WO2006044989A1

WO2006044989A1 - Devices and methods for delivery of pimecrolimus and other therapeutic agents

Info

Publication number: WO2006044989A1
Application number: PCT/US2005/037658
Authority: WO
Inventors: Vinayak D. Bhat; John Yan; Ashok A. Shah
Original assignee: Avantec Vascular Corporation
Priority date: 2004-10-18
Filing date: 2005-10-17
Publication date: 2006-04-27

Abstract

The present invention is directed to an intracorporeal device, such as a stent, and methods for reducing, inhibiting, or treating restenosis and hyperplasia by introducing an intracorporeal device into the patient's body with a coating of a primary therapeutic agent, pimecrolimus, which is configured to be released in a sustained or controlled manner. The device may be a structure or scaffolding with the source of the therapeutic agent proximate to the structure or scaffolding for release of the therapeutic agent into the patient's body. The device is suitable for use in a patient's vasculature, particularly the patient's coronary, carotid and peripheral arteries.

Description

DEVICES AND METHODS FOR DELIVERY OF PIMECROLIMUS AND OTHER THERAPEUTIC AGENTS

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of priority from U.S. Provisional Patent Application No. 60/619,849, filed on October 18, 2004, and U.S. Provisional Patent Application No. 60/623,292, filed on October 29, 2004. This application is also a continuation-in-part of U.S. Patent Application No. 10/993,935, filed on November 19, 2004, which claims the benefit of priority from U.S. Provisional Patent Application No. 60/524,990, filed on November 24, 2003, and which is also a continuation-in-part of U.S. Patent Application No. 10/607,836, filed on June 27, 2003, which claims benefit of priority from U.S. Provisional Patent Application Nos. 60/472,536, filed on May 21, 2003, 60/454,146, filed on March 11, 2003, 60/404,624, filed on August 19, 2002, and which is also a continuation-in-part of U.S. Patent Application No. 10/206,807, filed on July 25, 2002, which claims the benefit of priority from U.S. Provisional Patent Application Nos. 60/370,703, filed April 6, 2002, 60/355,317, filed February 7, 2002, 60/347,473, filed January 10, 2002 and which is also a continuation-in-part of U.S. Patent Application 10/002,595, filed on November 1, 2001. Each of the above applications is assigned to the assignee of the present application, the full disclosure of each which is incorporated herein by reference in its entirety.

[0002] The disclosure of this present application is also related to the disclosures of U.S. Patent Application Nos. 10/206,853 and 10/206,803, both filed July 25, 2002 and U.S. Patent Application No. 10/017,500 filed on December 14, 2001, all assigned to the same assignee as that of the present application, the full disclosures of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0003] The present invention relates generally to medical devices and methods. More particularly, the present invention relates to intracorporeal devices, such as vascular stents or grafts, which inhibit restenosis and hyperplasia. [0004] A number of percutaneous intravascular procedures have been developed for treating stenotic atherosclerotic regions of a patient's vasculature to restore adequate blood flow. One of the most successful of these treatments is percutaneous transluminal angioplasty (PTA). In PTA, a catheter, having an expandable distal end usually in the form of an inflatable balloon, is positioned in the blood vessel at the stenotic site. The expandable end is expanded to dilate the vessel to restore adequate blood flow beyond the diseased region. Other procedures for opening stenotic regions include directional arthrectomy, rotational arthrectomy, laser angioplasty, stenting, and the like. While these procedures have gained wide acceptance (either alone or in combination, particularly PTA in combination with stenting), they continue to suffer from significant disadvantages. A particularly common disadvantage with PTA and other known procedures for opening stenotic regions is the frequent occurrence of restenosis.

[0005] Restenosis refers to the re-narrowing of an artery after an initially successful angioplasty. Restenosis afflicts approximately up to 50% of all angioplasty patients and is the result of injury to the blood vessel wall during the lumen opening angioplasty procedure. In some patients, the injury initiates a repair response that is characterized by smooth muscle cell proliferation referred to as "hyperplasia" in the region traumatized by the angioplasty. This proliferation of smooth muscle cells re-narrows the lumen that was opened by the angioplasty within a few weeks to a few months, thereby necessitating a repeat PTA or other procedure to alleviate the restenosis.

[0006] A number of strategies have been proposed to treat hyperplasia and reduce restenosis. Previously proposed strategies include prolonged balloon inflation during angioplasty, treatment of the blood vessel with a heated balloon, treatment of the blood vessel with radiation following angioplasty, stenting of the region, and other procedures. While these proposals have enj oyed varying levels of success, no one of these procedures is proven to be entirely successful in substantially or completely avoiding all occurrences of restenosis and hyperplasia.

[0007] As an alternative or adjunctive to the above mentioned therapies, the administration of therapeutic agents following PTA for the inhibition of restenosis has also been proposed. Therapeutic treatments usually entail pushing or releasing a drug through a catheter or from a stent. While holding great promise, the delivery of therapeutic agents for the inhibition of restenosis has not been entirely successful. [0008] Accordingly, it would be a significant advancement to provide improved devices and methods for inhibiting restenosis and hyperplasia concurrently with or following angioplasty and/or other interventional treatments. At least some of these objectives will be met by the devices and methods of the present invention described hereinafter and in the claims.

BRIEF SUMMARY OF THE INVENTION

[0009] The present invention is directed to an intracorporeal device which has an expandable structure or scaffolding, such as a stent or graft. Associated with the structure or scaffolding is a primary therapeutic agent which includes pimecrolimus or a therapeutically effective pro-drug, analog, derivative or metabolite thereof to reduce restenosis and provide other therapeutic effects, hi addition to inhibiting the occurrence of restenosis, devices and method of the present invention also allow for the generation of a small amount of cellularization, endothelialization, or neointima, preferably, in a controlled manner.

[0010] The intracorporeal device embodying features of the present invention comprises a luminal delivery device which has a structure or scaffolding which is implantable in a body lumen and associated therewith a deliverable amount of pimecrolimus which is releasable from the structure or scaffolding. The structure or scaffolding may be in the form of a stent, which additionally may also maintain luminal patency, or may be in the form of a graft, which may protect or enhance the strength of a luminal wall. The structure or scaffolding may be radially expansible by a balloon or other expansion means and/or self-expanding and is preferably suitable for luminal placement in a body lumen. The structure or scaffolding is preferably expandable but it may have a substantially constant transverse size or diameter, or alternatively depending on the application and use, it may be contractable to a smaller configuration. A suitable stent for use in a device embodying features of the present invention is described in U.S. Patent No. 6,602,282, assigned to the assignee of the present application, the full disclosure of which is incorporated herein by reference.

[0011] The device is configured to be implantable within a corporeal body which includes a susceptible tissue site or it may be configured for implanting, with or without expansion, at a targeted corporeal site. As used herein, the term "susceptible tissue site" refers to a tissue site that is injured, or may become injured as a result of an impairment (e.g., disease, medical condition), or may become injured during or following an interventional procedure such as an intravascular intervention which is susceptible to the therapeutic agent for treatment. The susceptible tissue site may include tissues associated with intracorporeal lumens, organs, or localized tumors. The targeted corporeal site may include the susceptible tissue site or may be another corporeal site (e.g., other body organs or lumens). For example, the corporeal site may comprise the targeted intracorporeal site, such as an artery, which supplies blood to the susceptible tissue site.

[0012] The structure or scaffolding is configured for placement within a body lumen such as a patient's coronary, carotid, or other peripheral artery. The device may be a scaffold formed with an open lattice or it may have an essentially closed surface. The expandable structure may be formed of any suitable material such as metals, polymers, or a combination thereof. In one embodiment, the expandable structure may be formed of an at least partially biodegradable material selected from the group consisting of polymeric material, metallic materials, or combinations thereof. The at least partially biodegradable material preferably degrades over time. Examples of polymeric material include poly-L-lactic acid, having a delayed degradation to allow for the recovery of the vessel before the structure is degraded. Examples of metallic material include metals or alloys degradable in the corporeal body, such as stainless steel.

[0013] Primary and/or secondary therapeutic agents associated with the structure may be directly or indirectly coupled to, connected to, disposed on, disposed within, attached to, adhered to, bonded to, adjacent to, entrapped in, absorbed in, absorbed on, or otherwise secured to the structure or scaffolding. The therapeutic agent may be secured in such a manner as to become available to the tissue site, immediately or after a delayed period, upon introduction of the device to the site. A source of the primary therapeutic agent may be disposed or formed proximate to one or more surfaces of the structure or scaffolding of the device. The source may be disposed on an exterior or interior surface or within the interior of the structure itself between the interior and exterior surfaces, or any combination thereof. The association of the primary and/or secondary therapeutic agent with the structure or scaffolding may be continuous or in discrete segments.

[0014] The structure or scaffolding may have one or more secondary therapeutic agents which augment the function of the primary therapeutic agent or perform another therapeutic or diagnostic function. The one or more secondary therapeutic agents may be selected from the group consisting of immunosuppressants, antiinflammatories, anti-pro liferatives, anti- migratory agents, anti-fibrotic agents, proapoptotics, vasodilators, calcium channel blockers, anti-neoplasties, anti-cancer agents, antibodies, anti-thrombotic agents, anti-platelet agents, Ilb/IIIa agents, antiviral agents, MTOR (mammalian target of rapamycin) inhibitors, non- imniunosuppressant agents, tyrosine kinase inhibitors, CDK inhibitors, chemotherapeutic agents, thrombolytics, antimicrobials, antibiotics, antimitotics, growth factor antagonists, free radical scavengers, radiotherapeutic agents, radiopaque agents, radiolabeled agents, anti¬ coagulants, anti-angiogenesis agents, angiogenesis agents, PDGF-B and/or EGF inhibitors, ADP inhibitors, phosphodiesterase III inhibitors, glycoprotein Ilb/IIIa agents, adenosine reuptake inhibitors, healing and/or promoting agents, anti-oxidants, nitrogen oxide donors, antiemetics, antinauseants, bisphosphonates, NF-κB Decoy Oligo, proteins, oligomers, amino acids, peptides, genes, growth factors, anti-sense, derivatives, analogues, metabolites, pro¬ drugs, and/or combinations thereof.

[0015] The one or more secondary therapeutic agents may enable and/or enhance either or both the release and efficacy of the therapeutic agent or provide other therapeutic or diagnostic effects. The secondary therapeutic agent may be associated with the expandable structure in the same or different manner as the primary therapeutic agent. By way of example, one secondary therapeutic agent may reduce generation of endothelial cells while another secondary therapeutic agent may allow for more endothelialization to be achieved. The one or more secondary therapeutic agent may be released prior to, concurrent with, or subsequent to, the primary therapeutic agent, at similar or different rates, times, layers, and phases.

