US20040073294A1 - Method and apparatus for loading a beneficial agent into an expandable medical device - Google Patents

Method and apparatus for loading a beneficial agent into an expandable medical device Download PDF

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Publication number
US20040073294A1
US20040073294A1 US10/447,587 US44758703A US2004073294A1 US 20040073294 A1 US20040073294 A1 US 20040073294A1 US 44758703 A US44758703 A US 44758703A US 2004073294 A1 US2004073294 A1 US 2004073294A1
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US
United States
Prior art keywords
medical device
beneficial agent
openings
mandrel
dispensing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/447,587
Inventor
Stephen Diaz
Kinam Park
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innovational Holdings LLC
Original Assignee
Conor Medsystems LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Conor Medsystems LLC filed Critical Conor Medsystems LLC
Priority to US10/447,587 priority Critical patent/US20040073294A1/en
Priority to US10/668,125 priority patent/US20040127976A1/en
Priority to BR0314849-1A priority patent/BR0314849A/en
Priority to CA2752146A priority patent/CA2752146C/en
Priority to CA2499566A priority patent/CA2499566C/en
Priority to JP2004538367A priority patent/JP4532276B2/en
Priority to CNB038244780A priority patent/CN100482186C/en
Priority to PCT/US2003/029747 priority patent/WO2004026182A2/en
Priority to EP03754807.0A priority patent/EP1539039B1/en
Priority to KR1020057004788A priority patent/KR101079561B1/en
Priority to AU2003272615A priority patent/AU2003272615B2/en
Assigned to CONOR MEDSYSTEMS, INC. reassignment CONOR MEDSYSTEMS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PARK, KINAM, DIAZ, STEPHEN HUNTER
Priority to US10/822,063 priority patent/US20040220660A1/en
Publication of US20040073294A1 publication Critical patent/US20040073294A1/en
Priority to AU2004247027A priority patent/AU2004247027A1/en
Priority to JP2006533368A priority patent/JP2007501095A/en
Priority to EP11008893A priority patent/EP2433661A1/en
Priority to PCT/US2004/016315 priority patent/WO2004110302A2/en
Priority to EP04753187A priority patent/EP1628597A4/en
Priority to CA002525393A priority patent/CA2525393A1/en
Priority to US10/871,216 priority patent/US20040238978A1/en
Priority to US11/070,973 priority patent/US7658758B2/en
Priority to US11/252,824 priority patent/US20060096660A1/en
Priority to US11/325,223 priority patent/US20060178734A1/en
Assigned to INNOVATIONAL HOLDINGS LLC reassignment INNOVATIONAL HOLDINGS LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CONOR MEDSYSTEMS, INC.
Priority to US11/747,907 priority patent/US20080077233A1/en
Priority to AU2009202719A priority patent/AU2009202719B2/en
Assigned to INNOVATIONAL HOLDINGS LLC reassignment INNOVATIONAL HOLDINGS LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CONOR MEDSYSTEMS, INC.
Priority to JP2009283145A priority patent/JP5038385B2/en
Priority to US12/841,903 priority patent/US8349390B2/en
Priority to US13/736,752 priority patent/US9254202B2/en
Abandoned legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Definitions

  • the invention relates to a method and apparatus for loading a beneficial agent, such as a drug into an expandable medical device, and more particularly, the invention relates to a method and apparatus for dispensing a beneficial agent into an expandable medical device such as a stent.
  • Implantable medical devices are often used for delivery of a beneficial agent, such as a drug, to an organ or tissue in the body at a controlled delivery rate over an extended period of time. These devices may deliver agents to a wide variety of bodily systems to provide a wide variety of treatments.
  • Coronary stents are typically introduced percutaneously, and transported transluminally until positioned at a desired location. These devices are then expanded either mechanically, such as by the expansion of a mandrel or balloon positioned inside the device, or expand themselves by releasing stored energy upon actuation within the body. Once expanded within the lumen, these devices, called stents, become encapsulated within the body tissue and remain a permanent implant.
  • Known stent designs include monofilament wire coil stents (U.S. Pat. No. 4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and 4,776,337); and, most prominently, thin-walled metal cylinders with axial slots formed around the circumference (U.S. Pat. Nos. 4,733,665; 4,739,762; and 4,776,337).
  • Known construction materials for use in stents include polymers, organic fabrics and biocompatible metals, such as stainless steel, gold, silver, tantalum, titanium, and shape memory alloys, such as Nitinol.
  • restenosis is a major complication that can arise following vascular interventions such as angioplasty and the implantation of stents.
  • vascular interventions such as angioplasty and the implantation of stents.
  • restenosis is a wound healing process that reduces the vessel lumen diameter by extracellular matrix deposition, neointimal hyperplasia, and vascular smooth muscle cell proliferation, and which may ultimately result in renarrowing or even reocclusion of the lumen.
  • the overall restenosis rate is still reported in the range of 25% to 50% within six to twelve months after an angioplasty procedure. To treat this condition, additional revascularization procedures are frequently required, thereby increasing trauma and risk to the patient.
  • U.S. Pat. No. 5,716,981 discloses a stent that is surface-coated with a composition comprising a polymer carrier and paclitaxel (a well-known compound that is commonly used in the treatment of cancerous tumors).
  • paclitaxel a well-known compound that is commonly used in the treatment of cancerous tumors.
  • the patent offers detailed descriptions of methods for coating stent surfaces, such as spraying and dipping, as well as the desired character of the coating itself: it should “coat the stent smoothly and evenly” and “provide a uniform, predictable, prolonged release of the anti-angiogenic factor.”
  • Surface coatings can provide little actual control over the release kinetics of beneficial agents. These coatings are necessarily very thin, typically 5 to 8 microns deep.
  • the surface area of the stent by comparison is very large, so that the entire volume of the beneficial agent has a very short diffusion path to discharge into the surrounding tissue.
  • Increasing the thickness of the surface coating has the beneficial effects of improving drug release kinetics including the ability to control drug release and to allow increased drug loading.
  • the increased coating thickness results in increased overall thickness of the stent wall. This is undesirable for a number of reasons, including increased trauma to the vessel wall during implantation, reduced flow cross-section of the lumen after implantation, and increased vulnerability of the coating to mechanical failure or damage during expansion and implantation.
  • Coating thickness is one of several factors that affect the release kinetics of the beneficial agent, and limitations on thickness thereby limit the range of release rates, duration of drug delivery, and the like that can be achieved.
  • Another significant-problem is that expansion of the stent may stress the overlying polymeric coating causing the coating to plastically deform or even to rupture, which may therefore effect drug release kinetics or have other untoward effects. Further, expansion of such a coated stent in an atherosclerotic blood vessel will place circumferential shear forces on the polymeric coating, which may cause the coating to separate from the underlying stent surface. Such separation may again have untoward effects including embolization of coating fragments causing vascular obstruction.
  • the present invention relates to an apparatus and method for loading a beneficial agent in an expandable medical device.
  • a method for dispensing a beneficial agent into an expandable medical device includes the steps of placing an expandable medical device on a mandrel, the medical device forming a cylindrical device having a plurality of openings; and dispensing a beneficial agent into at least a portion of the plurality of openings.
  • a method for loading a beneficial agent in an expandable medical device includes the steps of dispensing a beneficial agent through a dispenser into a first opening in an expandable medical device; providing relative movement between the dispenser and the expandable medical device such that the dispenser is moved from alignment with the first opening in the expandable medical device to alignment with a second opening in the expandable medical device; and dispensing the beneficial agent into the second opening in the expandable medical device.
  • an apparatus for loading a beneficial agent in an expandable medical device includes a mandrel; an expandable medical device having a plurality of openings, the expandable medical device mounted on the mandrel; and a dispenser configured to dispense a beneficial agent into the plurality of openings in the expandable medical device.
  • a method for loading a stent with a beneficial agent includes the steps of providing a stent with a plurality of holes; and dispensing a beneficial agent through a piezo-electric micro-jet into the plurality of holes.
  • an apparatus for loading a beneficial agent in a medical device comprises a dispenser configured to dispense a beneficial agent into the plurality of openings in the medical device; an observation system configured to locate and identify the plurality of openings; and a central processing unit for controlling the dispensing of the beneficial agent into the openings of the medical device, wherein an amount and location of droplets of beneficial agent dispensed into each of the openings in the medical device is determined by the central processing unit based information obtained from the observation system.
  • a system for controlling a delivery of a beneficial agent into a plurality of openings of a medical device includes an observation system for mapping a medical device to obtain an actual position of a plurality of openings of the medical device; a central processing unit for comparing the actual position of the plurality of openings of the medical device to an anticipated position from a manufacturing specification; and a dispenser for dispensing a fluid beneficial agent into the plurality of openings.
  • a system for controlling a delivery of a beneficial agent into an opening includes a mandrel having a plurality of expandable medical devices; a dispenser configured to dispense a first layer and a second layer of a beneficial agent into a plurality of openings in the expandable medical device; and a central processing unit for controlling the dispensing of the beneficial agent into the openings of the expandable medical device.
  • a method of removing stents from a mandrel includes the steps of radially expanding the stents by injecting air into at least a portion of the mandrel to inflate the mandrel and expand the stents; deflating the mandrel; and sliding the expanded stents off the mandrel.
  • FIG. 1 is a perspective view of a therapeutic agent delivery device in the form of an expandable stent.
  • FIG. 2 is a cross-sectional view of a portion of a therapeutic agent delivery device having a beneficial agent contained in an opening in layers.
  • FIG. 3 is a cross-sectional view of a piezoelectric micro-jetting dispenser for delivery of a beneficial agent.
