous pulse, in microgram.Whole blood sirolimus concentration is shown in table 26, in ng/mL, and the total sirolimus estimated in blood, in microgram.The determination limit detected for whole blood sirolimus is 0.1 ng/mL.The percent of the sirolimus of balloon sirolimus level (testing on balloon after deployment) and the release calculated or loss is provided in table 27.Batch average respectively based on the sirolimus of each preparation on balloon of the calculating of the percent of the sirolimus of release or loss.

Table 25

Table 26

* based on 56 mL blood/kg

Table 27

* based on the balloon batch average of sirolimus

Produce the preparation 3 of multiple batches, to evaluate the common change of sirolimus size and effect (such as, average-size is the sirolimus of 2.5 microns, and relative average-size is the sirolimus of 1.5 microns).Result presents in table 28, table 29 and table 30.Use the normalized tremulous pulse weight of 0.025 g, by the concentration normalization in table 28.For table 29, batch average respectively based on the sirolimus of each preparation on balloon of the calculating of the percent of the sirolimus of release or loss.The determination limit that whole blood sirolimus detects is 0.1 ng/mL (for table 30).

Table 28

Table 29

* based on the balloon batch average of sirolimus

Table 30

embodiment 10: use PLGA to be coated with rapamycin by spraying dry

In this embodiment, by spray-drying process, rapamycin is coated with PLGA.The mixture of 75 (w/w) % PLGA and 25 (w/w) % rapamycin is dissolved, to form solution in THF.The mixture of other polar non-solute (such as acetonitrile) or polar non-solute also can be used for forming solution.From nozzle discharge solution, in the drying chamber evaporating solvent, encapsulate rapamycin granule to form PLGA-, collect via from hothouse continuous blow-down, thermal degradation is minimized.In another embodiment, by the slurry spraying dry of rapamycin, PLGA and water, to form the rapamycin granule of PLGA-encapsulating.

By adjustable spraying parameter (such as, pressure, temperature) and nozzle arrangements (such as, size, minor air cell, rotating disk), the particle diameter of rapamycin can be controlled.In this embodiment, adjustable spraying parameter and nozzle arrangements, with the rapamycin granule of production mean diameter for 5-150 nm and more preferably 10-100 nm.In other embodiments, adjustable spraying parameter and nozzle arrangements, with the rapamycin granule of production mean diameter for 1-10 micron and more preferably 1-5 micron.

embodiment 11: use PLGA to be coated with rapamycin by fluid bed coating

In this embodiment, by rapamycin granule (preferred crystallization, such as, degree of crystallinity is 25%-95%) micronization, and suspend on airbed, wherein on the rapamycin granule suspended, spray PLGA solution (such as, 10-50 % by weight, in THF).Also can use other polar non-solute.Subsequently by particle transport to hothouse, wherein solvent evaporation, with formed PLGA-encapsulating rapamycin granule.If needed, by the granule settling flux of encapsulating, spray PLGA solution, dry, until the coating layer thickness of the rapamycin granule of PLGA-encapsulating reaches the level of expectation, such as, 2-20 micron or about 10 microns.

embodiment 12: use PLGA to be coated with rapamycin by dish coating

In this embodiment, in drum container, the granule (such as PLGA pellet) of PLGA is joined in rapamycin granule, to form the rapamycin granule of PLGA-encapsulating.Such as, PLGA can be ground (such as by ball milling, jet grinding or cryogrinding) to suitable particle diameter (such as, about 30 microns).By the feed rate of PLGA pellet, particle diameter and the PLGA layer thickness of the rapamycin encapsulated can be controlled.In this embodiment, with 100-1000 μ g/ minute, the preferred 300-500 μ speed of g/ minute, is fed to PLGA pellet in drum container.

Although embodiment 10,11 and 12 provides machinery or physical method for encapsulating rapamycin in PLGA, they should not be construed as restriction the scope of the present disclosure.The chemical method (cohesion that such as core-shell emulsion preparation is complicated or in-situ polymerization) of encapsulating also can be used for the rapamycin forming encapsulating.

In order to easily describe and succinct, with reference to balloon be the therapentic part of tremulous pulse or blood vessel, there is provided herein great majority description.But method described herein, description, device and coating are applicable to alternative device and treatment position.