[0016] In one embodiment, the luminal prosthesis makes available one or more therapeutic agents to one or more selected locations within a patient's vasculature, including the susceptible tissue site, to reduce the formation or progression of restenosis and/or hyperplasia. As used herein, the term "make available" means to have provided the substance (e.g., therapeutic agent) at the time of release or administration, including having made the substance available at a corporeal location such as an intracorporeal location or target site, regardless of whether the substance is in fact delivered, used by, or incorporated into the intended site, such as the susceptible tissue site.

[0017] The therapeutic agents may be therapeutic as it is introduced to the subject under treatment, or it may become therapeutic after being introduced to the subject under treatment. For example, the therapeutic agent may become therapeutic by way of a native or non-native substance or condition, or another introduced substance or condition. Examples of native conditions include pH (e.g., acidity), chemicals, temperature, salinity, osmolality, and conductivity. Examples of non-native conditions include magnetic fields, electromagnetic fields (such as radiofrequency and microwave), and ultrasound.

[0018] In another embodiment, the primary and/or secondary therapeutic agents may be made available to the susceptible tissue site as a native environment of the area where the device is implanted changes. For example, a change in a pH of the area where the device is implanted may change over time so as to bring about the release of one or more of the therapeutic agents. Agent release may be direct, as for example when a polymeric drug acts as a matrix including both the therapeutic agent and a rate-sustaining or rate-controlling element. Agent release may alternatively be indirect, as for example by affecting the erosion or diffusion characteristic of the rate-sustaining or rate-controlling element or coating as either or both the matrix or non-matrix. Additionally, as the pH increases or decreases, the erosion of the rate-sustaining or rate-controlling element or coating changes allowing for initial and subsequent phase releases.

[0019] hi yet another embodiment, the primary and/or secondary therapeutic agent may be responsive to an external form of energy (non-native condition) to effect or modify the release of the therapeutic agent. The responsive compound may be associated with the therapeutic agent, a rate-sustaining or rate-controlling element, coating or matrix, the expandable structure, or a combination thereof. The energy to effect release of one or more of the therapeutic agents include ultrasound, magnetic resonance imaging, magnetic field, radio frequency, temperature change, x-ray, vibration, gamma radiation, microwave and the like. The energy source may be directed at the device after implantation to effect release of one or more of the therapeutic agents.

[0020] The devices of the present invention may be configured to release or make available the therapeutic agents at one or more phases, the one or more phases having similar or different performance (e.g., release) profiles. The therapeutic agent may be made available to the tissue at amounts which may be sustainable, intermittent, or continuous, hi one embodiment, the primary therapeutic agent, pimecrolimus, may be released over a predetermined time pattern comprising an initial phase wherein the delivery rate is below a threshold level and a subsequent phase wherein the delivery rate is above a threshold level. Time delayed substance release can be programmed to impact restenosis substantially at the onset of events leading to smooth muscle cell proliferation (hyperplasia). The present invention can further minimize substance washout by timing substance release to occur after at least initial cellularization and/or endothelialization which creates a barrier over the stent to reduce loss of the substance directly into the bloodstream. Moreover, the predetermined time pattern may reduce substance loading and/or substance concentration as well as potentially providing minimal to no hindrance to endothelialization of the vessel wall due to the minimization of drug washout and the increased efficiency of substance release.

[0021] The total amount of therapeutic agent made available to the tissue depends in part on the level and amount of desired therapeutic result. The therapeutic agent may be made available at one or more phases, each phase having similar or different release rate and duration as the other phases. The one or more release rates may be substantially constant, decreasing, increasing, substantially non-releasing over one or more time periods. The release rates, concentrations, time durations, and other characteristics for the primary and secondary therapeutic agents may be the same or different depending upon their effects.

[0022] The total amount of primary therapeutic agent made available or released may be in an amount ranging from about 0.1 μg (microgram) to about 1O g (grams), generally from about 10 μg to about 1 mg (milligram), usually from about 100 μg to about 500 μg. The primary therapeutic agent may be released in a time period, as measured from the time of implanting of the device, ranging from about 1 day to about 200 days, preferably from about 1 day to about 45 days, and most preferably from about 7 days to about 21 days. The release rate of the primary therapeutic agent per day may generally range from about 0.001 ng (nanogram) to about 500 μg, typically from about 100 ng to about 100 μg, usually from about 1 μg to about 50 μg. The concentration of the primary therapeutic agent within the receiving tissue will be within a range generally from about 0.001 ng of agent/mg of tissue to about 600 μg of agent/mg of tissue, typically from about 0.001 ng of agent/mg of tissue to about 100 μg of agent/mg of tissue, and usually from about 0.1 ng of agent/mg of tissue to about 10 μg of agent/mg of tissue.

[0023] The delivery of the primary therapeutic agent may be over an initial phase and one or more subsequent phases. The rate of delivery during an initial phase will generally range from about 0.001 ng per day to about 500 μg per day, typically from about 0.001 ng to about 50 μg per day, and usually from about 0.1 μg per day to about 50 μg per day. The rate of delivery at the subsequent phase may range from about 0.01 ng per day to about 500 μg per day, typically from about 0.01 μg per day to about 200 μg per day, usually from about 1 μg per day to about 100 μg per day. The primary therapeutic agent may be made available to the susceptible tissue site in a programmed, sustained, and/or controlled manner with increased efficiency and/or efficacy. There may also be additional phase(s) for release of the one or more secondary therapeutic agents.

[0024] The duration of the initial, subsequent, and any other additional phases may vary. For example, the release of the therapeutic agent may be delayed from the initial implantation of the device. Typically, the delay is sufficiently long to allow the generation of sufficient cellularization or endothelialization at the treated site to inhibit loss of the therapeutic agent into the vascular lumen. Typically, the duration of the initial phase will be sufficiently long to allow initial cellularization or endothelialization of at least part of the surface covered by the device. Typically, the duration of the initial phase, whether being a delayed phase or a release phase, is from about 1 hour to about 24 weeks, usually less than about 12 weeks, and preferably about 1 hour to about 8 weeks. The durations of the one or more subsequent phases may also vary, typically being from about 4 hours to about 24 weeks, usually from about 1 hour to about 12 weeks.

[0025] The device preferably includes a rate-sustaining or rate-controlling element, coating or matrix for affecting the rate of release of the primary and/or secondary therapeutic agents. The rate-sustaining or rate-controlling element, coating or matrix may be disposed on or formed adjacent to the structure. In one embodiment, the rate-sustaining or rate-controlling element may be disposed or formed adjacent at least a portion of the one or more surfaces of the structure (e.g., luminal or abluminal surfaces), or within the interior of the structure, or any combination thereof. The primary and/or secondary therapeutic agent may be disposed adjacent the rate-sustaining or rate-controlling element. Additionally and/or alternatively, the primary and/or secondary therapeutic agent may be mixed with the rate-sustaining or rate- controlling element incorporating the therapeutic agent in a matrix. The rate-sustaining or rate-controlling element may comprise multiple adjacent layers formed from the same or different material and any one of the layers may include the primary and/or secondary therapeutic agent.

[0026] The rate-sustaining or rate-controlling element may be formed of a non-degradable material, partially degradable material, substantially degradable material, or a combination thereof. The material may be synthetic, natural, non-polymeric, polymeric, metallic, bio- active, non bio-active, or a combination thereof. By way of example, a non-metallic material that at least partially degrades with time may be used as the rate-sustaining or rate-controlling element. Non-polymers having large molecular weights, polar or non-polar functional groups, electrical charge, steric hindrance groups, hydrophobic, hydrophilic, or amphiphilic moieties may also be used.

[0027] The rate-sustaining or rate-controlling element, coating or matrix may have a sufficient thickness so as to provide the desired release rate of the therapeutic agent. The rate-sustaining or rate-controlling element, coating or matrix will generally have a total thickness in a range from about 10 nm to about 100 μm. The thickness may also range from about 50 nm to about 100 μm, typically from about 100 nm to about 50 μm, and usually from about 100 nm to 10 μm.

[0028] The primary and/or secondary therapeutic agent may be associated with or otherwise directly or indirectly secured to at least a portion of the implantable structure or scaffolding using coating methods such as spraying, dipping, deposition (vapor or plasma), painting, or chemical bonding. Such coatings may be continuously or intermittently applied to the structure or may be applied in a random or pre-determined pattern. Furthermore, a biocompatible (e.g., blood compatible) layer may be formed over the source and/or the most outer layer of the device, to make or enhance the biocompatibility of the device.

[0029] The devices embodying features of the present invention having at least the primary therapeutic agent pimecrolimus associated therewith are delivered in a suitable manner to a tissue site, such as a blood vessel, where the primary therapeutic agent is released and/or made available to the susceptible tissue site. The therapeutic agent is made available to the susceptible tissue site, preferably, in a sustained or controlled manner over a period of time.

[0030] In another aspect of the present invention, the primary and/or secondary therapeutic agent may be directly or indirectly coupled to, connected to, disposed on, disposed within, attached to, adhered to, bonded to, adjacent to, entrapped in, absorbed in, absorbed on, or otherwise secured to or within a gelatinous substance. The gelatin substance may control or sustain release of the therapeutic agent from the device. In one embodiment, the gelatinous substance is bonded, normally covalently bonded, to a silane coupling agent formed adjacent the surface of the device. In another embodiment, the silane compound forms a bond with the surface of the device. The primary and/or secondary therapeutic agent is associated with the gelatinous substance in such a manner as to become available, immediately or after a delayed period, to the tissue site upon introduction of the device to the site.

[0031] The device, such as a metallic stent, may be prepared for a silylation process by undergoing a passivation process. In one embodiment, surface contaminants such as oils, greases, or lubricants are first removed from the surface of the device by general degreasing and cleaning methods. The device is thereafter subjected to a passivation solution (e.g., placed in the passivation solution), normally comprising an acidic solution such as a nitric acid-based solution, usually for a period of time from about 10 to about 15 minutes. Consequently, a metal oxide film is formed on the surface of the device.

[0032] The device is subjected to the silylation process preferably after it has undergone passivation. During the silylation process, the passivated device is exposed to a silane coupling agent. Silane (e.g., compounds of silicon and hydrogen of formula Si_nH_2n+2) and other monomelic silicon compounds have the ability to bond inorganic materials such as glass, mineral fillers, metals, and metallic oxides to organic materials such as polymers, resins, or other organic compounds.

[0033] The silane coupling agents normally comprise one or more organo-functional groups and one or more functional groups which can undergo hydrolysis to become silanols ("silanol forming group"). The one or more organo-functionality can react with functional groups in polymers such as industrial polymers, bio-molecules (e.g., peptides), and proteins (e.g., gelatin). The silanol forming groups can either or both react with one another forming oligomeric variations and/or react with active surfaces, normally surfaces having hydroxyl (-OH) groups. Examples of organo-functional groups include — NH₂, -SH, -NCO, -CHO, epoxy, vinyl groups (e.g., aliphatic including but not limited to acrylates, aromatic including but not limited to styrenated groups such as amino styrene). Examples of silanol forming groups, normally tri-functional groups, include halo groups such as -Cl or alkoxy groups such as methoxy (-(OCH₃) or ethoxy (-(OC₂H₅).