  • FIG. 4 is a cross-sectional view of a piezoelectric micro-jetting dispenser and an expandable medical device on a mandrel.
  • FIG. 5 is a perspective view of a system for loading an expandable medical device with a beneficial agent.
  • FIG. 6 is a perspective view of a bearing for use with the system of FIG. 5.
  • the present invention relates to a method and apparatus for loading a beneficial agent into an expandable medical device. More particularly, the invention relates to a method and apparatus for loading a beneficial agent in a stent.
  • beneficial agent as used herein is intended to have its broadest possible interpretation and is used to include any therapeutic agent or drug, as well as inactive agents such as barrier layers, carrier layers, therapeutic layers or protective layers.
  • drug and “therapeutic agent” are used interchangeably to refer to any therapeutically active substance that is delivered to a bodily conduit of a living being to produce a desired, usually beneficial, effect.
  • the present invention is particularly well suited for the delivery of antineoplastic, angiogenic factors, immuno-suppressants, anti-inflammatories and antiproliferatives (anti-restenosis agents) such as paclitaxel and Rapamycin for example, and antithrombins such as heparin, for example.
  • matrix or “biocompatible matrix” are used interchangeably to refer to a medium or material that, upon implantation in a subject, does not elicit a detrimental response sufficient to result in the rejection of the matrix.
  • the matrix typically does not provide any therapeutic responses itself, though the matrix may contain or surround a therapeutic agent, a therapeutic agent, an activating agent or a deactivating agent, as defined herein.
  • a matrix is also a medium that may simply provide support, structural integrity or structural barriers.
  • the matrix may be polymeric, non-polymeric, hydrophobic, hydrophilic, lipophilic, amphiphilic, and the like.
  • bioresorbable refers to a matrix, as defined herein, that can be broken down by either chemical or physical process, upon interaction with a physiological environment.
  • the bioresorbable matrix is broken into components that are metabolizable or excretable, over a period of time from minutes to years, preferably less than one year, while maintaining any requisite structural integrity in that same time period.
  • polymer refers to molecules formed from the chemical union of two or more repeating units, called monomers. Accordingly, included within the term “polymer” may be, for example, dimers, trimers and oligomers. The polymer may be synthetic, naturally-occurring or semisynthetic. In preferred form, the term “polymer” refers to molecules which typically have a M w greater than about 3000 and preferably greater than about 10,000 and a M w that is less than about 10 million, preferably less than about a million and more preferably less than about 200,000.
  • openings refers to holes of any shape and includes both through-openings and recesses.
  • FIG. 1 illustrates a medical device 10 according to the present invention in the form of a stent design with large, non-deforming struts 12 and links 14 , which can contain openings (or holes) 20 without compromising the mechanical properties of the struts or links, or the device as a whole.
  • the non-deforming struts 12 and links 14 may be achieved by the use of ductile hinges which are described in detail in U.S. Pat. No. 6,241,762 which is incorporated hereby by reference in its entirety.
  • the holes 20 serve as large, protected reservoirs for delivering various beneficial agents to the device implantation site.
  • the openings 20 can be circular 22 , rectangular 24 , or D-shaped 26 in nature and form cylindrical, rectangular, or D-shaped holes extending through the width of the medical device 10 . It can be appreciated that the openings 20 can be other shapes without departing from the present invention.
  • the volume of beneficial agent that can be delivered using openings 20 is about 3 to 10 times greater than the volume of a 5 micron coating covering a stent with the same stent/vessel wall coverage ratio.
  • This much larger beneficial agent capacity provides several advantages.
  • the larger capacity can be used to deliver multi-drug combinations, each with independent release profiles, for improved efficacy.
  • larger capacity can be used to provide larger quantities of less aggressive drugs and to achieve clinical efficacy without the undesirable side-effects of more potent drugs, such as retarded healing of the endothelial layer.
  • FIG. 2 shows a cross-section of a medical device 10 in which one or more beneficial agents have been loaded into the opening 20 in layers. Examples of some methods of creating such layers and arrangements of layers are described in U.S. patent application Ser. No. 09/948,989, filed on Sep. 7, 2001, which is incorporated herein by reference in its entirety. Although the layers are illustrated as discrete layers, the layers can also mix together upon delivery to result in an inlay of beneficial agent with concentration gradients of therapeutic agents but without distinct boundaries between layers.
  • the total depth of the opening 20 is about 100 to about 140 microns, typically 125 microns and the typical layer thickness would be about 2 to about 50 microns, preferably about 12 microns.
  • Each typical layer is thus individually about twice as thick as the typical coating applied to surface-coated stents.
  • each of the openings have an area of at least 5 ⁇ 10 ⁇ 6 square inches, and preferably at least 7 ⁇ 10 ⁇ 6 square inches.
  • the openings are filled about 50% to about 75% full of beneficial agent.
  • each layer is created independently, individual chemical compositions and pharmacokinetic properties can be imparted to each layer. Numerous useful arrangements of such layers can be formed, some of which will be described below.
  • Each of the layers may include one or more agents in the same or different proportions from layer to layer.
  • the layers may be solid, porous, or filled with other drugs or excipients. As mentioned above, although the layers are deposited separately, they may mix forming an inlay without boundaries between layers.
  • the opening 20 is filled with a beneficial agent.
  • the beneficial agent includes a barrier layer 40 , a therapeutic layer 30 , and a cap layer 50 .
  • different layers could be comprised of different therapeutic agents altogether, creating the ability to release different therapeutic agents at different points in time.
  • the layers of beneficial agent provide the ability to tailor a delivery profile to different applications. This allows the medical device according to the present invention to be used for delivery of different beneficial agents to a wide variety of locations in the body.
  • a protective layer in the form of a cap layer 50 is provided at a tissue contacting surface of a medical device.
  • the cap layer 50 can block or retard biodegradation of subsequent layers and/or blocks or retards diffusion of the beneficial agent in that direction for a period of time which allows the delivery of the medical device to a desired location in the body.
  • the barrier layer 40 is positioned on a side of the opening 20 facing the inside of the lumen. The barrier layer 40 prevents the therapeutic agent 30 from passing into the lumen and being carried away without being delivered to the lumen tissue.
  • the medical devices of the present invention can also be medical devices of other shapes useful for site-specific and time-release delivery of drugs to the body and other organs and tissues.
  • the drugs may be delivered to the vasculature including the coronary and peripheral vessels for a variety of therapies, and to other lumens in the body.
  • the drugs may increase lumen diameter, create occlusions, or deliver the drug for other reasons.
  • Medical devices and stents are useful for the prevention of amelioration of restenosis, particularly after percutaneous transluminal coronary angioplasty and intraluminal stent placement.
  • other agents such as anti-inflammatory agents may be incorporated into the multi-layers incorporated in the plurality of holes within the device. This allows for site-specific treatment or prevention any complications routinely associated with stent placements that are known to occur at very specific times after the placement occurs.
  • FIG. 3 shows a piezoelectric micro-jetting dispenser 100 used to dispense a beneficial agent into the opening of a medical device.
  • the dispenser 100 has a capillary tube 108 having a fluid outlet or orifice 102 , a fluid inlet 104 , and an electrical cable 106 .
  • the piezoelectric dispenser 100 preferably includes a piezo crystal 110 within a housing 112 for dispensing a fluid droplet through the orifice 102 .
  • the crystal 110 surrounds a portion of the capillary tube 108 and receives an electric charge that causes the crystal to vibrate. When the crystal vibrates inward, it forces a tiny amount of fluid out of the fluid outlet 102 of the tube 108 to fill an opening 20 in a medical device. In addition, when the crystal vibrates outward, the crystal pulls additional fluid into the tube 108 from a fluid reservoir connected to the inlet 104 to replace the fluid that has been dispensed into the opening of the medical device.
  • the micro-jetting dispenser 100 includes an annular piezoelectric (PZT) actuator 110 bonded to a glass capillary 108 .
  • the glass capillary 108 is connected at one end to a fluid supply (not shown) and at the other end has an orifice 102 generally in the range of about 0.5 to about 150 microns, and more preferably about 30 to about 60 microns.
  • PZT actuator When a voltage is applied to the PZT actuator, the cross-section of the capillary glass 108 is reduced/increased producing pressure variations of the fluid enclosed in the glass capillary 108 . These pressure variations propagate in the glass capillary 108 toward the orifice 102 .
  • the sudden change in cross-section (acoustic impedance) at the orifice 102 causes a droplet to be formed. This mode of producing droplets is generally called drop on demand (DOD).
  • DOD drop on demand
  • the micro-jetting dispenser 100 can require either positive or negative pressure at the fluid inlet 104 .
  • the pressure at the fluid inlet 104 can be provided by either a positive or a negative head by positioning of the fluid supply reservoir. For example, if the fluid reservoir is mounted only a few millimeters above the dispenser 100 , a constant positive pressure will be provided. However, if the fluid reservoir is mounted a few millimeters below the dispenser 100 , the orifice 102 will realize a negative pressure.
  • the pressure of the fluid at the inlet 104 can be regulated using existing compressed air or vacuum sources.
  • the pressure can be adjusted to provide a constant pressure flow to the dispenser 100 .
  • a wide range of fluids including beneficial agents can be dispensed through the dispenser 100 .
  • the fluids preferably have a viscosity of no greater than about 40 centipoise.
  • the droplet volume of the dispenser 100 is a function of the fluid, orifice 102 diameter, and actuator driving parameter (voltage and timing) and usually ranges from about 50 picoliters to about 200 picoliters per droplet. If a continuous droplet generation is desired, the fluid can be pressurized and a sinusoidal signal applied to the actuator to provide a continuous jetting of fluids. Depending on the beneficial agent dispensed, each droplet may appear more like a filament.