Unless otherwise indicated, otherwise in this description, use term " about " to may imply that the variable of 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 40% and/or 50%, depend on specific embodiment.When the key element be described is as of percent statement itself, variable does not refer to the percent of percent, but they are as absolute percent variable, that is, the key element being expressed as " about 5% " can actual be 5%+/-1%, or 4%-6%, depends on embodiment.Consider it is only rational change for those skilled in the art herein.Such as, when key element itself is stated as little percent, those of ordinary skill knows that this key element can not rationally arrive lower than 0, consider that (namely variable will be not less than 0, about 5% may imply that 5%+/-5% or 0-10%, but be not 5%+/-10% or-5%-15%, wherein for described key element those skilled in the art this is irrational).

Aforementioned explanation the present invention, should not regard restriction the present invention as.Although indicated herein and described embodiment of the present invention, it will be apparent to those of ordinary skill in the art that provides these embodiments by means of only illustrational mode.Without deviating from the invention, it may occur to persons skilled in the art that numerous change, amendment and substitute.It should be understood that various alternative can be used for of embodiment of the present invention described herein puts into practice the present invention.Intending following claim limits scope of the present invention, and is therefore encompassed in the method and structure within the scope of these claim and their equivalent.

embodiment 13: use centrifugal, by single emulsifying/evaporation, uses PLGA to be coated with rapamycin

In this embodiment, use centrifuge to filter emulsion, by single emulsifying/evaporation technique, make rapamycin be coated with PLGA.200 mg lactic acid-ethanol copolymers (RG504H 0, viscosity 0.45-0.6) are dissolved in 4 ml dichloromethane (oil phase).In oil phase, dissolve the liquid storage of 100 μ l rapamycins in dimethyl sulfoxide (10 mg/ml), use homogenizer, with 10100 rpm, homogenize 1 minute in 2% PVA (MW about 25,000,98% hydrolysis) solution.This emulsion is poured into immediately in 90 ml 1% PVA solution, allow dichloromethane evaporate.After 3 hours, by centrifugal for granule (1500 g, 10 minutes, 4 DEG C), wash 4 times in deionized water.Microparticle is settling flux in 5 ml deionized waters subsequently, freezing on dry ice, lyophilizing.By adding 100 μ l 2 mg/ml Alexa Fluor 647 carboxylic acid succinimido ester and rapamycins in oil phase, and adopting scheme same as described above, preparing fluorescently-labeled rapamycin-microparticle.

embodiment 14: use filter paper, by single emulsifying/evaporation, uses PLGA to be coated with rapamycin

In this embodiment, use filter paper to filter emulsion, by single emulsifying/evaporation technique, make rapamycin be coated with PLGA.5-10 g PVA (Polyscience Inc, MW about 25,000,98% is hydrolyzed) is dissolved, to produce 1% and 2% PVA solution in warm HPLC rank water.In 50 ml centrifuge tubes, add about 400 mg 50:50 DL-PLGAs (ester end-blocking, IV 0.55-0.75, Durect Corporation, Pelham, AL), and dissolve in 8 ml dichloromethane (oil phase).About 10 mg rapamycins are added, vortex, until granule is no longer visible in 1 mL dimethyl sulfoxide.200 μ l rapamycin liquid storages are added in oil phase.This solution is poured in about 100 ml 2% PVA, with about 17,500 rpm homogenize 1 minute.Emulsion is poured in 180 ml 1% PVA, do not cover and spend the night, evaporate to allow dichloromethane.Before filtering solution, frit funnel is lined with two 3# size Whatman filter paper (with the prior moistening of HPLC rank water).Pouring soln is by filter paper, and granule is stayed on filter paper.By by filter paper submergence in 10 mL water, make granule settling flux.Liquid rotating is moved in 100 ml round-bottomed flasks, freezing on dry ice, lyophilizing subsequently.