[0034] The silylation process normally involves the reaction between the silanol forming portion and the inorganic material (e.g., the metallic oxide of the passivated metal stent surface), usually forming a covalent bond, while the one or more organo-functional group reacts with the organic material such as gelatin having amino, carboxyl, or styrene groups (e.g., styrenated gelatin). When the silane coupling agent is styrenated, it can be prepared by reacting an epoxy-terminated silane with an amino-styrene. [0035] The gelatinous substance (either as the gelatinous substance or as the source including the gelatinous substance and the primary and/or secondary therapeutic agent (e.g., pre-mixed source)) is disposed (e.g., coated) on the silylated device. It should be appreciated by those skilled in the art that the use of the term "disposed" does not imply a particular order in the process. For example, the device may be immersed in a solution or mixture comprising the gelatinous substance or the gelatinous substance may be sprayed or coated on the device. In one embodiment, the gelatinous substance is bonded to the silylated device through functional groups such as carboxylic groups, amine groups or styrene groups (e.g., when the silane coupling agent itself is a stryrenated agent). The gelatinous substance may be acid treated (e.g., acidic gelatin) with or without styrene functionalities. In one embodiment, the gelatinous substance is styrenated prior to being disposed on the silylated device, which may or may not be itself styrenated, as discussed above.

[0036] The rate-controlling element or coating, as described above, may be disposed on or formed adjacent to the structure and/or the source (e.g., primary and/or secondary therapeutic agent associated with the gelatinous substance) for sustaining or controlling release of the therapeutic agent from the gelatinous substance. In one embodiment, the rate-sustaining or rate-controlling element may be disposed or formed adjacent at least a portion of the luminal, abluminal, or interior surfaces of the structure. The source of the primary and/or secondary therapeutic agents may be disposed adjacent the rate-sustaining or rate-controlling element. Additionally and/or alternatively, the one or more therapeutic primary and/or secondary therapeutic agents may be mixed with the rate-sustaining or rate-controlling element and thereafter associated with the gelatinous substance. The rate-sustaining or rate-controlling element may comprise multiple adjacent layers formed from the same or different material and any one of the layers may include the one or more therapeutic agent with or without the gelatinous substance.

[0037] While the present invention is described with respect to arterial deployment, it will be appreciated that deployment may be carried out in a patient's veins, aorta, or in previously implanted grafts, shunts, fistulas, and the like. Additionally, the device may be deployed in other body lumens, such as the biliary duct, which are subject to excessive neoplastic cell growth. Examples of further internal corporeal tissue and organ applications include various organs, nerves, glands, ducts, tumors, and the like, hi another embodiment, the device may further incorporate cardiac pacemaker leads or lead tips, cardiac defibrillator leads or lead tips, heart valves, sutures, needles, pacemakers, orthopedic devices, appliances, implants or replacements, or portions of any of the above.

[0038] The devices of the present invention may further be provided together with instructions for use (IFU), separately or as part of a kit. The kit may include a pouch or any other suitable package, such as a tray, box, tube, or the like, to contain the device and the IFU, where the IFU may be printed on a separate sheet or other media of communication and/or on the packaging itself, hi one embodiment, the kit may also include a mounting hook, such as a crimping device and/or an expansible inflation member, which may be permanently or releaseably coupled to the device of the present invention. In another embodiment, the kit may comprise the device and an IFU regarding use of a second compound prior to, concurrent with, or subsequent to, the interventional procedure or first therapeutic agent, and optionally the second compound.

[0039] These and other advantages of the present invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The following drawings should be read with reference to the detailed description. Like numbers in different drawings refer to like elements. The drawings, which are not necessarily to scale, illustratively depict embodiments of the present invention and are not intended to limit the scope of the invention.

[0041] FIGS. IA through 1C are cross-sectional views of a device embodying features of the present invention which has been implanted in a body lumen.

[0042] FIGS. 2 A through 2N are cross-sectional views of various embodiments of the device of FIG. IA taken along line 2-2.

[0043] FIG. 3 is a schematic representation of a stent for use as the device of the present invention.

[0044] FIGS. 4A through 4C are graphical representations of various release profiles of a therapeutic agent over a predetermined time period. [0045] FIGS. 5A through 51 illustrate a method for positioning the device of FIGS. 1 A-IC in a blood vessel.

[0046] FIG. 6 illustrates what is believed to be the molecular structure of pimecrolimus.

[0047] FIG. 7 is a representation of a stent surface having an oxide layer.

[0048] FIG. 8 is a representation of a reaction for forming a styrenated silane coupling agent.

[0049] FIG. 9 is a representation of a reaction between the passivated metal stent surface of FIG. 9 and a silane coupling agent after a hydrolysis/condensation reaction.

[0050] FIG. 10 is a representation of a gelatin structure.

[0051] FIG. 1 IA through 11C are representations of reactions between the gelatinous substance and different silane coupling agents.

[0052] FIG. 12 is a graphical representation of the proliferation of human smooth muscle cells in contact with various concentrations of pimecrolimus.

[0053] FIG. 13 is bar graph representing the viability of human smooth muscle cells at various amounts of pimecrolimus.

[0054] FIG. 14 is a graphical representation of pimecrolimus release profiles from various parylene coated stents over a predetermined time period.

[0055] FIGS. 15A and 15B are histologic slides illustrating bare stents after 28 days of implantation.

[0056] FIGS. 16A and 16B are histologic slides illustrating stents coated with pimecrolimus after 28 days of implantation.

DETAILED DESCRIPTION OF THE INVENTION

[0057] FIGS. IA through 1C and cross-sectional drawings FIGS. 2A through 2N illustrate a device 10, such as a stent 13, embodying features of the present invention. The device 10 generally comprises an expandable structure 16 implanted in an intracorporeal body and a source 25 proximate to the structure 16 including the primary therapeutic agent 28, pimecrolimus. Although the source 25, as depicted in the figures, is disposed proximate to a surface of the stent 13, the term "proximate" is not intended to be limited by the figures or descriptions herein. The device 10, as shown, is disposed in a body lumen 19 including a susceptible tissue site 22. It will be appreciated that the following depictions are for illustration purposes only and do not necessarily reflect the actual shape, size, configuration, or distribution of the device 10.

5 [0058] The prosthesis 13 may have a continuous structure or an intermittent structure as the case may be with many stents (e.g., a cross section of a stent does not entirely include a substrate forming the expandable structure, for example, some stents have a screen or mesh like cross section). The expandable structure 16 generally has a tissue facing surface 31, a luminal facing surface 34, and optionally an interior 37 which may include a lumen as shown

10 in FIG. 2B. The source 25 may be disposed or formed adjacent at least a portion of either or both the luminal facing surface 34, as shown in FIG. IB, the tissue facing surface 31, as shown in FIG. 1C, within the interior 37 of the expandable structure, and/or any combination thereof, hi one embodiment, devices 10 may be configured to make available to the tissue the most suitable therapeutic amount of the therapeutic agent while minimizing the presence

15 of unwanted metabolites and by-products of the therapeutic agent at the tissue site.

[0059] The source 25 for making the therapeutic agent available is associated with the expandable structure 16 in one or more configurations. The source as shown in FIGS. 2A and 2B, is within the expandable structure 16. For example, a matrix 40 may be formed by the expandable structure 16 and the therapeutic agent 28, or the therapeutic agent 28 may be

20 disposed within the interior 37 of the expandable structure 16. Now referring to FIG. 2C, the source 25 may further comprise a rate-sustaining or rate-controlling element 43 formed over at least a portion of the expandable structure 16 for sustaining or controlling the release of the therapeutic agent 28 from the matrix 40 or the interior 37 of the expandable structure. By way of example, the source may be the rate-sustaining or rate-controlling element itself when

25 the therapeutic agent is a polymeric therapeutic agent.

[0060] FIG. 2D illustrates features of an embodiment having the therapeutic agent 28 disposed between one of the tissue or luminal facing surfaces 31, 34 of the expandable structure 16 and the rate-sustaining or rate-controlling element 43. As shown in FIG. 2E, the source 25 includes the rate-sustaining or rate-controlling element 43 formed adjacent at least 30. a portion of one of the tissue or luminal facing surfaces 31, 34 of the expandable structure 16 and forming the matrix 40 with the therapeutic agent 28. As noted earlier, the therapeutic agent 28 may itself act as a rate-sustaining or rate-controlling element, as for example, when the polymeric therapeutic agent forms a matrix. The matrix 40 may be formed between the rate-sustaining or rate-controlling element 43 and the expandable structure 16.

[0061] A matrix interface 46 between the rate-sustaining or rate-controlling element 43 and the expandable structure 16 and/or between the therapeutic agent 28 and the rate-sustaining or rate-controlling element 43, is shown in FIGS. 2F and 2G respectively. In another embodiment, features of which are shown in FIG. 2H, an outer most layer of the prosthesis 13 may be formed of the therapeutic agent with or without a matrix interface 46. For example, this may be desirable to effect a bolus release of the therapeutic agent. It should be noted that although the therapeutic agent 28 is shown in most figures as discrete particles, it may form a smooth layer or a layer of particles, as for example as part of the matrix interface 46 as shown in FIG. 2H.

[0062] In an alternate embodiment, features of which are shown in FIG. 21, at least one layer of a second rate-sustaining or rate-controlling element 49 is formed over the matrix 40, further affecting the release rate of the therapeutic agent 28 to the susceptible tissue site 22. The second rate-sustaining or rate-controlling element 49 may be of the same or different material than that forming the first rate-sustaining or rate-controlling element 43.

[0063] Now referring to FIGS. 2 J and 2K, the source may comprise a plurality of compounds, as for example the first therapeutic agent 28 and an optional another compound, such as a secondary therapeutic agent 50 or an enabling compound 61 (FIG. 2N). Each of the plurality of compounds may be in the same or different area of the source. For example, as shown in FIG. 2K, the first therapeutic agent 28 may be present in matrix 40 while the second therapeutic agent 50 is in a second matrix 52 formed by the second therapeutic agent 50 and a second rate-sustaining or rate-controlling element 55. The rate-sustaining or rate-controlling elements 43 and 55 may be formed from the same or different material. The second therapeutic agent may act in synergy with the first therapeutic agent. For example, the second therapeutic agent may compensate for the possible reactions and metabolites that can be generated by the first therapeutic agent. By way of example, the first therapeutic agent may reduce generation of desired endothelial cells while the second therapeutic agent may allow for more endothelialization to be achieved. The secondary therapeutic agent may be released prior to, concurrent with, or subsequent to, the primary therapeutic agent, at similar or different rates and phases. [0064] In another embodiment, features of which are shown in FIGS. 2L and 2M, the therapeutic agent 28 is disposed within the interior or on the exterior of expandable structure 16 within a reservoir 58. The rate-sustaining or rate-controlling element 43 may be disposed adjacent the reservoir 58 and/or the therapeutic agent 28 for affecting the release of the therapeutic agent. As stated earlier, the figures and descriptions herein are not intended to limit the term "adjacent."