  • the dispenser is a piezoelectric microjetting device manufactured by MicroFab Technologies, Inc., of Plano, Tex.
  • the electric cable 106 is preferably connected to associated drive electronics (not shown) for providing a pulsed electric signal.
  • the electric cable 106 provides the electric signal to control the dispensing of the fluid through the dispenser 100 by causing the crystal to vibrate.
  • FIG. 4 shows an expandable medical device in the form of a stent 140 receiving a droplet 120 of a beneficial agent from a piezoelectric microjetting dispenser 100 .
  • the stent 140 is preferably mounted to a mandrel 160 .
  • the stent 140 can be designed with large, non-deforming struts and links (as shown in FIG. 1), which contain a plurality of openings 142 without compromising the mechanical properties of the struts or links, or the device as a whole.
  • the openings 142 serve as large, protected reservoirs for delivering various beneficial agents to the device implantation site.
  • the openings 142 can be circular, rectangular, or D-shaped in nature and form cylindrical, rectangular or D-shaped holes extending through the width of the stent 140 .
  • openings 142 having a depth less than the thickness of the stent 140 may also be used. It can be appreciated that other shaped holes 142 can be used without departing from the present invention.
  • the volume of the hole 142 will vary depending on the shape and size of the hole 142 .
  • a rectangular shaped opening 142 having a width of 0.1520 mm (0.006 inches) and a height of 0.1270 mm (0.005 inches) will have a volume of about 2.22 nanoliters.
  • a round opening having a radius of 0.0699 mm (0.00275 inches) will have a volume of about 1.87 nanoliters.
  • a D-shaped opening having a width of 0.1520 mm (0.006 inches) along the straight portion of the D has a volume of about 2.68 nanoliters.
  • the openings according to one example are about 0.1346 mm (0.0053 inches) in depth having a slight conical shape due to laser cutting.
  • FIG. 1 which includes ductile hinges
  • the beneficial agent may be contained in openings in stents having a variety of designs including many of the known stents.
  • the mandrel 160 can include a wire member 162 encapsulated by an outer jacket 164 of a resilient or a rubber-like material.
  • the wire member 162 may be formed from a metallic thread or wire having a circular cross-section.
  • the metallic thread or wire is preferably selected from a group of metallic threads or wire, including Nitinol, stainless steel, tungsten, nickel, or other metals having similar characteristics and properties.
  • the wire member 162 has an outer diameter of between about 0.889 mm (0.035 inches) and about 0.991 mm (0.039 inches) for use with a cylindrical or implantable tubular device having an outer diameter of about 3 mm (0.118 inches) and an overall length of about 17 mm (0.669 inches). It can be appreciated that the outer diameter of the wire member 162 will vary depending on the size and shape of the expandable medical device 140 .
  • Examples of rubber-like materials for the outer jacket 164 include silicone, polymeric materials, such as polyethylene, polypropylene, polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), polyurethane, polyamides, polyethylene terephthalate (PET), and their mixtures and copolymers.
  • PVC polyvinyl chloride
  • EVA ethyl vinyl acetate
  • PET polyethylene terephthalate
  • other materials for the outer jacket 164 can be implemented, including those rubber-like materials known to those skilled in the art.
  • the wire member 162 is encapsulated in a tubular outer jacket 164 having an inner diameter of about 0.635 mm (0.25 inches).
  • the outer jacket 164 can be mounted over the wire member 162 by inflating the tubular member to increase to a size greater than the outer diameter of the wire member 162 .
  • the tubular member can be inflated using an air pressure device known to those skilled in the art.
  • the wire member 162 is placed inside of the outer jacket 164 by floating the outer jacket 164 of silicon over the wire member 162 .
  • the wire member 162 can be encapsulated in an outer jacket of silicon or other rubber-like material by any method known to one skilled in the art.
  • a wire member 162 having an outer diameter of 0.939 mm (0.037 inches) is selected.
  • the wire member 162 is about 304.8 mm (12 inches) in length.
  • the outer jacket 164 has an inner diameter of about 0.635 mm (0.025 inches).
  • the expandable medical device or stent 140 is then loaded onto the mandrel 160 in any method known to one skilled in the art.
  • the stents 140 and the mandrel 160 are dipped into a volume of lubricant to lubricate the stents 140 and the mandrel 160 .
  • the stents 140 are then loaded onto the mandrel 160 .
  • the drying of the stents 140 and the mandrel 160 create a substantially firm fit of the stents 140 onto the mandrel 160 .
  • the stents 140 can be crimped onto the mandrel by a method known to one skilled in the art onto the mandrel 160 . The crimping ensures that the stents 140 will not move or rotate during mapping or filling of the openings.
  • FIG. 5 shows a system 200 for loading a beneficial agent in an expandable medical device.
  • the system 200 includes a dispenser 210 for dispensing a beneficial agent into an opening of an expandable medical device, a reservoir of beneficial agent 218 at least one observation system 220 , and a mandrel 230 having a plurality of expandable medical devices 232 attached to the mandrel 230 .
  • the system 200 also includes a plurality of bearings 240 for supporting the rotating mandrel 230 , a means for rotating and translating the mandrel 250 along a cylindrical axis of the expandable medical device 232 , a monitor 260 , and a central processing unit (CPU) 270 .
  • CPU central processing unit
  • the dispenser 210 is preferably a piezoelectric dispenser for dispensing a beneficial agent into the opening in the medical device 232 .
  • the dispenser 210 has a fluid outlet or orifice 212 , a fluid inlet 214 and an electrical cable 216 .
  • the piezoelectric dispenser 200 dispenses a fluid droplet through the orifice 212 .
  • At least one observation system 220 is used to observe the formation of the droplets and the positioning of the dispenser 210 relative to the plurality of openings in the medical device 232 .
  • the observation system 220 may include a charge coupled device (CCD) camera.
  • CCD charge coupled device
  • the first camera can be located above the micro-jetting dispenser 210 and observes the filling of the medical device 232 .
  • the first camera is also used for mapping of the mandrel 230 as will be described below.
  • a second camera is preferably located on a side of the micro-jetting dispenser 210 and observes the micro-jetting dispenser 210 from a side or orthogonal view.
  • the second camera is preferably used to visualize the micro-jetting dispenser during the positioning of the dispenser before loading of the medical device 232 with a beneficial agent.
  • the observation system 220 can include any number of visualization systems including a camera, a microscope, a laser, machine vision system, or other known device to one skilled in the art.
  • refraction of a light beam can be used to count droplets from the dispenser.
  • the total magnification to the monitor should be in the range of 50 to 100 times.
  • a LED synchronized light 224 with the PZT pulse provides lighting for the system 200 .
  • the delay between the PZT pulse and the LED pulse is adjustable, allowing the capture of the droplet formation at different stages of development.
  • the observation system 220 is also used in mapping of the mandrel 230 and medical devices 232 for loading of the openings.
  • the lighting is performed using a diffused flourescent lighting system. It can be appreciated that other lighting systems can be used without departing from the present invention.
  • a plurality of expandable medical devices 232 are mounted to the mandrel 230 as described above.
  • a mandrel which is about 12 inches in length can accommodate about 11 stents having a length of about 17 mm each.
  • Each mandrel 230 is labeled with a bar code 234 to ensure that each mandrel is properly identified, mapped, and then filled to the desired specifications.
  • the mandrel 230 is positioned on a plurality of bearings 240 .
  • the bearings 240 have a V-shaped notch 242 .
  • the mandrel 230 is positioned within the V-shaped notch 242 and secured using a clip 244 .
  • the clip 244 is preferably a coil spring, however, other means of securing the mandrel within the V-shaped notch can be used including any type of clip or securing means can be used.
  • the bearings 240 can be constructed of a metallic material, preferably different than the mandrel wire, such as stainless steel, copper, brass, or iron.
  • the mandrel 230 is connected to a means for rotating and translating the mandrel 250 along the cylindrical axis of the medical device 232 .
  • the means for rotating and translating the mandrel 250 can be any type or combination of motors or other systems known to one skilled in the art.
  • the mandrel 250 and medical device 232 are moved from a first position to a second position to fill the openings of the medical device 232 with the beneficial agent.
  • the system further includes a means for moving the dispensing system along the cylindrical axis of the medical device 232 from a first position to a second position.
  • a monitor 260 is preferably used to observe the loading of the medical device 232 with a beneficial agent. It can be appreciated that any type of monitor or other means of observing the mapping and loading process can be used.
  • a central processing unit 270 controls the loading of the medical device 232 with the beneficial agent.
  • the CPU 270 provides processing of information on the medical device 232 for the dispensing of the beneficial agent.
  • the CPU 270 is initially programmed with the manufacturing specifications as to the size, shape and arrangement of the openings in the medical device 232 .
  • a keyboard 272 is preferably used to assist with the loading of the CPU 270 and for input of information relating to the loading process.
  • the medical devices 232 are preferably affixed to the mandrel 230 and mapped prior to the loading process.
  • the mapping process allows the observation system and associated control system to determine a precise location of each of the openings which may vary slightly from device to device and mandrel to mandrel due to inaccuracies of loading the devices on the mandrels. This precise location of each of the openings is then saved as the specific map for that specific mandrel.
  • the mapping of the mandrel 230 is performed by using the observation system to ascertain the size, shape and arrangement of the openings of each medical device 232 located on the mandrel 230 . Once the mandrel 230 including the plurality of medical devices 232 have been mapped, the mapping results are compared to the manufacturing specifications to provide adjustments for the dispenser to correctly dispense the beneficial agent into each of the holes of the medical device 232 .