With reference now to Fig. 5, use Hitachi type S-4700 scanning electron microscope (SEM) to check the size and dimension of the microparticle of the encapsulating prepared in this embodiment.The rapamycin granule that SEM image shows the encapsulating prepared in this embodiment is generally smooth with spherical.Such as, the granule of at least 50%, 60%, 70%, 80% or 90% has usual spherical form.Fig. 5 also shows the general particle size range of about 0.5 μm of-Yue 10 μm.Such as, the size range of granule of at least 50%, 60%, 70%, 80% or 90% is about 0.5 μm of-Yue 10 μm.The mean diameter of the granule prepared in this embodiment is about 0.5 μm of-Yue 10 μm, about 1 μm of-Yue 10 μm, about 1 μm of-Yue 8 μm, about 1 μm of-Yue 7 μm, about 1 μm of-Yue 6 μm, about 1 μm of-Yue 5 μm or about 2 μm-Yue 4 μm.Confirm to there is rapamycin in microparticle inside by UV-VIS spectrum (Perkin-Elmer Lambda 25 UV-Vis spectrophotometer).

embodiment 15: crystalline rapamycin is encapsulated

5-10 g PVA (MW about 25,000,98% hydrolysis) is dissolved, to produce 1% and 2% PVA solution in warm HPLC rank water.In 50 ml centrifuge tubes, add about 200 mg 50:50 DL-PLGAs (ester end-blocking, IV 0.55-0.75), and dissolve in 4 ml dichloromethane (oil phase).About 50 ml 1% PVA are added, with about 17,500 rpm homogenize 2 minutes in oil phase.Allow emulsion not cover spend the night, evaporate to allow dichloromethane.With about 17,500 rpm, by about 1 mg rapamycin homogenize 2 minutes in 20 ml 2% PV.Subsequently rapamycin mixture is joined in polymer emulsion, with about 17,500 rpm homogenize 2 minutes.Before filtering solution, frit funnel is lined with two 3# size Whatman filter paper (with the prior moistening of HPLC rank water).Pouring soln is by filter paper, and granule is stayed on filter paper.By by filter paper submergence in 10 mL water, make granule settling flux.Liquid rotating is moved in 100 ml round-bottomed flasks, freezing on dry ice, lyophilizing subsequently.

With reference now to Fig. 6, use Hitachi type S-4700 scanning electron microscope (SEM) to check the size and dimension of the granule prepared in this embodiment.The rapamycin granule that SEM image shows the encapsulating prepared in this embodiment is generally smooth with spherical.Such as, the granule of at least 50%, 60%, 70%, 80% or 90% has usual spherical form.Fig. 6 also shows the general particle size range of about 1 μm of-Yue 50 μm.Such as, the size range of granule of at least 50%, 60%, 70%, 80% or 90% is about 1 μm of-Yue 50 μm.The mean diameter of the granule prepared in this embodiment is about 1 μm of-Yue 50 μm, about 1 μm of-Yue 40 μm, about 5 μm of-Yue 40 μm, about 5 μm of-Yue 35 μm, about 5 μm of-Yue 30 μm, about 10 μm of-Yue 30 μm, or about 10 μm of-Yue 20 μm.Confirm to there is rapamycin in microparticle inside by UV-VIS spectrum (Perkin-Elmer Lambda 25 UV-Vis spectrophotometer).

embodiment 16: the microparticle of encapsulating characterizes

On Beckman Coulter enumerator, bulk resistivity measurement method is used to determine the size of the microparticle encapsulated and count.By counting at least 10,000 granule, measure average-size.Use scanning electronic microscope examination microparticle surfaces morphology and shape.The surface charge of microparticle is measured by zeta potential measurement.

The surface morphology of the SEM image showed smooth of granule, and the size that confirmation is obtained by bulk resistivity measurement.The distribution of sizes observed in SEM image is the characteristic of microparticle encapsulation process described herein.

embodiment 17: encapsulation efficiency characterizes

The rapamycin microparticle of 5 mg encapsulatings is dissolved, supersound process 5 minutes, constant vortex 30 minutes in 1 ml acetonitrile (HPLC rank).Using the plate reader that UV-is equipped with, by measuring the absorbance of solution under 278 nm, measuring the amount of rapamycin.As the ratio of the rapamycin existed in granule interior with the amount of the rapamycin added when starting, computational envelope efficiency.

Claims

1. a medical treatment device, described device comprises:

Balloon; With

In the coating gone up at least partially of balloon,

Wherein said coating comprises the granule of medicament, and

Each granule of its Chinese medicine is encapsulated in the polymeric material at least partly.

2. the medical treatment device of claim 1, wherein at least 50% medicament surface area encapsulating in the polymeric material.