[0065] In a further embodiment, features of which are shown in FIG. 2N, the optional another compound may comprise an enabling compound 61 responsive to an external form of energy, or native condition, to effect the release of the first therapeutic agent 28. The responsive compound 61 may be associated with the first therapeutic agent 28, the rate- sustaining or controlling element 43, the expandable structure 16, or a combination thereof. As shown in FIG. 2N, the responsive compound 61 is associated with the first therapeutic agent 28. The enabling compound 61 may be formed from magnetic particles coupled to the therapeutic agent 28. The energy source may be a magnetic source for directing a magnetic field at the prosthesis 13 after implantation to effect release of the therapeutic agent 28. The magnetic particles 61 may be formed from magnetic beads and will typically have a size in a range from about 1 nm to about 100 nm. The magnetic source exposes the prosthesis 13 to its magnetic field at an intensity typically in the range from about 0.01T to about 2T, which will activate the magnetic particles 61 and thereby effect release of the therapeutic agent 28 from the prosthesis 13. The another enabling compound 61 may be present in other configurations of the prosthesis 13 as described above. Other suitable external energy sources, which may or may not require an enabling compound or their performance may not be affected by the presence or absence of an enabling compound, include ultrasound, magnetic resonance imaging, magnetic field, radio frequency, temperature change, electromagnetic, x-ray, radiation, heat, gamma, vibration, microwave, and a combination thereof.

[0066] By way of example, an external ultrasound energy source may be used having a frequency in a range from 20 IcHz (kilohertz) to 100 MHz (megahertz), preferably in a range from 0.1 MHz to 20 MHz, and an intensity level in a range from 0.05 W/cm² (Watts per centimeter square) to 10 W/cm², preferably in a range from 0.5 W/cm² to 5 W/cm². The ultrasound energy may be directed at the prosthesis 13 from a distance in a range from 1 mm (millimeters) to 30 cm (centimeters), preferably in a range from 1 cm to 20 cm. The ultrasound may be continuously applied or pulsed, for a time period in a range from 5 seconds to 30 minutes, preferably in a range from 1 minute to 15 minutes. The temperature of the prosthesis 13 during this period will be in a range from 36°C (degree Celsius) to 48⁰C. The ultrasound may be used to increase a porosity of the prosthesis 13, thereby allowing release of the therapeutic agent 28 from the prosthesis 13. Other sources of energy, such as heat or vibrational energy, may also be used to increase the porosity or alter the configuration of at least a portion of the prosthesis.

[0067] Now referring to FIG. 3, the expandable structure 16 may comprise a stent 70 or a graft: (not shown). When the expandable structure comprises a stent, the expandable structure 16 will usually comprise at least two radially expandable, usually cylindrical, ring segments 73 as shown in FIG. 3. Typically, the expandable structure 16 will have at least four, and often five, six, seven, eight, ten, or more ring segments 73. At least some of the ring segments 73 will be adjacent to each other but others may be separated by other non-ring structures. The description of stent structures herein is not intended to be exhaustive and it should be appreciated that other variations of stent designs may be used in the present invention.

[0068] The stent 70 generally comprises from 4 to 50 ring segments 73, with eight being illustrated. Each ring segment 73 is joined to the adjacent ring segment by at least one of sigmoidal links 76, with three being illustrated. Each ring segment 73 includes a plurality of strut/hinge units, e.g., six strut/hinge units, and three out of each six strut/hinge structures on each ring segment 73 will be joined by the sigmoidal links 76 to the adjacent ring segment. As shown in FIG. 3, stent 70 is in a collapsed or non-expanded configuration. The stent 70 is described in more detail in U.S. Patent No. 6,602,281, assigned to the assignee of the present application, the full disclosure of which is incorporated herein by reference.

[0069] As used herein, the term "radially expandable" includes segments that can be converted from a small diameter configuration to a larger diameter radially expanded, usually cylindrical, configuration which is achieved when the expandable structure 16 is implanted at a desired target site. The expandable structure 16 may be minimally resilient, e.g., malleable, thus requiring the application of an internal force to expand and set it at the target site.

Typically, the expansive force can be provided by a balloon, such as the balloon of an angioplasty catheter for vascular procedures. The expandable structure 16 preferably provides sigmoidal links 76 between successive unit segments to enhance flexibility and crimpability of the stent 70. [0070] Alternatively, the expandable structure 16 maybe self-expanding. Self-expanding structures are provided by utilizing a resilient material, such as a tempered stainless steel or a superelastic alloy such as a NITDSfOL™ alloy, and forming the body segment so that it possesses a desired radially-expanded diameter when it is unconstrained, i.e., released from the radially constraining forces of a sheath, hi order to remain anchored in the body lumen, the expandable structure 16 will remain partially constrained by the lumen. The self- expanding expandable structure 16 can be tracked and delivered in its radially constrained configuration, e.g., by placing the expandable structure 16 within a delivery sheath or tube and removing the sheath at the target site.

[0071] The dimensions of the expandable structure 16 will depend on its intended use. Typically, the expandable structure will have a length in a range from about 5 mm to about 100 mm, usually being from about 8 mm to about 50 mm, for vascular applications. The diameter of a cylindrically shaped expandable structure for vascular applications, in a non- expanded configuration, typically ranges from about 0.5 mm to about 10 mm, usually from about 0.8 mm to about 8 mm. The diameter in an expanded configuration typically ranges from about 1.0 mm to about 100 mm, usually from about 2.0 mm to about 30 mm. The expandable structure usually will have a thickness in a range from about 0.025 mm to 2.0 mm, usually from about 0.05 mm to about 0.5 mm.

[0072] The ring segments 73, and other components of the expandable structure 16, may be formed from conventional materials used for body lumen stents and grafts, typically being formed from malleable metals or alloys, such as 300 series stainless steel, resilient metals, such as superelastic and shape memory alloys (e.g., NITINOL™ alloys, spring stainless steels, and the like), non-metallic materials, such as polymeric materials, or a combination thereof. The polymeric materials may include those polymeric materials that are substantially non-degradable, biodegradable, or substantially biodegradable, such as those described in relation to the materials of choice for the rate-sustaining or rate-controlling element. When the expandable structure material is formed of the rate-sustaining or rate- controlling element material, the expandable structure 16 may function both as the prosthesis 13 and the direct source of the therapeutic agent 28. hi one embodiment, the device 10 may comprise a biodegradable structure with a polymeric source, such as a polymeric therapeutic agent. [0073] Other suitable materials for use as the structure 16 include carbon or carbon fiber, cellulose acetate, cellulose nitrate, silicone, polyethylene terphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polytetrafluoroethylene, polycaprolactone, polyhydroxybutyrate valerate, another biocompatible/biodegradable polymer, protein, extracellular matrix components, collagen, fibrin, another biologic agent, or a suitable mixture or copolymer of any of the materials listed above, degradable, non-degradable, metallic, or otherwise. Additional structures that may be incorporated into the expandable structure 16 of the present invention are illustrated in U.S. Patent Nos. 5,195,417, 5,102,417, and 4,776,337, the full disclosures of which are incorporated herein by reference.

[0074] Referring now to FIG. 4A, a graphical representation of one embodiment of therapeutic agent release over a predetermined time period is shown. The predetermined rate pattern shown in FIG. 4 A improves the efficacy of the delivery of the therapeutic agent 28 to the susceptible tissue 22 site by making the therapeutic agent available at none to some lower delivery rate during an initial phase. Once a subsequent phase is reached, the delivery rate of the therapeutic agent may be substantially higher.

[0075] Time delayed therapeutic agent release can be programmed to impact restenosis (or other targeted conditions as the case may be) when there is at least a partial formation of the initial cellular deposition or proliferation (hyperplasia). The present invention can further reduce any washout of the therapeutic agent by timing the release of the therapeutic agent to occur after at least initial cellularization. Moreover, the predetermined rate pattern may reduce loading and/or concentration of the therapeutic agent. The predetermined rate pattern may further provide limited, reduced, or no hindrance to endothelialization of the vessel wall due to the minimization of washout of the therapeutic agent and the increased efficiency of its release.

[0076] FIGS. 4B and 4C represent further graphical representations of various release profiles of the therapeutic agent over a predetermined time period. In both these embodiments, the rate of release of the therapeutic agent may exhibit a steeper or higher rate release slope during the initial phase as compared to the slope of rate release during the subsequent phase. FIG. 4B illustrates a steeper or higher slope of release during the initial phase as that compared to the slope of release during the initial phase depicted in FIG. 4C. [0077] FIGS. 5 A through 5F illustrate a method for making a therapeutic agent 28 available to a susceptible tissue site 22. As shown in FIG. 5 A, an intravasculature balloon catheter 100 having a tubular body 103 (not shown) is introduced through a guiding catheter 106 via hemostatic valve and sheath (not shown) and through the femoral artery to the coronary vasculature over the aortic arch 112. As shown in FIG. 5B, a guidewire 115 will usually be positioned at the target site 118 including the susceptible tissue site 22, which typically includes a region of stenosis to be treated by balloon angioplasty. Usually the balloon catheter 100 and guidewire 115 will be introduced together with the guidewire 115 being periodically extended distally of the catheter 100 until the target site 118 is reached.

[0078] Once at the target site 118, a balloon 121 is inflated to expand the occlusion at the target site 118 as shown in FIGS. 5 C and 5D. After balloon angioplasty treatment is completed, the balloon 121 will be deflated, with guidewire 115 remaining in place. The balloon 121 may then be removed over guidewire 115, again with the guidewire 115 remaining in place as seen in FIGS. 5E and 5F. A second balloon assembly 100' including a device 10 according to present invention is then introduced over the catheter body 103 as shown in FIG. 5G. After the second balloon assembly 100' is in place, the device, such as stent 10 which is in place over the second balloon assembly 100', may be deployed by inflating balloon 121' as shown in FIG. 5H. After the stent 10 has been properly deployed, the balloon 121' maybe deflated and the catheter 100' removed leaving the stent 10 in place, as shown in FIG. 51. It should be appreciated that depending on the nature of the site under treatment, the device of the present invention may be introduced to the site during the introduction of the first balloon catheter without the need for pre-dilatation.