  • the mapping of the mandrel 230 is performed on an opening by opening comparison.
  • the observation system maps a first opening in the medical device and compares the mapping result to the manufacturing specifications. If the first opening is positioned as specified by the manufacturing specifications, no adjustment is needed. However, if the first opening is not positioned as specified by the manufacturing specifications, an adjustment is recorded and an adjustment is made during the dispensing process to correct for the position which is different than as specified in the manufacturing specifications. The mapping is repeated for each opening of the medical device until each medical device 232 has been mapped.
  • the mapping process can be designed to proceed to map at every other opening or to skip any number of openings without departing from the present invention.
  • the medical device 232 is filled with the beneficial agent based on the manufacturers' specification and adjustments from the mapping results.
  • the CPU provides the programmed data for filling of each medical device 232 .
  • the programmed data includes the medical device design code, date created, lot number being created, number of medical devices 232 on the mandrel, volume of each opening in the medical device 232 , different beneficial agents to be loaded or dispensed into the openings in the medical device 232 , the number of layers, drying/baking time for each layer, and any other data.
  • the medical device 232 will have at least 10 beneficial agent layers which will be filled including at least one barrier layer, at least one therapeutic layer having a beneficial agent, and at least one cap layer.
  • the beneficial agent layers may include layers which vary in concentration and strength of each solution of drug or therapeutic agent, amount of polymer, and amount of solvent.
  • the operator will input or scan the bar code 234 of the mandrel into the CPU 270 before the filling process begins.
  • the initial filling generally includes a mixture of polymer and solvent to create a barrier layer.
  • Each of the openings are typically filled to about 80% capacity and then the mandrel is removed from the system and placed into an oven for baking. The baking process evaporates the liquid portion or solvent from the openings leaving a solid layer.
  • the mandrel is typically baked for about 60 minutes plus or minus 5 minutes at about 55 degrees C.
  • the CPU software receives the bar code of the mandrel and will not begin filling the second layer until at least 60 minutes since the last filling.
  • the second layer and subsequent layers are then filled in the same manner as the first layer until the opening has been filled to the desired capacity.
  • the reservoir 218 can also be bar coded to identify the solution in the reservoir.
  • the observation system 220 also can verify that the dispenser 210 is dispensing the beneficial agent into the openings through either human observation on the monitor 270 or via data received from the observation system and conveyed to the CPU to confirm the dispensing of the beneficial agent in the openings of the medical device 232 .
  • refraction of a light beam can be used to count droplets dispensed at a high speed.
  • the dispensers 100 run very consistently for hours at a time, but will drift from day to day. Also, any small change in the waveform will change the drop size. Therefore, the output of the dispenser 100 can be calibrated by firing a known quantity of drops into a cup and then measuring the amount of drug in the cup. Alternatively, the dispenser 100 can be fired into a cup of known volume and the number of drops required to exactly fill it can be counted.
  • the micro-jetting dispenser 100 dispenses a plurality of droplets into the opening.
  • the dispenser is capable of dispensing 3000 shots per second through a micro-jetting dispenser of about 40 microns.
  • the droplets are preferably dispensed at between about 8 to 20 shots per hole depending on the amount of fill required.
  • the micro-jetting dispenser fills each hole (or the holes desired) by proceeding along the horizontal axis of the medical device 232 .
  • the CPU 270 turns the dispenser 100 on and off to fill the openings substantially without dispensing liquid between openings on the medical device.
  • the means for rotating the mandrel rotates the mandrel and a second passing of the medical device 232 along the horizontal axis is performed.
  • the medical devices 232 are stents having a diameter of about 3 mm and a length of about 17 mm and can be filled in about six passes. Once the medical device 232 is filled, the dispenser 210 moves to the next medical device 232 which is filled in the same manner.
  • the CPU 270 insures that the mandrel is filled accurately by having safety factors built into the filling process. It has also been shown that by filling the openings utilizing a micro-jetting dispenser, the amount of drugs or therapeutic agent used is substantially less than coating the medical device 232 using previously known method including spraying or dipping. In addition, the micro-jetting of a beneficial agent provides an improved work environment by exposing the worker to a substantially smaller quantity of drugs than by other known methods.
  • the system 200 also includes an electrical power source 290 which provides electricity to the piezoelectric micro-jetting dispenser 210 .
  • the medical devices 232 can be removed from the mandrel by expanding the devices and sliding them off the mandrel.
  • stents can be removed from the mandrel by injecting a volume of air between the outer diameter of the wire member 162 and the inner diameter of the outer jacket. The air pressure causes the medical device 232 to expand such that the inner diameter of the medical device 232 is greater than the outer diameter of the mandrel.
  • a die is place around the mandrel to limit the expansion of the medical device 232 as the air pressure between the outer diameter of the wire member 162 and the inner diameter of the outer jacket 164 .
  • the die can be constructed of stainless steel or plastics such that the medical devices 232 are not damaged during removal from the mandrel.
  • the medical devices 232 are removed four at a time from the mandrel.
  • a 12-inch mandrel will accommodate about 11, 3 mm by 17 mm medical devices having approximately 597 openings.
  • a plurality of medical devices preferably 11 medical devices per mandrel are placed onto a series of mandrels.
  • Each mandrel is bar coded with a unique indicia which identifies at least the type of medical device, the layers of beneficial agents to be loaded into the opening of the medical devices, and a specific identity for each mandrel.
  • the bar code information and the mapping results are stored in the CPU for loading of the stent.
  • a first mixture of poly(latide-co-glycolide) (PLGA) (Birmingham Polymers, Inc.), and a suitable solvent, such as DMSO is prepared.
  • the mixture is loaded by droplets into holes in the stent.
  • the stent is then preferably baked at a temperature of 55 degrees C. for about 60 minutes to evaporate the solvent to form a barrier layer.
  • a second layer is laid over the first by the same method of filling polymer solution into the opening followed by solvent evaporation. The process is continued until 9 individual layers have been loaded into the openings of the medical device to form the barrier layer.
  • a second mixture of paclitaxel, PLGA, and a suitable solvent such as DMSO forming a therapeutic layer is then introduced into the openings of the medical device over the barrier layer.
  • the solvent is evaporated to form a drug filled protective layer and the filling and evaporation procedure repeated until the hole is filled until the desired amount of paclitaxel has been added to the openings of the medical device.
  • a third mixture of PLGA and DMSO is then introduced into the openings over the therapeutic agent to form a cap layer.
  • the solvent is evaporated and the filling and evaporation procedure repeated until the cap layer has been added to the medical device, in this embodiment, a single cap layer has been added.
  • the reservoir is replaced and the piezoelectric micro-jetting dispenser is cleaned.
  • the replacement of the reservoir and cleaning of the dispenser insures that the different beneficial layers have a desired solution including the correct amount of drugs, solvent, and polymer.
  • the PLGA polymer degrades via hydrolysis and the paclitaxel is released.