3. the medical treatment device of claim 1, wherein at least 75% medicament surface area encapsulating in the polymeric material.

4. the medical treatment device of claim 1, wherein at least 90% medicament surface area encapsulating in the polymeric material.

5. the medical treatment device of claim 1, wherein at least 95% medicament surface area encapsulating in the polymeric material.

6. the medical treatment device of claim 1, the average thickness of wherein said polymeric layer is 2 microns-20 microns.

7. the medical treatment device of claim 6, the average thickness of wherein said polymeric layer is 5 microns-15 microns.

8. the medical treatment device of claim 7, the average thickness of wherein said polymeric layer is about 10 microns.

9. the medical treatment device of claim 1, the degree of crystallinity of wherein said medicament is at least 5%.

10. the medical treatment device of claim 1, the degree of crystallinity of wherein said medicament is at least 20%.

The medical treatment device of 11. claim 1, the degree of crystallinity of wherein said medicament is 25%-95%.

The medical treatment device of 12. claim 1, the mean diameter of the medicament of wherein said encapsulating is 5 nm-150 nm.

The medical treatment device of 13. claim 12, the mean diameter of the medicament of wherein said encapsulating is 10 nm-100 nm.

The medical treatment device of 14. claim 1, the mean diameter of the medicament of wherein said encapsulating is 1 micron-50 microns.

The medical treatment device of 15. claim 14, the mean diameter of the medicament of wherein said encapsulating is 1 micron-10 microns.

The medical treatment device of 16. claim 1, the weight ratio of wherein said medicament and described polymeric material is 1:99-70:30.

The medical treatment device of 17. claim 1, the weight ratio of wherein said medicament and described polymeric material is 25:75-40:60.

The medical treatment device of 18. claim 1, the weight ratio of wherein said medicament and described polymeric material is 40:60-60:40.

The medical treatment device of 19. claim 1, wherein by the mixture of spraying dry medicament, polymeric material and solvent, encapsulates in the polymeric material at least partly by described medicament.

The medical treatment device of 20. claim 19, wherein said mixture is solution, and described solvent is polar non-solute.

The medical treatment device of 21. claim 20, wherein said polar non-solute is selected from oxolane, acetonitrile and their mixture.

The medical treatment device of 22. claim 19, wherein said mixture is slurry, and described solvent is water.

The medical treatment device of 23. claim 1, the solution wherein by spraying polymeric material on pharmacy particle is also dry, is encapsulated at least partly in the polymeric material by described medicament.

The medical treatment device of 24. claim 23, wherein said solution comprises described polymeric material and polar non-solute.

The medical treatment device of 25. claim 24, wherein said polar non-solute is selected from oxolane, acetonitrile and their mixture.

The medical treatment device of 26. claim 1, wherein by adding the granule of polymeric material in drum container to medicament, encapsulates in the polymeric material at least partly by described medicament.

The medical treatment device of 27. claim 26, the mean diameter of the granule of wherein said polymeric material is 10 microns-100 microns.

The medical treatment device of 28. claim 26, the granule of wherein said polymeric material adds with the 100 μ g-1000 μ speed of g/ minute.

The medical treatment device of 29. claim 28, the granule of wherein said polymeric material adds with the 300 μ g-500 μ speed of g/ minute.

The medical treatment device of 30. claim 1, wherein by forming the mixture based on emulsion comprising described medicament and described polymeric material, be separated with the described mixture based on emulsion with by the medicament of described polymer-encapsulating, described medicament is encapsulated in the polymeric material at least partly.

The medical treatment device of 31. claim 30, wherein said polymeric material is the mixture of PVA and PLGA.

The medical treatment device of 32. claim 31, the mean molecule quantity of wherein said PVA is about 20,000-about 30,000.

The medical treatment device of 33. claim 31, the lactic acid of wherein said PLGA: the weight ratio of glycolic is about 60:40 for about 40:60-.

The medical treatment device of 34. claim 30, wherein said medicament is unbodied.

The medical treatment device of 35. claim 34, wherein by forming the mixture based on emulsion comprising described medicament and described polymeric material, an evaporation part based on the mixture of emulsion, and filters the remaining mixture based on emulsion, is encapsulated at least partly in the polymeric material by described medicament.

The medical treatment device of 36. claim 35, wherein by the medicament settling flux of described encapsulating and lyophilizing.