[0079] The molecular structure of the primary therapeutic agent 28 pimecrolimus is illustrated in FIG. 6. Pimecrolimus is the 33-epi-chloro-derivative of the macrolactam ascomycin. It has an empirical formula of C₄₃H₆₈CINO₁₁ and a molecular weight of 810.48. Pimecrolimus is a cell-selective inhibitor of the production and release of pro-inflammatory cytokines. It is believed that pimecrolimus binds to macrophilin-12 and inhibits the Ca- dependent phosphatase calcineurin. Consequently, pimecrolimus is believed to block the synthesis of inflammatory cytokines in T cells at the level of gene transcription and in particular, regulates both Thl-(IL-2 and- TNf-) and Th2-(IL-4, IL-5, IL-10) type cytokine synthesis. In addition, pimecrolimus is believed to prevent the release of cytokines and pro¬ inflammatory mediators from activated mast cells. Pimecrolimus does not appear to effect the growth of keratinocyte or endothelial cell lines. Pimecrolimus exhibits high anti- inflammatory activity in animal models of skin inflammation after both topical and systemic application. Pimecrolimus appears to combine high anti-inflammatory activity with a low potential to impair local and systemic immunosurveillance.

[0080] As described earlier with respect to FIG. 2 J, the structure or scaffolding 16 may have one or more secondary therapeutic agents 50 which augment the function of the primary therapeutic agent 28 or perform another therapeutic or diagnostic function. The secondary therapeutic agent 50 may be selected from a list comprising a variety of agents. Specific examples of the therapeutic agent include mycophenolic acid, mycophenolic acid derivatives (e.g., 2-methoxymethyl derivative, 2-methyl derivative), VX-148, VX-944, mycophenolate mofetil, mizoribine, methylprednisolone, dexamethasone, CERTIC AN™ (e.g., everolimus, RAD), rapamycin, 32-deoxorapamycin (e.g., SAR943), ABT-578, ABT-773, ABT-797, TRIPTOLIDE™, METHOTREXATE™, phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), 1,4-dihydropyridines (e.g., benidipine, nifedipine, nicarrdipine, isradipine, felodipine, amlodipine, nilvadipine, nisoldipine, manidipine, nitrendipine, barnidipine (HYPOC A™)), ASCOMYCIN™, WORTMANNIN™, LY294002, CAMPTOTHECIN™, silibinin, sylymarin, baicalein, histone deacetylase (e.g., trichostatin A), PD-0183812, butyrolactone I, substituted purines (e.g., olomoucine, CGP74514), polyhydroxylated flavones (e.g., flavopyridol), oxindole inhibitors (e.g., GW-8510, GW- 2059, GW-5181), indolinone derivatives (e.g., SU-5416), zoledronic acid (e.g., ZOMETA™, (l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate), isoquinoline, HA-1077 (e.g., l-(5-isoquinolinesulfonyl)-homopiperazine hydrochloride), TAS-301 (e.g., 3- bis(4-methoxyphenyl)methylene-2-indolinone), TOPOTECAN™, hydroxyurea, cyclophosphamide, cyclosporine, daclizumab, azathioprine, prednisone, diferuloymethane, diferuloylmethane, diferulylmethane, GEMCITABINE™, cilostazol (e.g., PLETAL™), TRANILAST™, enalapril, quercetin, suramin, estradiol, cycloheximide, tiazofurin, zafurin, AP23573, non-immunosuppressive analogues of rapamycin (e.g., rapalog, SAR943 (32- deoxorapamycin), AP21967, SAR943 (32-deoxorapamycin)), CCI - 779, sodium mycophenolic acid, benidipine hydrochloride, sirolimus, rapamune, phenylaminopyrimidine (or phenylpyrimidine-amine) derivatives (e.g., imatinib (GLIVEC™)), other tyrosine inhibitors (e.g., 4-[6-methoxy-7-(3-piperidine-l-yl-propoxy)-quinazolin-4-yl]-piperazine-l- carboxylicacid(4-isoρropoxyphenyl) amide, CT53518, MLN518, 5-Chloro-3-[(3,5- dimethylpyrrol-2-yl)methylene]-2-indolinone, SU6656, 5-Chloro-3-[(3,5-dimethylpyrrol-2- yl)methylene]-2-indolinone, SU5614), water-soluble N,N-dimethylgly-cine ester prodrug CEP7055 that converts to CEP5214 in vivo from cephalon, 4-Amino-5-(4-chlorophenyl)-7-(t- butyl)pyrazolo[3,4-d]pyrimidine (e.g., PP2, AGl 879), 6,7-Dimethyl-2-phenylquinoxaline (e.g., AG1295), TAUTOMYCIN™, radicicol, damnacanthal, herbimycin A, 6-(2,6-dichloro- phenyl)-8-methyl-2-(3-methylsulfanyl- phenylammo)-8h-pyrido(2,3-d)pyrimidin-7-one (e.g., PD173955), PD166326, PD183805, 4-[(3-Bromophenyl)amino]-6- propionylamidoquinazoline (e.g., PD174265), 5-Chloro-3-[(3,5-dimethylpyrrol-2- yl)methylene]-2-indolinone (e.g., PD153035), 4-[(3-Bromophenyl)amino]-6- acrylamidoquinazoline (e.g., PD168393), TARCEVA™ (e.g., erlotinib HCl), CI-1033, AEE788, CP-724,714, geldanamycin, 17-(allylamino)-17-demethoxygeldanamycin (17-AG or 12-AAG), IRESSAT™, ZD4910, EGFR/ErbB2 inhibitor (e.g., CI1033, EKB569, GW2016, PKIl 66), VEGF receptor inhibitors (e.g., ZK222584, ZD6474), VEGFR/FGFR/PDGFR inhibitors (e.g., SU6668, SUl 1248, PTK787), NGF receptor (e.g., CEP2583), anti-EGF receptor MAbs (e.g., MAb225, ERBITUX™), anti-ErbB2 MAbs (e.g., MAb4D5, HERCEPTIN™), AVASTIN™, an anti-VEGF MAb, NF-κB Decoy Oligo, albumin, TSCl, TSC2, hamartin KIAA0243, VEGF, EGF, PDGF, FGF, antisense phosphorothioate oligodeoxynucleotide (ODN), Anti-MTOR, Anti-p27 Anti-p53, Anti-Cdk, agent incorporated in a vector (e.g., HVJ Envelop vector), IGF, IGF-I, IGFBP, IGFBP-3, rhlGFBP-3, and/or combinations thereof. In the present application, the "chemical name" of any of the therapeutic agents or other compounds is used to refer to the compound itself and to pro-drugs (precursor substances that are converted into an active form of the compound in the body), and/or pharmaceutical derivatives, analogues, or metabolites thereof (bio-active compound to which the compound converts within the body directly or upon introduction of other agents or conditions (e.g., enzymatic, chemical, energy), or environment (e.g., pH)).

[0081] As described earlier with respect to FIG. 2C, the device 16 preferably includes a rate-sustaining or rate-controlling element or coating 43 for affecting the rate of release of the primary and/or secondary therapeutic agents 28, 50. The rate-sustaining or rate-controlling element 43 may be formed of a non-degradable material, partially degradable material, substantially degradable material, or a combination thereof. The material may be synthetic, natural, non-polymeric, polymeric, metallic, bio-active, non bio-active, or a combination thereof.

[0082] Suitable biodegradable rate-sustaining or rate-controlling element or coating 43 materials include, but are not limited to, poly(lactic acid), poly(glycolic acid), poly dioxanone, poly(ethyl glutamate), poly(hydroxybutyrate), polyhydroxyvalerate, polycaprolactone, polyanhydride, poly(ortho esters), poly (iminocarbonates), polyester- amids, polycyanoacrylates, polyphosphazenes, aliphatic polyesters, poly-L-lactic acid, poly- e-caprolactone, mixtures, copolymers, and combinations thereof. Other suitable examples of biodegradable rate-sustaining or rate-controlling elements or coatings 43 include polyamide esters made from amino acids (e.g., L-lysine, 1-leucine) along with other building blocks such as diols (e.g., hexanediol) and diacids (e.g., sebacic acid).

[0083] An example of a biodegradable material of the present invention is a copolymer of poly-L-lactic acid (having an average molecular weight of about 200,000 daltons) and poly-e- caprolactone (having an average molecular weight of about 30,000 daltons). Poly-e- caprolactone (PCL) is a semi crystalline polymer with a melting point in a range from 59 ⁰C to 64 ⁰C and a degradation time of about 2 years. Thus, poly-1-lactic acid (PLLA) can be combined with PCL to form a matrix that generates the desired release rates. A preferred ratio of PLLA to PCL is 75:25 (PLLA/PCL). As generally described by Rajasubramanian et al. in an article titled, "Fabrication of resorbable microporus intravascular stents for gene therapy applications" in ASAIO Journal, 40, pp. M584-589 (1994), the full disclosure of which is incorporated herein by reference, a 75:25 PLLA/PCL copolymer blend exhibits sufficient strength and tensile properties to allow for easier coating of the PLLA/PLA matrix on the expandable structure. Additionally, a 75:25 PLLA/PCL copolymer matrix allows for sustained or controlled drug delivery over a predetermined time period as a lower PCL content makes the copolymer blend less hydrophobic while a higher PLLA content leads to reduced bulk porosity. Typically, the intracorporeal life span of the 75% PLLA- 25% PCL copolymer is about 1 to 2 years.

[0084] Suitable nondegradable or slow degrading rate-sustaining or rate-controlling element 43 materials include, but are not limited to, polyurethane, polyethylene, polyethylene imines, cellulose acetate butyrate, ethylene vinyl alcohol copolymer, silicone, polytetrafluorethylene (PTFE), parylene, parylene C, N, D, or F, parylene C, PARYLAST™, PARYLAST C™, poly (methyl methacrylate butyrate), poly-N-butyl methacrylate, poly (methyl methacrylate), poly 2-hydroxy ethyl methacrylate, poly ethylene glycol methacrylates, poly vinyl chloride, poly(dimethyl siloxane), poly(tetrafluoroethylene), poly (ethylene oxide), poly ethylene vinyl acetate, poly carbonate, poly acrylamide gels, N-vinyl- 2-pyrrolidone, maleic anhydride, nylon, cellulose acetate butyrate (CAB), synthetic or natural polymeric substances, mixtures, copolymers, and combinations thereof. In a preferred embodiment the rate-sustaining or rate-controlling element 43 is formed from a material selected from the group consisting of silicone, polytetrafluoroethylene, parylene, parylene C, non-porous parylene C, PARYLAST™, PARYLAST C™, polyurethane, cellulose acetate butyrate, mixtures, copolymers and combinations thereof. These polymers can have a foam structure, porous structure, nano-porous structure, non-porous structure, structure with mechanical disruption (e.g., fractures, cracks, openings, fissures, perforations or combinations thereof).

[0085] Suitable natural material for the rate-sustaining or rate-controlling element 43 include, but are not limited to, fibrin, albumin, collagen, gelatin, glycosoaminoglycans, oligosaccharides and poly saccharides, chondroitin, phosholipids, phosphorylcholine, glycolipids, proteins, oligomers, amino acids, peptides, cellulose, mixtures, copolymers, or combinations thereof. Other suitable materials for the rate-sustaining or rate-controlling element 43 include titanium, chromium, NITINOL™, gold, stainless steel, metal alloys, or a combination thereof. By way of example, a combination of two or more metals or metal alloys with different galvanic potentials to accelerate corrosion by galvanic corrosion pathways may be used. Non-polymer compounds having large molecular weights, polar or non-polar functional groups, electrical charge, steric hindrance groups, hydrophobic, hydrophilic, or amphiphilic moieties may also be used for the rate-sustaining or rate- controlling element 43.