Abstract

The present invention relates to method and apparatus for dispensing a beneficial agent into an expandable medical device. The method includes the step of placing an expandable medical device on a mandrel, the medical device forming a cylindrical device having a plurality of openings and dispensing a beneficial agent into the plurality of openings.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims priority to U.S. Provisional Patent Application Serial No. 60/412,489, filed on Sep. 20, 2002, which is incorporated herein by reference in its entirety.[0001]
  • FIELD OF THE INVENTION
  • The invention relates to a method and apparatus for loading a beneficial agent, such as a drug into an expandable medical device, and more particularly, the invention relates to a method and apparatus for dispensing a beneficial agent into an expandable medical device such as a stent. [0002]
  • DESCRIPTION OF THE RELATED ART
  • Implantable medical devices are often used for delivery of a beneficial agent, such as a drug, to an organ or tissue in the body at a controlled delivery rate over an extended period of time. These devices may deliver agents to a wide variety of bodily systems to provide a wide variety of treatments. [0003]
  • One of the many implantable medical devices which have been used for local delivery of beneficial agents is the coronary stent. Coronary stents are typically introduced percutaneously, and transported transluminally until positioned at a desired location. These devices are then expanded either mechanically, such as by the expansion of a mandrel or balloon positioned inside the device, or expand themselves by releasing stored energy upon actuation within the body. Once expanded within the lumen, these devices, called stents, become encapsulated within the body tissue and remain a permanent implant. [0004]
  • Known stent designs include monofilament wire coil stents (U.S. Pat. No. 4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and 4,776,337); and, most prominently, thin-walled metal cylinders with axial slots formed around the circumference (U.S. Pat. Nos. 4,733,665; 4,739,762; and 4,776,337). Known construction materials for use in stents include polymers, organic fabrics and biocompatible metals, such as stainless steel, gold, silver, tantalum, titanium, and shape memory alloys, such as Nitinol. [0005]
  • Of the many problems that may be addressed through stent-based local delivery of beneficial agents, one of the most important is restenosis. Restenosis is a major complication that can arise following vascular interventions such as angioplasty and the implantation of stents. Simply defined, restenosis is a wound healing process that reduces the vessel lumen diameter by extracellular matrix deposition, neointimal hyperplasia, and vascular smooth muscle cell proliferation, and which may ultimately result in renarrowing or even reocclusion of the lumen. Despite the introduction of improved surgical techniques, devices, and pharmaceutical agents, the overall restenosis rate is still reported in the range of 25% to 50% within six to twelve months after an angioplasty procedure. To treat this condition, additional revascularization procedures are frequently required, thereby increasing trauma and risk to the patient. [0006]
  • One of the techniques under development to address the problem of restenosis is the use of surface coatings of various beneficial agents on stents. U.S. Pat. No. 5,716,981, for example, discloses a stent that is surface-coated with a composition comprising a polymer carrier and paclitaxel (a well-known compound that is commonly used in the treatment of cancerous tumors). The patent offers detailed descriptions of methods for coating stent surfaces, such as spraying and dipping, as well as the desired character of the coating itself: it should “coat the stent smoothly and evenly” and “provide a uniform, predictable, prolonged release of the anti-angiogenic factor.” Surface coatings, however, can provide little actual control over the release kinetics of beneficial agents. These coatings are necessarily very thin, typically 5 to 8 microns deep. The surface area of the stent, by comparison is very large, so that the entire volume of the beneficial agent has a very short diffusion path to discharge into the surrounding tissue. [0007]
  • Increasing the thickness of the surface coating has the beneficial effects of improving drug release kinetics including the ability to control drug release and to allow increased drug loading. However, the increased coating thickness results in increased overall thickness of the stent wall. This is undesirable for a number of reasons, including increased trauma to the vessel wall during implantation, reduced flow cross-section of the lumen after implantation, and increased vulnerability of the coating to mechanical failure or damage during expansion and implantation. Coating thickness is one of several factors that affect the release kinetics of the beneficial agent, and limitations on thickness thereby limit the range of release rates, duration of drug delivery, and the like that can be achieved. [0008]
  • In addition to sub-optimal release profiles, there are further problems with surface coated stents. The fixed matrix polymer carriers frequently used in the device coatings typically retain approximately 30% of the beneficial agent in the coating indefinitely. Since these beneficial agents are frequently highly cytotoxic, sub-acute and chronic problems such as chronic inflammation, late thrombosis, and late or incomplete healing of the vessel wall may occur. Additionally, the carrier polymers themselves are often highly inflammatory to the tissue of the vessel wall. On the other hand, use of biodegradable polymer carriers on stent surfaces can result in the creation of “virtual spaces” or voids between the stent and tissue of the vessel wall after the polymer carrier has degraded, which permits differential motion between the stent and adjacent tissue. Resulting problems include micro-abrasion and inflammation, stent drift, and failure to re-endothelialize the vessel wall. [0009]
  • Another significant-problem is that expansion of the stent may stress the overlying polymeric coating causing the coating to plastically deform or even to rupture, which may therefore effect drug release kinetics or have other untoward effects. Further, expansion of such a coated stent in an atherosclerotic blood vessel will place circumferential shear forces on the polymeric coating, which may cause the coating to separate from the underlying stent surface. Such separation may again have untoward effects including embolization of coating fragments causing vascular obstruction. [0010]
  • In addition, it is not currently possible to deliver some drugs with a surface coating due to sensitivity of the drugs to water, other compounds, or conditions in the body which degrade the drugs. For example, some drugs lose substantially all their activity when exposed to water for a period of time. When the desired treatment time is substantially longer than the half life of the drug in water, the drug cannot be delivered by known coatings. Other drugs, such as protein or peptide based therapeutic agents, lose activity when exposed to enzymes, pH changes, or other environmental conditions. These drugs which are sensitive to compounds or conditions in the body often cannot be delivered using surface coatings. [0011]
  • Accordingly, it would be desirable to provide an apparatus and method for loading a beneficial agent into an expandable medical device, such as a stent, for delivery of agents, such as drugs, to a patient. [0012]
  • SUMMARY OF THE INVENTION
  • The present invention relates to an apparatus and method for loading a beneficial agent in an expandable medical device. [0013]
  • In accordance with one aspect of the invention, a method for dispensing a beneficial agent into an expandable medical device includes the steps of placing an expandable medical device on a mandrel, the medical device forming a cylindrical device having a plurality of openings; and dispensing a beneficial agent into at least a portion of the plurality of openings. [0014]
  • In accordance with another aspect of the invention, a method for loading a beneficial agent in an expandable medical device includes the steps of dispensing a beneficial agent through a dispenser into a first opening in an expandable medical device; providing relative movement between the dispenser and the expandable medical device such that the dispenser is moved from alignment with the first opening in the expandable medical device to alignment with a second opening in the expandable medical device; and dispensing the beneficial agent into the second opening in the expandable medical device. [0015]
  • In accordance with a further aspect of the invention, an apparatus for loading a beneficial agent in an expandable medical device includes a mandrel; an expandable medical device having a plurality of openings, the expandable medical device mounted on the mandrel; and a dispenser configured to dispense a beneficial agent into the plurality of openings in the expandable medical device. [0016]
  • In accordance with a further aspect of the invention, a method for loading a stent with a beneficial agent includes the steps of providing a stent with a plurality of holes; and dispensing a beneficial agent through a piezo-electric micro-jet into the plurality of holes. [0017]
  • In accordance with an additional aspect of the invention, an apparatus for loading a beneficial agent in a medical device comprises a dispenser configured to dispense a beneficial agent into the plurality of openings in the medical device; an observation system configured to locate and identify the plurality of openings; and a central processing unit for controlling the dispensing of the beneficial agent into the openings of the medical device, wherein an amount and location of droplets of beneficial agent dispensed into each of the openings in the medical device is determined by the central processing unit based information obtained from the observation system. [0018]
  • In accordance with another aspect of the invention, a system for controlling a delivery of a beneficial agent into a plurality of openings of a medical device includes an observation system for mapping a medical device to obtain an actual position of a plurality of openings of the medical device; a central processing unit for comparing the actual position of the plurality of openings of the medical device to an anticipated position from a manufacturing specification; and a dispenser for dispensing a fluid beneficial agent into the plurality of openings. [0019]
  • In accordance with a further aspect of the invention, a system for controlling a delivery of a beneficial agent into an opening includes a mandrel having a plurality of expandable medical devices; a dispenser configured to dispense a first layer and a second layer of a beneficial agent into a plurality of openings in the expandable medical device; and a central processing unit for controlling the dispensing of the beneficial agent into the openings of the expandable medical device. [0020]
  • In accordance with another aspect of the invention, a method of removing stents from a mandrel includes the steps of radially expanding the stents by injecting air into at least a portion of the mandrel to inflate the mandrel and expand the stents; deflating the mandrel; and sliding the expanded stents off the mandrel. [0021]
  • BRIEF DESCRIPTION OF THE DRAWING FIGURES
  • The invention will now be described in greater detail with reference to the preferred embodiments illustrated in the accompanying drawings, in which like elements bear like reference numerals, and wherein: [0022]
  • FIG. 1 is a perspective view of a therapeutic agent delivery device in the form of an expandable stent. [0023]
  • FIG. 2 is a cross-sectional view of a portion of a therapeutic agent delivery device having a beneficial agent contained in an opening in layers. [0024]
  • FIG. 3 is a cross-sectional view of a piezoelectric micro-jetting dispenser for delivery of a beneficial agent. [0025]
  • FIG. 4 is a cross-sectional view of a piezoelectric micro-jetting dispenser and an expandable medical device on a mandrel. [0026]
  • FIG. 5 is a perspective view of a system for loading an expandable medical device with a beneficial agent. [0027]
  • FIG. 6 is a perspective view of a bearing for use with the system of FIG. 5.[0028]
  • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention relates to a method and apparatus for loading a beneficial agent into an expandable medical device. More particularly, the invention relates to a method and apparatus for loading a beneficial agent in a stent. [0029]
  • First, the following terms, as used herein, shall have the following meanings: [0030]
  • The term “beneficial agent” as used herein is intended to have its broadest possible interpretation and is used to include any therapeutic agent or drug, as well as inactive agents such as barrier layers, carrier layers, therapeutic layers or protective layers. [0031]
  • The terms “drug” and “therapeutic agent” are used interchangeably to refer to any therapeutically active substance that is delivered to a bodily conduit of a living being to produce a desired, usually beneficial, effect. The present invention is particularly well suited for the delivery of antineoplastic, angiogenic factors, immuno-suppressants, anti-inflammatories and antiproliferatives (anti-restenosis agents) such as paclitaxel and Rapamycin for example, and antithrombins such as heparin, for example. [0032]
  • The term “matrix” or “biocompatible matrix” are used interchangeably to refer to a medium or material that, upon implantation in a subject, does not elicit a detrimental response sufficient to result in the rejection of the matrix. The matrix typically does not provide any therapeutic responses itself, though the matrix may contain or surround a therapeutic agent, a therapeutic agent, an activating agent or a deactivating agent, as defined herein. A matrix is also a medium that may simply provide support, structural integrity or structural barriers. The matrix may be polymeric, non-polymeric, hydrophobic, hydrophilic, lipophilic, amphiphilic, and the like. [0033]
  • The term “bioresorbable” refers to a matrix, as defined herein, that can be broken down by either chemical or physical process, upon interaction with a physiological environment. The bioresorbable matrix is broken into components that are metabolizable or excretable, over a period of time from minutes to years, preferably less than one year, while maintaining any requisite structural integrity in that same time period. [0034]
  • The term “polymer” refers to molecules formed from the chemical union of two or more repeating units, called monomers. Accordingly, included within the term “polymer” may be, for example, dimers, trimers and oligomers. The polymer may be synthetic, naturally-occurring or semisynthetic. In preferred form, the term “polymer” refers to molecules which typically have a M[0035] w greater than about 3000 and preferably greater than about 10,000 and a Mw that is less than about 10 million, preferably less than about a million and more preferably less than about 200,000.