The medical treatment device of 37. claim 35, wherein by the first polymer solution, the second polymer solution, terpolymer solution and liquid medicine being merged, forms the described mixture based on emulsion.

The medical treatment device of 38. claim 37, wherein said first and terpolymer solution comprise the first polymer and water.

The medical treatment device of 39. claim 38, wherein said first polymer is PVA.

The medical treatment device of 40. claim 38, the polymer concentration of wherein said first polymer solution is about 1%-about 5%.

The medical treatment device of 41. claim 38, the polymer concentration of wherein said terpolymer solution is about 0.5%-about 2%.

The medical treatment device of 42. claim 37, wherein said second polymer solution comprises the second polymer and organic solvent.

The medical treatment device of 43. claim 42, wherein said second polymer is PLGA.

The medical treatment device of 44. claim 42, wherein said organic solvent is dichloromethane.

The medical treatment device of 45. claim 37, wherein said liquid medicine comprises described medicament and polar non-solute.

The medical treatment device of 46. claim 45, wherein said polar non-solute is dimethyl sulfoxide.

The medical treatment device of 47. claim 37, wherein by making described liquid medicine mix with the second polymer solution, in described mixture, add the first polymer solution, mixture described in homogenize, with add terpolymer solution, form the described mixture based on emulsion.

The medical treatment device of 48. claim 30, wherein said medicament is crystallization.

The medical treatment device of 49. claim 48, wherein by forming the mixture based on emulsion comprising described medicament and described polymeric material, an evaporation part based on the mixture of emulsion, and filters the remaining mixture based on emulsion, is encapsulated at least partly in polymeric layer by described medicament.

The medical treatment device of 50. claim 48, wherein by the medicament settling flux of described encapsulating and lyophilizing.

The medical treatment device of 51. claim 50, wherein by making the first polymer solution, the second polymer solution, terpolymer solution and described medicament merge, forms the described mixture based on emulsion.

The medical treatment device of 52. claim 51, wherein said first polymer solution comprises the first polymer and organic solvent.

The medical treatment device of 53. claim 52, wherein said first polymer solution and the second polymer solution merge, and allow organic solvent evaporation.

The medical treatment device of 54. claim 52, wherein said first polymer is PLGA.

The medical treatment device of 55. claim 52, wherein said organic solvent is dichloromethane.

The medical treatment device of 56. claim 51, wherein said second and terpolymer solution comprise the second polymer and water.

The medical treatment device of 57. claim 56, wherein said second polymer is PVA.

The medical treatment device of 58. claim 56, wherein the polymer concentration of the second polymer solution is about 0.5%-about 2%.

The medical treatment device of 59. claim 56, the polymer concentration of wherein said terpolymer solution is about 1%-about 5%.

The medical treatment device of 60. claim 51, wherein by making the first polymer solution mix to form emulsion with the second polymer solution, make medicament mix to form suspension with terpolymer solution, and emulsion and suspension are merged, form the described mixture based on emulsion.

The medical treatment device of 61. claim 1, wherein said medicament is macrolide immunosuppressant.

The medical treatment device of 62. claim 61, wherein said macrolide immunosuppressant is rapamycin or derivatives thereof, prodrug, hydrate, ester, salt, polymorphic, derivant or analog.

The medical treatment device of 63. claim 61, wherein said macrolide immunosuppressant is selected from rapamycin, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl) benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxy ethyl)] benzyl-rapamycin, 40-O-pi-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4 (S)-Ji)-propyl-2'-alkene-1'-base]-rapamycin, (2':E, 4'S)-40-O-(4', 5'-dihydroxy penta-2'-alkene-1'-base)-rapamycin, 40-O-(2-hydroxyl) ethoxy carbonyl methyl-rapamycin, 40-O-(3-hydroxyl) propyl group-rapamycin, 40-O-(6-hydroxyl) hexyl-rapamycin, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl rapamycin, 40-O-[(3S)-2,2-dimethyl dioxolane-3-base] methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxy third-1-base]-rapamycin, 40-O-(2-acetoxyl group) ethyl rapamycin, 40-O-(2-nicotinoyl oxygen base) ethyl rapamycin, 40-O-[2-(N-morpholino) acetoxyl group] ethyl rapamycin, 40-O-(2-N-imidazole radicals acetoxyl group) ethyl rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl) acetoxyl group] ethyl rapamycin, 39-O-demethyl-39,40-O, O-ethylidene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxyl) ethyl rapamycin, 28-O-methyl-rapamycin, 40-O-(2-amino-ethyl)-rapamycin, 40-O-(2-acetamidoethyl)-rapamycin, 40-O-(2-nicotinoyl amino-ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazoles is-2'-base carbethoxyl group acylamino-also) ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamino group ethyl)-rapamycin, 40-O-(2-tolylsulfonyl-amino-ethyl)-rapamycin, 40-O-[2-(4', 5'-di ethoxy carbonyl-1', 2', 3'-triazole-1'-base)-ethyl]-rapamycin, 42-table-(tetrazole radical) rapamycin (tacrolimus) and 42-[3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester] rapamycin.