[0086] The degradable material may degrade by bulk degradation or hydrolysis. For example, the rate-sustaining or rate-controlling element 43 degrades or hydrolyzes throughout, or by surface degradation or hydrolysis, in which a surface of the rate-sustaining or rate-controlling element 43 degrades or hydrolyzes over time while maintaining bulk integrity. In another embodiment, hydrophobic rate-sustaining or rate-controlling elements 43 are preferred as they tend to release therapeutic agent 28 at desired release rates. In yet another embodiment, a non-degradable rate-sustaining or rate-controlling element 43 may release the therapeutic agent by diffusion, hi still another embodiment, if the rate-sustaining or rate-controlling element 43 is formed of non-polymeric material, the therapeutic agent 28 may be released as a result of the interaction (e.g., chemical reaction, high molecular weight, steric hindrance, hyrophobicity, hydrophilicity, amphilicity, heat) of the therapeutic agent with the rate-sustaining or rate-controlling element material (e.g, a non-polymer compound).

[0087] Li another embodiment, when the rate-sustaining or rate-controlling element 43 does not form at least a sufficient matrix with the therapeutic agent, the therapeutic agent 28 may be released by diffusion through the rate-sustaining or rate-controlling element. By way of example, a rate-sustaining or rate-controlling element having low molecular weight and/or relatively high hydrophilicity in the tissue or blood, may diffuse through the source (e.g., a matrix). This increases the surface area or volume for the therapeutic agent to be released from, thus, affecting the release rate of the therapeutic agent.

[0088] In still another embodiment, the therapeutic agent 28 may be released either from a reservoir 58 or a matrix comprising any of the polymers 43 described herein (FIGS. 2L and 2M). hi another embodiment, the therapeutic agents may be covalently attached to amino acids and released as the polymer biodegrades. Other biodegradable poly ester urethanes made from copolymers of poly lactide, poly capro lactone, poly ethylene glycol, polyester- amid, and poly acrylic acid can also be used to release the therapeutic agent as described above.

[0089] The devices 10 of the present invention may be configured to release or make available the therapeutic agent 28 at one or more phases, the one or more phases having similar or different performance release profiles (e.g., rates of delivery). The duration of the initial, subsequent, and any other additional phases may vary. For example, the release of the therapeutic agent may be delayed from the initial implantation of the device. Typically, the delay is sufficiently long to allow sufficient cellularization, endothelialization, or fibrin deposition at the treated site and/or on at least a part of the device after implantation. The therapeutic agent may be made available to the tissue at amounts which may be sustainable, intermittent, or continuous; in one or more phases and/or effective to reduce any one or more of smooth muscle cell proliferation, inflammation, immune response, hypertension, or those complementing the activation of the same. Any one of the at least one therapeutic agents may perform one or more functions, including preventing or reducing proliferative/restenotic activity, reducing or inhibiting thrombus formation, reducing or inhibiting platelet activation, reducing or preventing vasospasm, or the like.

[0090] When the device 10 includes a source 25 having a plurality of therapeutic agents including piniecrolimus as a primary therapeutic agent 28 and one or more optional secondary therapeutic agents 50, the plurality of therapeutic agents may be released at different times and/or rates, from the same or different layers. Each of the plurality of agents maybe made available independently of one another (e.g., sequential), simultaneous with one another, or concurrently with and/or subsequent to the interventional procedure. For example, the primary therapeutic agent (e.g., pimecrolimus) may be released within a time period of 1 day to 45 days with the secondary therapeutic agent (e.g, mycophenolic acid) released within a time period of 2 days to 3 months, from the time of the interventional procedure.

[0091] The structure or scaffolding 16 of the device 10 may incorporate the primary therapeutic agent 28 and/or the optional secondary therapeutic agent 50, by coating, spraying, dipping, deposition (vapor or plasma), or painting the therapeutic agent onto the prosthesis. Usually, the therapeutic agent is dissolved in a solvent. Suitable solvents include aqueous solvents (e.g., water with pH buffers, pH adjusters, organic salts, and inorganic salts), alcohols (e.g., methanol, ethanol, propanol, isopropanol, hexanol, and glycols), nitriles (e.g., acetonitrile, benzonitrile, and butyronitrile), amides (e.g., formamide and N- dimethylformamide), ketones, esters, ethers, dimethyl sulfoxide (DMSO), gases (e.g., CO₂), and the like. For example, the device may be sprayed with or dipped in the solution and dried so that therapeutic crystals are left on a surface thereof.

[0092] Alternatively, a matrix solution including a rate-sustaining or rate-controlling element material 43 and the therapeutic agent 28 may be prepared by dissolving the rate- sustaining or rate-controlling element material and the therapeutic agent in a solution. The expandable structure 16 may then be coated with the matrix solution by spraying, dipping, deposition, or painting the matrix onto the prosthesis. By way of example, when the matrix is formed from polymeric material, the matrix solution is finely sprayed on the prosthesis while the prosthesis is rotating on a mandrel. The thickness of the matrix coating may be controlled by the time period of spraying and a speed of rotation of the mandrel. The thickness of the matrix-agent coating is typically in a range from about 0.01 μm to about 100 μm, preferably in a range from about 0.1 μm to about 50 μm. Once the prosthesis has been coated with the matrix coating, the stent may be placed in a vacuum or oven to complete evaporation of the solvent.

[0093] Referring now to FIG. 7, the device 10 comprising a metallic stent 16, 70 (FIG. 3) and a source 25 including primary and/or secondary therapeutic agents 28, 50 associated with the gelatinous substance may be prepared by undergoing a silylation process. Optionally, prior to the silylation process, the stent device 16 is first subjected to a cleaning process during which the surface contaminants such as oils, greases, or lubricants are removed from the surface of the device by general degreasing and cleaning methods. The device is thereafter subjected to a passivation solution, such as a nitric acid-based solution, for a period of time in a range from 10 to 15 minutes. Thereafter, a metal oxide film is formed on the surface of the device 16, as generally depicted in FIG. 7.

[0094] During the silylation process, preferably after the device has undergone passivation, the device 16 is exposed to a silane coupling agent. Silanes and other monomelic silicon compounds have the ability to bond inorganic materials such as glass, mineral fillers, metals, and metallic oxides to organic materials such as polymers, resins, or other organic compounds. The silane coupling agents normally comprise one or more organo-functional groups and one or more functional groups which can undergo hydrolysis to become silanols. Silane coupling agents typically have a molecular structure as shown in formula #1 below:

wherein R₁ includes R₃ and optionally R_4;

wherein R₃ is an organo-functional group, normally selected from the group consisting of amino ( — NH₂), mercapto (-SH), isocyanato (-NCO), aldhehyde (-CHO), epoxy (C₂H₄O ring), and vinyl groups (aliphatic (-CH=CH₂), acrylate (0-CO-CH=CH₂), and amino styrene (-CHOH=CH₂-NH-BZ-CH=CH₂);

wherein R₄ is (CH₂)_n wherein n ranges from 0 to about 15, preferably 3; and

wherein R₂ is a silanol forming group, normally a tri-functional group, usually selected from the group consisting of halo groups such as -Cl₃ and alkoxy groups (-OCH₃)_n, wherein n ranges from about 1 to about 6, preferably 1 (methoxy (-(OCH₃)) or 2 (ethoxy (- (OC₂H₅)).

[0095] Referring now to FIG. 8, when the silane coupling agent is styrenated, it can be prepared by reacting an epoxy-terminated silane with amino-styrene. The silylation process normally involves the reaction between the silanol forming portion and the inorganic material (e.g., the metallic oxide of the passivated metal stent surface) while the one or more organo- functional group reacts with the organic material such as the gelatin (including a plurality of amino and carboxyl groups). Optionally, the gelatin is a styrenated gelatin as disclosed by Nakayama et al. in a publication titled "Development of high performance stent: gelatinous photogel-coated stent that permits drug delivery and gene transfer" in John Wiley & Sons, hie. (2001), the full disclosure of which is incorporated herein by reference in its entirety. Li one reaction, the silane coupling agent undergoes hydrolysis followed by condensation reaction as shown in Formula Wl, below, and is deposited on the passivated metal stent (FIG. 7) as shown in FIG. 9:

R₁-Si-(OCH₃)S > Ri-Si-(OH)_n

[0096] In one embodiment, the gelatinous substance is disposed (e.g., bonded) on the silylated device through functional groups of the gelatinous substance such as carboxylic groups, amine groups, or styrene groups (if the silane coupling agent itself is a stryrenated agent). Gelatin has a structure generally depicted in FIG. 10. The gelatinous substance may be acid treated with or without styrene functionalities, and is generally depicted as formula #3, below:

NH₂ - G - COOH, wherein G denotes gelatin structure.

Some reactions between the gelatinous substance and different silane coupling agents are shown in FIGS. 1 IA through 11C. It will be appreciated that the mechanisms of reaction between the various functional groups follow typical organic reactions.

[0097] As described above, the gelatinous substance may control or sustain release of the primary and/or secondary therapeutic agent 28, 50 from the stent 16. In one embodiment, the therapeutic agent is mixed with the gelatinous substance and thereafter disposed on the device. For example, the device may be sprayed with or dipped in the solution/mixture comprising the therapeutic agent and the gelatinous substance and then dried so that source is left on a surface thereof. Alternatively, the gelatinous substance may be disposed on the device and the therapeutic agent is disposed between this layer and a subsequent layer of the gelatinous substance.

[0098] Non-limiting examples of the present invention are set forth below.

[0099] Example 1 : A stainless steel DURAFLEX™ stent (available from Avantec Vascular Corporation, the assignee of the present application) having dimensions of 3.0 mm x 14 mm was sprayed with a solution of 25 mg/ml of pimecrolimus in a 100% ethanol solvent. The stent was dried and the ethanol was evaporated leaving pimecrolimus on the stent surface. A 75:25 PLLA/PCL copolymer (sold commercially by Polysciences) was prepared in a 1, 4 Dioxane solvent (sold commercially by Aldrich Chemicals). The pimecrolimus loaded stent was mounted on a mandrel rotated at 200 rpm, and coated by spraying with a spray gun (sold commercially by Binks Manufacturing). The copolymer solution was finely sprayed onto the pimecrolimus loaded stent as it was rotated for a time period of 10 to 30 seconds. The stent was then placed in an oven and maintained at 25° to 35°C for up to 24 hours to complete evaporation of the solvent. The stent was then ready for implantation within a patient in a conventional fashion.