  • The term “openings” refers to holes of any shape and includes both through-openings and recesses. [0036]
  • Implantable Medical Devices With Holes [0037]
  • FIG. 1 illustrates a [0038] medical device 10 according to the present invention in the form of a stent design with large, non-deforming struts 12 and links 14, which can contain openings (or holes) 20 without compromising the mechanical properties of the struts or links, or the device as a whole. The non-deforming struts 12 and links 14 may be achieved by the use of ductile hinges which are described in detail in U.S. Pat. No. 6,241,762 which is incorporated hereby by reference in its entirety. The holes 20 serve as large, protected reservoirs for delivering various beneficial agents to the device implantation site.
  • As shown in FIG. 1, the [0039] openings 20 can be circular 22, rectangular 24, or D-shaped 26 in nature and form cylindrical, rectangular, or D-shaped holes extending through the width of the medical device 10. It can be appreciated that the openings 20 can be other shapes without departing from the present invention.
  • The volume of beneficial agent that can be delivered using [0040] openings 20 is about 3 to 10 times greater than the volume of a 5 micron coating covering a stent with the same stent/vessel wall coverage ratio. This much larger beneficial agent capacity provides several advantages. The larger capacity can be used to deliver multi-drug combinations, each with independent release profiles, for improved efficacy. Also, larger capacity can be used to provide larger quantities of less aggressive drugs and to achieve clinical efficacy without the undesirable side-effects of more potent drugs, such as retarded healing of the endothelial layer.
  • FIG. 2 shows a cross-section of a [0041] medical device 10 in which one or more beneficial agents have been loaded into the opening 20 in layers. Examples of some methods of creating such layers and arrangements of layers are described in U.S. patent application Ser. No. 09/948,989, filed on Sep. 7, 2001, which is incorporated herein by reference in its entirety. Although the layers are illustrated as discrete layers, the layers can also mix together upon delivery to result in an inlay of beneficial agent with concentration gradients of therapeutic agents but without distinct boundaries between layers.
  • According to one example, the total depth of the [0042] opening 20 is about 100 to about 140 microns, typically 125 microns and the typical layer thickness would be about 2 to about 50 microns, preferably about 12 microns. Each typical layer is thus individually about twice as thick as the typical coating applied to surface-coated stents. There would be at least two and preferably about ten to twelve such layers in a typical opening, with a total beneficial agent thickness about 25 to 28 times greater than a typical surface coating. According to one preferred embodiment of the present invention, each of the openings have an area of at least 5×10−6 square inches, and preferably at least 7×10−6 square inches. Typically, the openings are filled about 50% to about 75% full of beneficial agent.
  • Since each layer is created independently, individual chemical compositions and pharmacokinetic properties can be imparted to each layer. Numerous useful arrangements of such layers can be formed, some of which will be described below. Each of the layers may include one or more agents in the same or different proportions from layer to layer. The layers may be solid, porous, or filled with other drugs or excipients. As mentioned above, although the layers are deposited separately, they may mix forming an inlay without boundaries between layers. [0043]
  • As shown in FIG. 2, the [0044] opening 20 is filled with a beneficial agent. The beneficial agent includes a barrier layer 40, a therapeutic layer 30, and a cap layer 50.
  • Alternatively, different layers could be comprised of different therapeutic agents altogether, creating the ability to release different therapeutic agents at different points in time. The layers of beneficial agent provide the ability to tailor a delivery profile to different applications. This allows the medical device according to the present invention to be used for delivery of different beneficial agents to a wide variety of locations in the body. [0045]
  • A protective layer in the form of a [0046] cap layer 50 is provided at a tissue contacting surface of a medical device. The cap layer 50 can block or retard biodegradation of subsequent layers and/or blocks or retards diffusion of the beneficial agent in that direction for a period of time which allows the delivery of the medical device to a desired location in the body. When the medical device 10 is a stent which is implanted in a lumen, the barrier layer 40 is positioned on a side of the opening 20 facing the inside of the lumen. The barrier layer 40 prevents the therapeutic agent 30 from passing into the lumen and being carried away without being delivered to the lumen tissue.
  • Typical formulations for therapeutic agents incorporated in these medical devices are well known to those skilled in the art. [0047]
  • Uses for Implantable Medical Devices [0048]
  • Although the present invention has been described with reference to a medical device in the form of a stent, the medical devices of the present invention can also be medical devices of other shapes useful for site-specific and time-release delivery of drugs to the body and other organs and tissues. The drugs may be delivered to the vasculature including the coronary and peripheral vessels for a variety of therapies, and to other lumens in the body. The drugs may increase lumen diameter, create occlusions, or deliver the drug for other reasons. [0049]
  • Medical devices and stents, as described herein, are useful for the prevention of amelioration of restenosis, particularly after percutaneous transluminal coronary angioplasty and intraluminal stent placement. In addition to the timed or sustained release of anti-restenosis agents, other agents such as anti-inflammatory agents may be incorporated into the multi-layers incorporated in the plurality of holes within the device. This allows for site-specific treatment or prevention any complications routinely associated with stent placements that are known to occur at very specific times after the placement occurs. [0050]
  • Methods and Systems for Loading a Beneficial Agent in a Medical Device [0051]
  • FIG. 3 shows a piezoelectric [0052] micro-jetting dispenser 100 used to dispense a beneficial agent into the opening of a medical device. The dispenser 100 has a capillary tube 108 having a fluid outlet or orifice 102, a fluid inlet 104, and an electrical cable 106. The piezoelectric dispenser 100 preferably includes a piezo crystal 110 within a housing 112 for dispensing a fluid droplet through the orifice 102. The crystal 110 surrounds a portion of the capillary tube 108 and receives an electric charge that causes the crystal to vibrate. When the crystal vibrates inward, it forces a tiny amount of fluid out of the fluid outlet 102 of the tube 108 to fill an opening 20 in a medical device. In addition, when the crystal vibrates outward, the crystal pulls additional fluid into the tube 108 from a fluid reservoir connected to the inlet 104 to replace the fluid that has been dispensed into the opening of the medical device.
  • In one embodiment as shown in FIG. 3, the [0053] micro-jetting dispenser 100 includes an annular piezoelectric (PZT) actuator 110 bonded to a glass capillary 108. The glass capillary 108 is connected at one end to a fluid supply (not shown) and at the other end has an orifice 102 generally in the range of about 0.5 to about 150 microns, and more preferably about 30 to about 60 microns. When a voltage is applied to the PZT actuator, the cross-section of the capillary glass 108 is reduced/increased producing pressure variations of the fluid enclosed in the glass capillary 108. These pressure variations propagate in the glass capillary 108 toward the orifice 102. The sudden change in cross-section (acoustic impedance) at the orifice 102, causes a droplet to be formed. This mode of producing droplets is generally called drop on demand (DOD).
  • In operation, the [0054] micro-jetting dispenser 100, depending on the viscosity and contact angle of the fluid, can require either positive or negative pressure at the fluid inlet 104. Typically, there are two ways to provide pressure at the fluid inlet 104. First, the pressure at the fluid inlet 104 can be provided by either a positive or a negative head by positioning of the fluid supply reservoir. For example, if the fluid reservoir is mounted only a few millimeters above the dispenser 100, a constant positive pressure will be provided. However, if the fluid reservoir is mounted a few millimeters below the dispenser 100, the orifice 102 will realize a negative pressure.
  • Alternatively, the pressure of the fluid at the [0055] inlet 104 can be regulated using existing compressed air or vacuum sources. For example, by inserting a pressure vacuum regulator between the fluid source and the dispenser 100, the pressure can be adjusted to provide a constant pressure flow to the dispenser 100.
  • In addition, a wide range of fluids including beneficial agents can be dispensed through the [0056] dispenser 100. The fluids preferably have a viscosity of no greater than about 40 centipoise. The droplet volume of the dispenser 100 is a function of the fluid, orifice 102 diameter, and actuator driving parameter (voltage and timing) and usually ranges from about 50 picoliters to about 200 picoliters per droplet. If a continuous droplet generation is desired, the fluid can be pressurized and a sinusoidal signal applied to the actuator to provide a continuous jetting of fluids. Depending on the beneficial agent dispensed, each droplet may appear more like a filament.
  • It can be appreciated that other fluid dispensing devices can be used without departing from the present invention. In one embodiment, the dispenser is a piezoelectric microjetting device manufactured by MicroFab Technologies, Inc., of Plano, Tex. [0057]
  • The [0058] electric cable 106 is preferably connected to associated drive electronics (not shown) for providing a pulsed electric signal. The electric cable 106 provides the electric signal to control the dispensing of the fluid through the dispenser 100 by causing the crystal to vibrate. FIG. 4 shows an expandable medical device in the form of a stent 140 receiving a droplet 120 of a beneficial agent from a piezoelectric microjetting dispenser 100. The stent 140 is preferably mounted to a mandrel 160. The stent 140 can be designed with large, non-deforming struts and links (as shown in FIG. 1), which contain a plurality of openings 142 without compromising the mechanical properties of the struts or links, or the device as a whole. The openings 142 serve as large, protected reservoirs for delivering various beneficial agents to the device implantation site. The openings 142 can be circular, rectangular, or D-shaped in nature and form cylindrical, rectangular or D-shaped holes extending through the width of the stent 140. In addition, openings 142 having a depth less than the thickness of the stent 140 may also be used. It can be appreciated that other shaped holes 142 can be used without departing from the present invention.