The medical treatment device of 64. claim 1, wherein said medicament is rapamycin.

The medical treatment device of 65. claim 1, wherein said polymeric material comprises can the polymer of bio-absorbable.

The medical treatment device of 66. claim 65, wherein saidly the polymer of bio-absorbable can be selected from polylactide (PLA); PLGA (PLGA); Condensing model; Poe; Poly-(N-(2-hydroxypropyl) Methacrylamide); Poly-(dl-lactide) (DLPLA); Poly-(l-lactide) (LPLA); PGA (PGA); Poly-(dioxanone) (PDO); Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester copolymer (PGA-TMC); L-PLGA (PGA-LPLA); Dl-PLGA (PGA-DLPLA); L-lactide-dl-lactide copolymer (LPLA-DLPLA); Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester-dioxanone terpolymer) (PDO-PGA-TMC), polyvinyl alcohol (PVA), poly arginine, and composition thereof or copolymer.

The medical treatment device of 67. claim 66, wherein said biodegradable polymer is selected from PLGA, PVA, poly arginine, and their mixture.

The medical treatment device of 68. claim 1, wherein said polymeric material comprises PLGA and PVA.

The medical treatment device of 69. claim 1, wherein said polymeric material comprises PLGA.

The medical treatment device of 70. claim 69, wherein said PLGA comprises about 50:50 lactic acid: glycolic.

The medical treatment device of 71. claim 1, wherein said polymeric material comprises lasting polymer.

The medical treatment device of 72. claim 1, described device is also included in the binding agent that the outer surface of the granule of the encapsulating of medicament deposits.

The medical treatment device of 73. claim 72, the weight ratio of wherein said binding agent and described polymer is 1:99-25:75.

The medical treatment device of 74. claim 72, the weight ratio of wherein said binding agent and described polymer is 1:99-10:90.

The medical treatment device of 75. claim 72, the solution wherein by spraying binding agent on the granule of the encapsulating of medicament is also dry, deposits described binding agent.

The medical treatment device of 76. claim 75, wherein said solution comprises described binding agent and water.

The medical treatment device of 77. claim 72, wherein said binding agent comprise following one of at least: poly arginine, poly arginine 9-L-pArg, DEAE-dextran (DEAE-cellulose-dextran), DMAB (two (dodecyl) ditallowdimethyl ammonium bromide), PEI (polymine), TAB (four (dodecyl) ammonium bromide) and DMTAB (dimethyl two (myristyl) ammonium bromide).

The medical treatment device of 78. claim 72, wherein said binding agent is poly arginine.

The medical treatment device of 79. claim 78, the mean molecule quantity of wherein said poly arginine is about 70kDa.

The medical treatment device of 80. claim 78, the mean molecule quantity of wherein said poly arginine is 5-15kDa.

The medical treatment device of 81. claim 1, wherein uses eSTAT coating process on balloon, deposit the granule of the encapsulating of described medicament.

The medical treatment device of 82. claim 1, wherein after making balloon inflation, the medicament of described device release at least 3%.

The medical treatment device of 83. claim 1, wherein after making balloon inflation, the medicament of described device release at least 5% or at least 10%.

The medical treatment device of 84. claim 1, wherein makes balloon inflation after 76 hours, and described device release is at least about 2 ng/mg, at least about 3 ng/mg, at least about 5 ng/mg, at least about 10 ng/mg, at least about 20 ng/mg, at least about 30 ng/mg, or at least about the medicament of 40 ng/mg.