[0100] Example 2: The surface of a DURAFLEX™ stent having dimensions of 3.0 mm x 14 mm was roughened to increase the surface area of the stent. In addition to the surface roughening, the surface area and the volume of the stent was further increased by creating 10 ran wide by 5 run deep grooves along the links of the stent strut. The grooves were created in those stent areas experiencing low stress during expansion so as not to compromise the stent radial strength. Pimecrolimus was loaded onto the stent and in the stent grooves by dipping the stent in a solution of pimecrolimus and a low surface tension solvent (e.g., isopropyl alcohol, ethanol, or methanol). The stent was then dried with pimecrolimus remaining on the stent surface and in the grooves which served as a reservoir. A parylene coating is then vacuum deposited onto the stent to serve as a rate-sustaining or rate-controlling element. Upon implantation within a patient's vasculature, pimecrolimus is eluted from the stent over a period of time in the range from 1 day to 45 days.

[0101] Example 3: Pimecrolimus was dissolved in methanol and sprayed onto a DURAFLEX™ stent having dimensions of 3.0 mm x 14 mm. The stent was left to dry with the solvent evaporating, leaving pimecrolimus on the stent. A rate-sustaining or rate- controlling coating (e.g., silicone, polyurethane, polytetrafluorethylene, parylene, parylene C, non-porous parylene C, PARYLAST™, PARYLAST™C) was deposited on the stent covering the pimecrolimus. The amount of pimecrolimus on the stent varied from about 10 μg to 2 mg. The coated stent was then placed within a patient's vasculature and the release rates for the pimecrolimus ranged from 1 day to 45 days.

[0102] Example 4: A matrix solution including the matrix polymer and pimecrolimus was coated onto the stent of Example 2. The stent was then coated or sprayed with a top coat of a second rate-sustaining or rate-controlling element, hi another similar example, the pimecrolimus was coated on the stent via a rate-sustaining or rate-controlling element, and then covered with a top coat of a matrix material without a drag. Top coats provide further sustained or controlled release rates, improved biocompatibility, and/or resistance to scratching and cracking upon stent delivery or expansion within a body lumen.

[0103] Example 5: Pimecrolimus was combined with another or secondary therapeutic agent (e.g., rapamycin and/or its analogs). Pimecrolimus was coupled to a first coating while the secondary therapeutic agent was coupled to a second coating. The pimecrolimus was released for a time period of about 1 day to about 45 days after being implanted within a vessel, while the second therapeutic agent was released for a longer period in one instance and a shorter period in another instance. By way of example, when the second therapeutic agent was rapamycin, the second therapeutic agent was released at a shorter period.

[0104] Example 6: The anti-proliferative properties of pimecrolimus were measured using a standard thymidine incorporation proliferation assay. Cultured human smooth muscle cells (HSMCs) were exposed to varying concentration doses of pimecrolimus, ranging from 0.01 μmol to 10 μmol, for a period of 2 hours. A positive control of HSMCs with no pimecrolimus exposure was also carried out for control purposes. The cells were then exposed to tritiated-thymidine, which gets incorporated in proliferating cells. The thymidine was measured using a scintillation counter. The extent of proliferation in absence (controls) and presence of pimecrolimus was measured and the IC50 (e.g., concentration at which 50 % (percent) of cells were prevented from proliferating) of the drug was calculated. The proliferation assay enables the evaluation of the potency of an anti-proliferative agent. As shown in the graph of FIG. 12, the IC50 of pimecrolimus for HSMCs was between 0.01 μmol to 0.1 μmol, which indicates that pimecrolimus has potent anti-proliferative effects. Generally, as the μmol concentration of pimecrolimus increases, the undesirable proliferation of HSMCs decreases. In particular, at 0.03 μmol and greater concentrations of pimecrolimus, the % proliferation dipped below the 50% mark, at 0.2 μmol and greater concentrations of pimecrolimus, the % proliferation dipped below the 40% mark, and at 0.5 μmol and greater concentrations of pimecrolimus, the % proliferation dipped below the 30% mark

[0105] Example 7: The effect of the pimecrolimus on the viability of human smooth muscle cells was evaluated using the standard trypan blue viability assay. Cultured HSMCs were exposed to varying concentration doses of pimecrolimus, ranging from an amount of 10 μg (12 μmol) to about 600 μg (727 μmol), for a period of 2 hours. A positive control of HSMCs with no pimecrolimus exposure was also carried out for control purposes. The cells were then exposed to trypan blue, which incorporates into dead cells. The viability was expressed as a percentage of live cells remaining after two hours at each concentration. The viability assay enables the evaluation of the toxicity of the drug. As shown in FIG. 13, pimecrolimus provided high viability (e.g., 80% viability or greater) at concentrations up to 600 μg, indicating that although pimecrolimus has anti-proliferative effects, it is not due to toxicity; pimecrolimus is a cytostatic agent. [0106] Example 8: The elution characteristics of pimecrolimus were evaluated. Specifically, the concentration and degradation of pimecrolimus over time was measured using high performance liquid chromatography (HPLC) with UV detection. Five DURAFLEX™ stents having dimensions of 3 mm x 14 mm were coated with pimecrolimus. This was carried out by spraying approximately 50 to 600 μg/ml of pimecrolimus solution comprising a solvent, in this case ethanol, onto the stent. The stent was dried and the ethanol was evaporated leaving pimecrolimus on the stent surface. A parylene coating of approximately 10 to 30 μg/mm² was then vacuum deposited onto the stent covering the pimecrolimus to serve as a rate-sustaining or rate-controlling element. The five stents each had different vacuum deposition coating techniques (e.g., how fast parylene was deposited on the stent surface). As shown in FIG. 14, the normal (1) and normal (2) stents were identically coated with a parylene sublimation temperature rise of 0.5 °C/min, the faster (2) stent was coated with a parylene sublimation temperature rise of 1.0 °C/min, the faster (1) stent was coated with a parylene sublimation temperature rise of 2.0 °C/min, and the slowest stent was coated with a parylene sublimation temperature rise of 0.25 °C/min. The drug elution properties of these pimecrolimus parylene coated stents was measured using the HPLC method. As clearly seen in FIG. 14, the pimecrolimus release profiles from the various parylene coated stents described above all exhibited a steeper or higher slope of pimecrolimus rate release during an initial phase (e.g., up to 3 days) as compared to the slope of pimecrolimus rate release during the subsequent phase (e.g., after 3 days). It is believed that upon stent crimping and expansion, the non-porous parylene coating cracks, fractures, or other mechanical disruptions in the coating structure allow the pimecrolimus to elute or move from the stent.

[0107] Example 9: DURAFLEX™ stents having dimensions of 3 mm x 14 mm were coated with pimecrolimus and placed in porcine coronary arteries of juvenile farm pigs weighing between about 20 kgs (kilograms) and 50 kgs. One or two pimecrolimus loaded stents were implanted per animal along with a bare metal stent without a therapeutic agent to serve as a control. For example, stents were loaded with 200 μg of pimecrolimus without a rate delaying or controlling coating. Stents were implanted in the major epicardial vessels of the chosen pigs. The appropriate vasculature was accessed via the right or left femoral artery and the stents were implanted and sized to approximately a 1.25:1 balloon to artery ratio by angiographic analysis. All stents were carefully tracked during implantation to assure precise recording of sample group and location. Animals were then followed for 28 days by quantitative coronary angiography (QCA) before euthanasia.

[0108] After QCA, the animal hearts were excised and pressure perfused to be fixed with formalin. The excised hearts were then sent to a pathology lab for processing, cutting, and staining of the stents for histological analysis. The prepared slides underwent morphometric and histopathologic examination. Morphometry was performed in accordance with an approved morphometric analysis protocol. A trained pathologist performed histological analysis in accordance to an approved protocol. Personnel conducting both the morphometry and histopathology were blinded to the type of stent implanted.

[0109] Animal preparation began by daily administration of ASA 650 mg p.o. and Ticlid 500 mg p.o. to the animal starting one week prior to anesthesia. Following an overnight fast, the pigs were anesthetized with Ketamine 20 mg/kg, Xylazine 2 mg/kg, and Atropine 0.6 mg, which was administered intramuscularly. General anesthesia was induced by administering 1-3% Isoflurane. A 7 French or 8 French introducer sheath was placed into the animal's femoral artery. A 0.035" (inch) guidewire was then introduced into the animal's femoral artery through the introducer sheath and advanced therein through the animal's aorta and into the appropriate coronary ostium. A guiding catheter was advanced over the guidewire through the ascending aorta and into the appropriate coronary ostium. The guidewire was then removed. The stents were mounted on a delivery balloon catheter and advanced over the in-place guiding catheter until the stent was in the desired location within the animal vasculature. The balloon on the catheter was inflated to deploy the stent at the target site. The balloon was inflated to a pressure required to achieve a 1.25:1 ratio of stent to artery size. After stent deployment, the balloon was deflated and the catheters were removed from the animal. Further angiography was performed to determine appropriate stent sizing and expansion.

[0110] After implantation, the animals were administrated a daily dose of ASA 650 mg p.o. and Ticlid 500 mg p.o. and followed by QCA for 28 days. After this time period, the animals were euthanized with an overdose of potassium chloride. The thorax of each animal was opened by a left lateral intercostal incision and the heart removed. The entire heart was infused with 1000 ml of saline solution followed by 2 liters of formalin under a pressure of about 120 mm Hg. All stents were subjected to histological evaluations, including morphometric and histopathologic analysis. [0111] The niorphometric analysis of each stent segment measured the % stenosis and neointimal area of both the pimecrolimus coated stents and the bare metal control stents. The % stenosis measured a mean value of 17.03 with a standard deviation of 7.00 and the neointimal area measured a mean value of 1.13 with a standard deviation of 0.53 for 24 pimecrolimus coated stents. In comparison, 27 bare metal control stents measured a % stenosis mean value of 25.56 with a standard deviation of the 16.94 and a neointimal area mean value of 1.97 with a standard deviation of 1.40. Thus, pimecrolimus loaded stents exhibited significantly lower percent stenosis and neointimal area as compared to bare metal control stents. FIGS. 15A and 15B are histologic slides illustrating bare metal stents after 28 days of implantation. FIGS. 16A and 16B are histologic slides illustrating stents coated with pimecrolimus after 28 days of implantation. As can be seen in a comparison between both sets of slides, the body lumens 19 implanted with pimecrolimus coated stents exhibit a significantly reduced stenotic build up (e.g., reduced stenotic percentage) as compared to the body lumens 19 implanted with bare metal control stents.

[0112] Example 10: An amino propyltriethoxysilane was attached to a passivated stainless steel DURAFLEX™ stent having dimensions of 3.0 mm x 14 mm, evolving ethanol as a by¬ product. The silylated stent was then reacted with acidic gelatin. The primary and/or secondary therapeutic agent was added to the gelatinous substance prior to the gelatinous substance being applied to the stent. In a similar example, the primary and/or secondary therapeutic agent was applied after the stent had been coated with the gelatinous substance.