  • The volume of the [0059] hole 142 will vary depending on the shape and size of the hole 142. For example, a rectangular shaped opening 142 having a width of 0.1520 mm (0.006 inches) and a height of 0.1270 mm (0.005 inches) will have a volume of about 2.22 nanoliters. Meanwhile, a round opening having a radius of 0.0699 mm (0.00275 inches) will have a volume of about 1.87 nanoliters. A D-shaped opening having a width of 0.1520 mm (0.006 inches) along the straight portion of the D, has a volume of about 2.68 nanoliters. The openings according to one example are about 0.1346 mm (0.0053 inches) in depth having a slight conical shape due to laser cutting.
  • Although a tissue supporting device configuration has been illustrated in FIG. 1, which includes ductile hinges, it should be understood that the beneficial agent may be contained in openings in stents having a variety of designs including many of the known stents. [0060]
  • The [0061] mandrel 160 can include a wire member 162 encapsulated by an outer jacket 164 of a resilient or a rubber-like material. The wire member 162 may be formed from a metallic thread or wire having a circular cross-section. The metallic thread or wire is preferably selected from a group of metallic threads or wire, including Nitinol, stainless steel, tungsten, nickel, or other metals having similar characteristics and properties.
  • In one example, the [0062] wire member 162 has an outer diameter of between about 0.889 mm (0.035 inches) and about 0.991 mm (0.039 inches) for use with a cylindrical or implantable tubular device having an outer diameter of about 3 mm (0.118 inches) and an overall length of about 17 mm (0.669 inches). It can be appreciated that the outer diameter of the wire member 162 will vary depending on the size and shape of the expandable medical device 140.
  • Examples of rubber-like materials for the [0063] outer jacket 164 include silicone, polymeric materials, such as polyethylene, polypropylene, polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), polyurethane, polyamides, polyethylene terephthalate (PET), and their mixtures and copolymers. However, it can be appreciated that other materials for the outer jacket 164 can be implemented, including those rubber-like materials known to those skilled in the art.
  • In one embodiment, the [0064] wire member 162 is encapsulated in a tubular outer jacket 164 having an inner diameter of about 0.635 mm (0.25 inches). The outer jacket 164 can be mounted over the wire member 162 by inflating the tubular member to increase to a size greater than the outer diameter of the wire member 162. The tubular member can be inflated using an air pressure device known to those skilled in the art. The wire member 162 is placed inside of the outer jacket 164 by floating the outer jacket 164 of silicon over the wire member 162. However, it can be appreciated that the wire member 162 can be encapsulated in an outer jacket of silicon or other rubber-like material by any method known to one skilled in the art.
  • In one embodiment for loading stents having a diameter of about 3 mm (0.118 inches) and a length of about 17 mm (0.669 inches), a [0065] wire member 162 having an outer diameter of 0.939 mm (0.037 inches) is selected. In one example, the wire member 162 is about 304.8 mm (12 inches) in length. The outer jacket 164 has an inner diameter of about 0.635 mm (0.025 inches).
  • The expandable medical device or [0066] stent 140 is then loaded onto the mandrel 160 in any method known to one skilled in the art. In one embodiment, the stents 140 and the mandrel 160 are dipped into a volume of lubricant to lubricate the stents 140 and the mandrel 160. The stents 140 are then loaded onto the mandrel 160. The drying of the stents 140 and the mandrel 160 create a substantially firm fit of the stents 140 onto the mandrel 160. Alternatively, or in addition to drying, the stents 140 can be crimped onto the mandrel by a method known to one skilled in the art onto the mandrel 160. The crimping ensures that the stents 140 will not move or rotate during mapping or filling of the openings.
  • FIG. 5 shows a [0067] system 200 for loading a beneficial agent in an expandable medical device. The system 200 includes a dispenser 210 for dispensing a beneficial agent into an opening of an expandable medical device, a reservoir of beneficial agent 218 at least one observation system 220, and a mandrel 230 having a plurality of expandable medical devices 232 attached to the mandrel 230. The system 200 also includes a plurality of bearings 240 for supporting the rotating mandrel 230, a means for rotating and translating the mandrel 250 along a cylindrical axis of the expandable medical device 232, a monitor 260, and a central processing unit (CPU) 270.
  • The [0068] dispenser 210 is preferably a piezoelectric dispenser for dispensing a beneficial agent into the opening in the medical device 232. The dispenser 210 has a fluid outlet or orifice 212, a fluid inlet 214 and an electrical cable 216. The piezoelectric dispenser 200 dispenses a fluid droplet through the orifice 212.
  • At least one [0069] observation system 220 is used to observe the formation of the droplets and the positioning of the dispenser 210 relative to the plurality of openings in the medical device 232. The observation system 220 may include a charge coupled device (CCD) camera. In one embodiment, at least two CCD cameras are used for the filling process. The first camera can be located above the micro-jetting dispenser 210 and observes the filling of the medical device 232. The first camera is also used for mapping of the mandrel 230 as will be described below. A second camera is preferably located on a side of the micro-jetting dispenser 210 and observes the micro-jetting dispenser 210 from a side or orthogonal view. The second camera is preferably used to visualize the micro-jetting dispenser during the positioning of the dispenser before loading of the medical device 232 with a beneficial agent. However, it can be appreciated that the observation system 220 can include any number of visualization systems including a camera, a microscope, a laser, machine vision system, or other known device to one skilled in the art. For example, refraction of a light beam can be used to count droplets from the dispenser. The total magnification to the monitor should be in the range of 50 to 100 times.
  • In one embodiment, a LED synchronized light [0070] 224 with the PZT pulse provides lighting for the system 200. The delay between the PZT pulse and the LED pulse is adjustable, allowing the capture of the droplet formation at different stages of development. The observation system 220 is also used in mapping of the mandrel 230 and medical devices 232 for loading of the openings. In one embodiment, rather than using a LED synchronized light 224, the lighting is performed using a diffused flourescent lighting system. It can be appreciated that other lighting systems can be used without departing from the present invention.
  • A plurality of expandable [0071] medical devices 232 are mounted to the mandrel 230 as described above. For example, a mandrel which is about 12 inches in length can accommodate about 11 stents having a length of about 17 mm each. Each mandrel 230 is labeled with a bar code 234 to ensure that each mandrel is properly identified, mapped, and then filled to the desired specifications.
  • The [0072] mandrel 230 is positioned on a plurality of bearings 240. As shown in FIG. 6, one example of the bearings 240 have a V-shaped notch 242. The mandrel 230 is positioned within the V-shaped notch 242 and secured using a clip 244. The clip 244 is preferably a coil spring, however, other means of securing the mandrel within the V-shaped notch can be used including any type of clip or securing means can be used. The bearings 240 can be constructed of a metallic material, preferably different than the mandrel wire, such as stainless steel, copper, brass, or iron.
  • The [0073] mandrel 230 is connected to a means for rotating and translating the mandrel 250 along the cylindrical axis of the medical device 232. The means for rotating and translating the mandrel 250 can be any type or combination of motors or other systems known to one skilled in the art.
  • In one embodiment, the [0074] mandrel 250 and medical device 232 are moved from a first position to a second position to fill the openings of the medical device 232 with the beneficial agent. In an alternative embodiment, the system further includes a means for moving the dispensing system along the cylindrical axis of the medical device 232 from a first position to a second position.
  • A [0075] monitor 260 is preferably used to observe the loading of the medical device 232 with a beneficial agent. It can be appreciated that any type of monitor or other means of observing the mapping and loading process can be used.
  • A central processing unit [0076] 270 (or CPU) controls the loading of the medical device 232 with the beneficial agent. The CPU 270 provides processing of information on the medical device 232 for the dispensing of the beneficial agent. The CPU 270 is initially programmed with the manufacturing specifications as to the size, shape and arrangement of the openings in the medical device 232. A keyboard 272 is preferably used to assist with the loading of the CPU 270 and for input of information relating to the loading process.
  • The [0077] medical devices 232 are preferably affixed to the mandrel 230 and mapped prior to the loading process. The mapping process allows the observation system and associated control system to determine a precise location of each of the openings which may vary slightly from device to device and mandrel to mandrel due to inaccuracies of loading the devices on the mandrels. This precise location of each of the openings is then saved as the specific map for that specific mandrel. The mapping of the mandrel 230 is performed by using the observation system to ascertain the size, shape and arrangement of the openings of each medical device 232 located on the mandrel 230. Once the mandrel 230 including the plurality of medical devices 232 have been mapped, the mapping results are compared to the manufacturing specifications to provide adjustments for the dispenser to correctly dispense the beneficial agent into each of the holes of the medical device 232.
  • In an alternative embodiment, the mapping of the [0078] mandrel 230 is performed on an opening by opening comparison. In operation, the observation system maps a first opening in the medical device and compares the mapping result to the manufacturing specifications. If the first opening is positioned as specified by the manufacturing specifications, no adjustment is needed. However, if the first opening is not positioned as specified by the manufacturing specifications, an adjustment is recorded and an adjustment is made during the dispensing process to correct for the position which is different than as specified in the manufacturing specifications. The mapping is repeated for each opening of the medical device until each medical device 232 has been mapped. In addition, in one embodiment, if an opening is mapped and the opening is positioned pursuant to the manufacturing specifications, the mapping process can be designed to proceed to map at every other opening or to skip any number of openings without departing from the present invention.
  • After the mandrel has been mapped, the [0079] medical device 232 is filled with the beneficial agent based on the manufacturers' specification and adjustments from the mapping results. The CPU provides the programmed data for filling of each medical device 232. The programmed data includes the medical device design code, date created, lot number being created, number of medical devices 232 on the mandrel, volume of each opening in the medical device 232, different beneficial agents to be loaded or dispensed into the openings in the medical device 232, the number of layers, drying/baking time for each layer, and any other data.