The medical treatment device of 85. claim 1, wherein said balloon is the turnover balloon with side, nearly chamber; Wherein on the side, nearly chamber of turnover balloon, provide described coating.

The medical treatment device of 86. claim 85, wherein said balloon overturns in conduit.

The medical treatment device of 87. claim 86, wherein uses balloon inflation pressure or by moving the far-end of balloon in distally by balloon, or their combination, can by described balloon release conduit.

The medical treatment device of 88. claim 85, the balloon of wherein said reversing overturns on the outside of conduit.

The medical treatment device of 89. claim 88, the balloon wherein by partly not overturning reversing on the outside of conduit controls the treated length of the balloon reversed.

The medical treatment device of 90. claim 88, described device is also included in the sheath provided on the balloon of reversing.

The medical treatment device of 91. claim 90, wherein once the balloon of coating arrives therapentic part, described sheath regracting, arranges near therapentic part, arranges in treatment site, and contiguous therapentic part, in therapentic part distally, or in therapentic part.

The medical treatment device of 92. claim 1, described device also comprises setting for blocking the closer that body fluid flows towards balloon before balloon inflation.

The medical treatment device of 93. claim 92, wherein said closer comprises the second balloon.

The medical treatment device of 94. claim 92, wherein said balloon comprises the first and second parts, and Part I comprises closer, and Part II comprises coating.

The medical treatment device of 95. claim 92, wherein said balloon comprises distal node and adjacent node, and wherein said distal node comprises coating, and wherein said adjacent node comprises closer, or wherein said adjacent node comprises coating, and wherein said distal node comprises closer.

The medical treatment device of 96. claim 92, wherein the distal part of balloon is coated with, and wherein the neighbouring part of balloon is uncoated, and the neighbouring part of wherein said balloon is closer, or, wherein the neighbouring part of balloon is coated with, and wherein the distal part of balloon is uncoated, and the distal part of wherein said balloon is closer.

97. 1 kinds of methods at target site release medicine, described method comprises

Generator, described device comprises balloon and the coating gone up at least partially at balloon, and wherein said coating comprises the granule of medicament, and each granule of its Chinese medicine is encapsulated in the polymeric material at least partly;

Arrange that described device arrives target site to allow balloon; With

Make the balloon inflation of device,

Wherein after making balloon inflation, at least some medicament is released into target site.

The method of 98. claim 97, wherein said target site is blood vessel.

The method of 99. claim 97, wherein after making balloon inflation, is released into blood vessel by the medicament of at least 3%.

The method of 100. claim 97, wherein after making balloon inflation, is released into blood vessel by the medicament of at least 5%.

The method of 101. claim 97, wherein after making balloon inflation, is released into blood vessel by the medicament of at least 10%.

The method of 102. claim 97, wherein said medicament is macrolide immunosuppressant.

The method of 103. claim 102, wherein said macrolide immunosuppressant is rapamycin or derivatives thereof, prodrug, hydrate, ester, salt, polymorphic, derivant or analog.

The method of 104. claim 102, wherein said macrolide immunosuppressant is selected from rapamycin, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl) benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxy ethyl)] benzyl-rapamycin, 40-O-pi-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4 (S)-Ji)-propyl-2'-alkene-1'-base]-rapamycin, (2':E, 4'S)-40-O-(4', 5'-dihydroxy penta-2'-alkene-1'-base)-rapamycin, 40-O-(2-hydroxyl) ethoxy carbonyl methyl-rapamycin, 40-O-(3-hydroxyl) propyl group-rapamycin, 40-O-(6-hydroxyl) hexyl-rapamycin, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl rapamycin, 40-O-[(3S)-2,2-dimethyl dioxolane-3-base] methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxy third-1-base]-rapamycin, 40-O-(2-acetoxyl group) ethyl rapamycin, 40-O-(2-nicotinoyl oxygen base) ethyl rapamycin, 40-O-[2-(N-morpholino) acetoxyl group] ethyl rapamycin, 40-O-(2-N-imidazole radicals acetoxyl group) ethyl rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl) acetoxyl group] ethyl rapamycin, 39-O-demethyl-39,40-O, O-ethylidene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxyl) ethyl rapamycin, 28-O-methyl-rapamycin, 40-O-(2-amino-ethyl)-rapamycin, 40-O-(2-acetamidoethyl)-rapamycin, 40-O-(2-nicotinoyl amino-ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazoles is-2'-base carbethoxyl group acylamino-also) ethyl)-rapamycin, 40-O-(2-ethoxycarbonylamino group ethyl)-rapamycin, 40-O-(2-tolylsulfonyl-amino-ethyl)-rapamycin, 40-O-[2-(4', 5'-di ethoxy carbonyl-1', 2', 3'-triazole-1'-base)-ethyl]-rapamycin, 42-table-(tetrazole radical) rapamycin (tacrolimus) and 42-[3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester] rapamycin.