[0113] Example 11 : Propanoldehyde triethoxysilane was attached to a passivated stainless steel stent by condensation reaction evolving ethanol as a by-product. Type B amino terminated gelatin was reacted with the aldehyde functional group of the silylated stent. The primary and/or secondary therapeutic agent was added to the gelatinous substance prior to the gelatinous substance being applied to the stent, hi a similar example, the primary and/or secondary therapeutic agent was applied after the stent had been coated with the gelatinous substance.

[0114] Example 12: A styrenated tri-ethoxysilane coupling agent was attached to a passivated stainless steel stent by condensation reaction evolving alcohol (e.g., methanol or ethanol) as a by-product. Styrenated gelatin was applied to the silylated stent. The primary and/or secondary therapeutic agent was added to the gelatinous substance prior to the gelatinous substance being applied to the stent. In a similar example, the primary and/or secondary therapeutic agent was applied after the stent had been coated with the gelatinous substance. The coated stent was then subjected to visible light in presence of carboxylated camporquinone initiator, causing the reaction between the styrene groups of the gelatin and the styrene groups present on the of the silylated stent. It is believed that this reaction formed cross-linked covalent bonds between gelatin and the groups on the silylated stent. The cross-link density may be controlled by adjusting the amount of styrenation in the gelatin molecule. It is further believed that controlling the cross-link density of the coating will help control the release or elution of the therapeutic agent from the coated stent.

[0115] Although certain embodiments and methods have been disclosed herein, it will be apparent from the foregoing disclosure to those skilled in the art that variations and modifications of such embodiments and methods can be made to the present invention. For example, individual features of one embodiment can be combined with any or all the features of another embodiment. As another example, the stent may be coated or provided with a jacket having one or more therapeutic or diagnostic agents incorporated therein. Terms such a "element", "member", "device", "section", "portion", "step", "means" and words of similar import when used herein shall not be construed as invoking the provisions of 35 U.S. C. § 112(6) unless the following claims expressly use the term "means" followed by a particular function without specific structure or the term "step" followed by a particular function without specific action. Unless described otherwise, conventional materials and methods of construction may be used to make the catheters and stents. Various alternatives, modifications, and equivalents may be employed without departing from the true spirit and scope of the present invention. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.

Claims

WHAT IS CLAIMED IS:

L A method for treating a patient, comprising: providing an intracorporeal device having a structure and a primary therapeutic agent associated with the structure, wherein the primary therapeutic agent includes pimecrolimus or a therapeutically effective pro-drug, analog, derivative or metabolite thereof; implanting the intracorporeal device at a site within the patient; and releasing the primary therapeutic agent at the site to deliver pimecrolimus or a therapeutically effective pro-drug, analog, derivative or metabolite thereof to susceptible tissue so as to inhibit restenosis.

2. The method of claim 1 , wherein the primary therapeutic agent acts to inhibit proinflammatory cytokine production or release.

3. The method of claim 1 , wherein releasing comprises delivering the primary therapeutic agent over a predetermined time period comprising an initial phase and a subsequent phase.

4. The method of claim 3, wherein the initial phase has a higher or steeper slope of pimecrolimus rate release as compared to the slope of pimecrolimus rate release during the subsequent phase.

5. The method of claim 1 , wherein releasing comprises increasing a concentration of the primary therapeutic agent to the susceptible tissue site.

6. The method of claim 5, wherein increasing the concentration of the primary therapeutic agent decreases undesirable proliferation of human smooth muscle cells.

7. The method of claim 1, wherein a concentration of the primary therapeutic agent is in a range from 0.01 μmol to 0.1 μmol so as to prevent undesirable proliferation of human smooth muscle cells.

8. The method of claim 1 , wherein a concentration of the primary therapeutic agent is greater than 0.03 μmol so as to prevent undesirable proliferation of human smooth muscle cells.

^ 9. The method of claim 1 , wherein a concentration of the primary therapeutic agent is greater than 0.2 μmol so as to prevent undesirable proliferation of human smooth muscle cells.

10. The method of claim 1 , wherein a concentration of the primary therapeutic agent is greater than 0.5 μmol so as to prevent undesirable proliferation of human smooth muscle cells.

11. The method of claim 10, wherein anti-proliferation of human smooth muscle cells is not due to toxicity of the primary therapeutic agent.

12. The method of claim 1 , wherein the primary therapeutic agent provides sufficient viability of human smooth muscle cells at concentrations up to 600 micrograms.

13. The method of claim 1 , wherein the implanted pimecrolimus intracorporeal device provides a reduced stenosis as compared to an implanted bare intracoporeal device.

14. The method of claim 1 , wherein the implanted intracorporeal device provides a reduced neointimal area as compared to an implanted bare intracoporeal device.

15. The method of claim 1 , wherein releasing comprises controlling the primary therapeutic agent release from the structure with a rate-controlling element.

16. The method of claim 15, further comprising eluting the primary therapeutic agent through cracks, fractures, openings, fissures, or perforations in the rate- controlloing element.

17. The method of claim 1 , wherein releasing comprises controlling the primary therapeutic agent release from the structure with a gelatinous substance.

18. The method of claim 1, wherein releasing comprises delivering the primary therapeutic agent over a time period in a range of about 1 day to about 200 days from the implanting of the intracorporeal device within the patient.

19. The method of claim 1, wherein releasing comprises delivering a total amount of the primary therapeutic agent in a range from about 0.1 microgram to about 10 grams.

20. The method of claim 1 , wherein releasing comprises delivering the primary therapeutic agent at a rate in a range from about 0.001 nanogram per day to about 500 micrograms per day.

21. The method of claim 1 , wherein releasing comprises delivering the at primary therapeutic agent to the susceptible tissue site so as to effectuate a mammalian tissue concentration ranging from about 0.001 nanograms of primary therapeutic agent per milligram of tissue to about 600 micrograms of primary therapeutic agent per milligram of tissue.

22. The method of claim 1, further comprising releasing to the susceptible tissue at least one secondary therapeutic agent associated with the structure.

23. The method of claim 22, wherein the at least one secondary therapeutic agent is selected from the group consisting of rapamycin, rapamycin analogs, and combinations thereof.

24. A method for treating a patient, comprising: providing an intracorporeal device having a structure, a primary therapeutic agent associated with the structure, and a rate-controlling element associated with the structure or primary therapeutic agent, wherein the primary therapeutic agent includes pimecrolimus or a therapeutically effective pro-drug, analog, derivative or metabolite thereof; implanting the intracorporeal device within the patient; and releasing the primary therapeutic agent from the structure to a susceptible tissue site by eluting pimecrolimus or a therapeutically effective pro-drug, analog, derivative or metabolite thereof though at least one mechanical disruption in the rate-controlloing element.

25. The method of claim 24, wherein the at least one mechanical disruption comprises a crack, fracture, opening, fissure, or perforation in the rate-controlling element.

26. A method for treating a patient, comprising: providing an intracorporeal device having a structure, a therapeutic agent associated with the structure, and a gelatinous substance associated with the therapeutic agent; implanting the intracorporeal device within the patient; and releasing the therapeutic agent from the structure to a susceptible tissue site through the gelatinous substance.

27. An intracorporeal device for therapeutic use in a patient's body, comprising: an expandable structure; and at least one primary therapeutic agent associated with the structure which includes pimecrolimus or a therapeutically effective pro-drug, analog, derivative or metabolite thereof and which is releasable in the patient's body so as to inhibit restenosis.

28. The device of claim 27, wherein the at least one primary therapeutic agent comprises a derivative of ascomycin macrolactam.

29. The device of claim 27, wherein the at least one primary therapeutic agent is disposed adjacent to at least one surface of the structure or within the interior of the structure.

30. The device of claim 27, further comprising a rate-controlling element disposed adjacent to at least one surface of the structure or within the interior of the structure.

31. The device of claim 30, wherein the rate-controlling element is disposed adjacent or mixed in with the at least one primary therapeutic agent.

32. The device of claim 30, wherein the rate-controlling element comprises a non-porous structure.

33. The device of claim 30, wherein the rate-controlling element comprises parylene or parylene C.

34. The device of claim 30, wherein the rate-controlling element comprises a structure with at least one mechanical disruption.

35. The device of claim 34, wherein the at least one mechanical disruption comprises a crack, fracture, opening, fissure, or perforation in the rate-controlling element.

36. The device of claim 30, wherein the rate-controlling element comprises gelatin.

37. The device of claim 27, further comprising a gelatinous substance associated with the at least one primary therapeutic agent.

38. The device of claim 37, wherein the gelatinous substance is bonded to a silane coupling agent formed adjacent to at least one surface of the structure.

39. The device of claim 38, wherein the silane coupling agent comprises one or more organo-functional groups and one or more silaiiol forming groups.

40. The device of claim 37, wherein the gelatinous substance comprises gelatin treated with acid or is styrenated.

41. The device of claim 27, further comprising at least one secondary therapeutic agent associated with the structure.

42. The device of claim 41, wherein the at least one secondary therapeutic agent is selected from the group consisting of rapamycin, rapamycin analogs, and combinations thereof.

43. An intracorporeal device for therapeutic use in a patient's body, comprising: an expandable structure; at least one therapeutic agent associated with the structure; and a gelatinous substance associated with the at least one therapeutic agent so as to control release of the at least one therapeutic agent from the structure into the patient's body so as to inhibit restenosis.

44. The device of claim 43, wherein the gelatinous substance is bonded to a silane coupling agent formed adjacent to at least one surface of the structure.

45. The device of claim 44, wherein the silane coupling agent comprises one or more organo-functional groups and one or more silanol forming groups.

46. The device of claim 43, wherein the gelatinous substance comprises gelatin treated with acid or styrenated.

47. The device of claim 43, wherein the at least one therapeutic agent is selected from the group consisting of immunosuppressants, antiinflammatories, anti- proliferatives, anti-migratory agents, anti-fibrotic agents, proapoptotics, vasodilators, calcium channel blockers, anti-neoplasties, anti-cancer agents, antibodies, anti-thrombotic agents, anti-platelet agents, Ilb/IIIa agents, antiviral agents, MTOR (mammalian target of rapamycin) inhibitors, non-immunosuppressant agents, tyrosine kinase inhibitors, CDK inhibitors, chemotherapeutic agents, thrombolytics, antimicrobials, antibiotics, antimitotics, growth factor antagonists, free radical scavengers, radiotherapeutic agents, radiopaque agents, radiolabeled agents, anti-coagulants, anti-angiogenesis agents, angiogenesis agents, PDGF-B and/or EGF inhibitors, ADP inhibitors, phosphodiesterase III inhibitors, glycoprotein Ilb/IIIa agents, adenosine reuptake inhibitors, healing and/or promoting agents, anti-oxidants, nitrogen oxide donors, antiemetics, antinauseants, bisphosphonates, NF-κB Decoy Oligo, proteins, oligomers, amino acids, peptides, genes, growth factors, anti-sense, derivatives, analogues, metabolites, pro-drugs, and/or combinations thereof.