The method of 105. claim 97, wherein said medicament is rapamycin.

The method of 106. claim 97, wherein said polymeric material comprises biodegradable polymer.

The method of 107. claim 106, wherein saidly the polymer of bio-absorbable can be selected from polylactide (PLA); PLGA (PLGA); Condensing model; Poe; Poly-(N-(2-hydroxypropyl) Methacrylamide); Poly-(dl-lactide) (DLPLA); Poly-(l-lactide) (LPLA); PGA (PGA); Poly-(dioxanone) (PDO); Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester copolymer (PGA-TMC); L-PLGA (PGA-LPLA); Dl-PLGA (PGA-DLPLA); L-lactide-dl-lactide copolymer (LPLA-DLPLA); Acetic acid, hydroxy-, bimol. cyclic ester-carbonic acid 1,3-PD ester-dioxanone terpolymer) (PDO-PGA-TMC); Polyvinyl alcohol (PVA), and composition thereof or copolymer.

The method of 108. claim 107, wherein said biodegradable polymer is selected from PLGA, PVA, poly arginine, and their mixture.

The method of 109. claim 97, wherein said polymeric material comprises PLGA and PVA.

The method of 110. claim 97, wherein said polymeric layer comprises PLGA.

The method of 111. claim 110, wherein said PLGA comprises about 50:50 lactic acid: glycolic.

The method of 112. claim 110, wherein said polymeric layer comprises lasting polymer.

The method of 113. claim 97, wherein said device is also included in the binding agent that the outer surface of the granule of the encapsulating of medicament deposits.

The method of 114. claim 113, wherein said binding agent comprise following one of at least: poly arginine, poly arginine 9-L-pArg, DEAE-dextran (DEAE-cellulose-dextran), DMAB (two (dodecyl) ditallowdimethyl ammonium bromide), PEI (polymine), TAB (four (dodecyl) ammonium bromide) and DMTAB (dimethyl two (myristyl) ammonium bromide).

The method of 115. claim 113, wherein said binding agent is poly arginine.

The method of 116. claim 97, wherein uses eSTAT coating process on balloon, deposit the granule of the encapsulating of described medicament.

117. one kinds of methods forming the crystalline rapamycin of polymer-encapsulating, described method comprises: form the mixture based on emulsion comprising described medicament and described polymeric material; An evaporation part based on the mixture of emulsion, and filters the remaining mixture based on emulsion.

The method of 118. claim 117, described method also comprises the medicament of settling flux and lyophilizing encapsulating.

The method of 119. claim 117, wherein by making the first polymer solution, the second polymer solution, terpolymer solution and described medicament merge, forms the described mixture based on emulsion.

The method of 120. claim 119, wherein said first polymer solution comprises the first polymer and organic solvent.

The method of 121. claim 120, wherein merges described first polymer solution and the second polymer solution, allows organic solvent evaporation.

The method of 122. claim 121, wherein said first polymer is PLGA.

The method of 123. claim 122, wherein said organic solvent is dichloromethane.

The method of 124. claim 119, wherein said second and terpolymer solution comprise the second polymer and water.

The method of 125. claim 124, wherein said second polymer is PVA.

The method of 126. claim 125, wherein the polymer concentration of the second polymer solution is about 0.5%-about 2%.

The method of 127. claim 125, the polymer concentration of wherein said terpolymer solution is about 1%-about 5%.

The method of 128. claim 119, wherein by making the first polymer solution mix to form emulsion with the second polymer solution, make medicament mix to form suspension with terpolymer solution, and emulsion and suspension are merged, form the described mixture based on emulsion.