  • In one embodiment, the [0080] medical device 232 will have at least 10 beneficial agent layers which will be filled including at least one barrier layer, at least one therapeutic layer having a beneficial agent, and at least one cap layer. The beneficial agent layers may include layers which vary in concentration and strength of each solution of drug or therapeutic agent, amount of polymer, and amount of solvent.
  • In operation, the operator will input or scan the [0081] bar code 234 of the mandrel into the CPU 270 before the filling process begins. The initial filling generally includes a mixture of polymer and solvent to create a barrier layer. Each of the openings are typically filled to about 80% capacity and then the mandrel is removed from the system and placed into an oven for baking. The baking process evaporates the liquid portion or solvent from the openings leaving a solid layer. The mandrel is typically baked for about 60 minutes plus or minus 5 minutes at about 55 degrees C. To assist in error prevention, the CPU software receives the bar code of the mandrel and will not begin filling the second layer until at least 60 minutes since the last filling. The second layer and subsequent layers are then filled in the same manner as the first layer until the opening has been filled to the desired capacity. The reservoir 218 can also be bar coded to identify the solution in the reservoir.
  • The [0082] observation system 220 also can verify that the dispenser 210 is dispensing the beneficial agent into the openings through either human observation on the monitor 270 or via data received from the observation system and conveyed to the CPU to confirm the dispensing of the beneficial agent in the openings of the medical device 232. Alternatively, refraction of a light beam can be used to count droplets dispensed at a high speed.
  • The [0083] dispensers 100 run very consistently for hours at a time, but will drift from day to day. Also, any small change in the waveform will change the drop size. Therefore, the output of the dispenser 100 can be calibrated by firing a known quantity of drops into a cup and then measuring the amount of drug in the cup. Alternatively, the dispenser 100 can be fired into a cup of known volume and the number of drops required to exactly fill it can be counted.
  • In filling the openings of the [0084] medical device 232, the micro-jetting dispenser 100 dispenses a plurality of droplets into the opening. In one preferred embodiment, the dispenser is capable of dispensing 3000 shots per second through a micro-jetting dispenser of about 40 microns. However, the droplets are preferably dispensed at between about 8 to 20 shots per hole depending on the amount of fill required. The micro-jetting dispenser fills each hole (or the holes desired) by proceeding along the horizontal axis of the medical device 232. The CPU 270 turns the dispenser 100 on and off to fill the openings substantially without dispensing liquid between openings on the medical device. Once the dispenser has reached an end of the medical device 232, the means for rotating the mandrel rotates the mandrel and a second passing of the medical device 232 along the horizontal axis is performed. In one embodiment, the medical devices 232 are stents having a diameter of about 3 mm and a length of about 17 mm and can be filled in about six passes. Once the medical device 232 is filled, the dispenser 210 moves to the next medical device 232 which is filled in the same manner.
  • The [0085] CPU 270 insures that the mandrel is filled accurately by having safety factors built into the filling process. It has also been shown that by filling the openings utilizing a micro-jetting dispenser, the amount of drugs or therapeutic agent used is substantially less than coating the medical device 232 using previously known method including spraying or dipping. In addition, the micro-jetting of a beneficial agent provides an improved work environment by exposing the worker to a substantially smaller quantity of drugs than by other known methods.
  • The [0086] system 200 also includes an electrical power source 290 which provides electricity to the piezoelectric micro-jetting dispenser 210.
  • The [0087] medical devices 232 can be removed from the mandrel by expanding the devices and sliding them off the mandrel. In one example, stents can be removed from the mandrel by injecting a volume of air between the outer diameter of the wire member 162 and the inner diameter of the outer jacket. The air pressure causes the medical device 232 to expand such that the inner diameter of the medical device 232 is greater than the outer diameter of the mandrel. In one embodiment, a die is place around the mandrel to limit the expansion of the medical device 232 as the air pressure between the outer diameter of the wire member 162 and the inner diameter of the outer jacket 164. The die can be constructed of stainless steel or plastics such that the medical devices 232 are not damaged during removal from the mandrel. In addition, in a preferred embodiment, the medical devices 232 are removed four at a time from the mandrel. A 12-inch mandrel will accommodate about 11, 3 mm by 17 mm medical devices having approximately 597 openings.
  • EXAMPLE 1
  • In the example below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. [0088]
    TABLE I
    Solutions Drug Polymer Solvent
    A None 4% PLGA DMSO
    50/50
    IV = 0.82
    DA 0.64% 8% PLGA DMSO
    paclitaxel
    50/50
    IV = 0.59
    DA 0.64% 8% PLGA DMSO
    paclitaxel
    50/50
    IV = 0.60
    DD 0.14% 8% PLGA DMSO
    paclitaxel
    50/50
    IV = 0.59
    L None 8% PLGA DMSO
    50/50
    IV = 0.59
  • [0089]
    TABLE II
    Layer
    No., this
    Layer No. Solution Solution
    1 A 1
    2 A 2
    3 A 3
    4 A 4
    5 A 5
    6 A 6
    7 A 7
    8 A 8
    9 A 9
    10 DA 1
    11 DA 2
    12 DD 1
    13 L 1
  • A plurality of medical devices, preferably 11 medical devices per mandrel are placed onto a series of mandrels. Each mandrel is bar coded with a unique indicia which identifies at least the type of medical device, the layers of beneficial agents to be loaded into the opening of the medical devices, and a specific identity for each mandrel. The bar code information and the mapping results are stored in the CPU for loading of the stent. [0090]
  • A first mixture of poly(latide-co-glycolide) (PLGA) (Birmingham Polymers, Inc.), and a suitable solvent, such as DMSO is prepared. The mixture is loaded by droplets into holes in the stent. The stent is then preferably baked at a temperature of 55 degrees C. for about 60 minutes to evaporate the solvent to form a barrier layer. A second layer is laid over the first by the same method of filling polymer solution into the opening followed by solvent evaporation. The process is continued until 9 individual layers have been loaded into the openings of the medical device to form the barrier layer. [0091]
  • A second mixture of paclitaxel, PLGA, and a suitable solvent such as DMSO forming a therapeutic layer is then introduced into the openings of the medical device over the barrier layer. The solvent is evaporated to form a drug filled protective layer and the filling and evaporation procedure repeated until the hole is filled until the desired amount of paclitaxel has been added to the openings of the medical device. [0092]
  • A third mixture of PLGA and DMSO is then introduced into the openings over the therapeutic agent to form a cap layer. The solvent is evaporated and the filling and evaporation procedure repeated until the cap layer has been added to the medical device, in this embodiment, a single cap layer has been added. [0093]
  • In order to provide a plurality of layers of beneficial agents having a desired solution, the reservoir is replaced and the piezoelectric micro-jetting dispenser is cleaned. The replacement of the reservoir and cleaning of the dispenser insures that the different beneficial layers have a desired solution including the correct amount of drugs, solvent, and polymer. [0094]
  • Following implantation of the filled medical device in vivo, the PLGA polymer degrades via hydrolysis and the paclitaxel is released. [0095]
  • While the invention has been described in detail with reference to the preferred embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made and equivalents employed, without departing from the present invention. [0096]

Claims (76)

What is claimed is:
1. A method for dispensing a beneficial agent into an expandable medical device, the method comprising:
placing an expandable medical device on a mandrel, the medical device forming a cylindrical device having a plurality of openings; and
dispensing a beneficial agent into the plurality of openings.
2. The method of claim 1, further comprising dispensing the beneficial agent with a piezoelectric microjetting dispenser.
3. The method of claim 2, further comprising moving the dispenser from a first position to a second position to fill the plurality of openings of the medical device with the beneficial agent.
4. The method of claim 2, further comprising moving the mandrel from a first position to a second position to fill the plurality of openings of the medical device with the beneficial agent.
5. The method of claim 1, further comprising rotating the mandrel to fill the plurality of openings with the beneficial agent.
6. The method of claim 1, wherein the plurality of openings have different volumes and the amount of beneficial agent dispensed is adjusted based on the size of the opening.
7. The method of claim 1, further comprising adjusting an amount of the beneficial agent dispensed into an opening based on an amount of beneficial agent previously dispensed into the opening.
8. The method of claim 1, wherein the medical device is an expandable intraluminal prosthesis.
9. The method of claim 1, wherein the medical device is a stent.
10. The method of claim 1, wherein the mandrel includes a resilient outer surface which seals a bottom side of the openings.
11. The method of claim 1, further comprising dissolving the beneficial agent in a solvent before dispensing.
12. The method of claim 1, wherein the beneficial agent comprises a drug.
13. The method of claim 1, further comprising filling the plurality of openings with a barrier layer comprising a matrix material.
14. The method of claim 1, further comprising filling the plurality of openings with a cap layer comprising a bioresorbable matrix.
15. The method of claim 1, further comprising lubricating the medical device and the mandrel and sliding the cylindrical device onto the mandrel.
16. The method of claim 1, further comprising mapping the medical device on the mandrel to obtain an actual specification of the medical device including locations of the openings.
17. The method of claim 16, wherein the mapping is performed by a camera.
18. The method of claim 16, wherein the mapping is performed by a machine vision system.
19. The method of claim 16, further comprising storing a plurality of coordinates from the mapping of the medical device on a central processing unit.
20. The method of claim 19, further comprising providing the central processing unit with a plurality of coordinates from a manufacturing specification for the medical device.
21. The method of claim 20, further comprising comparing the plurality of coordinates of the actual specification to the plurality of coordinates from the manufacturing specification for the medical device.
22. The method of claim 21, further comprising adjusting the dispensing of the beneficial agent based on a series of adjustments, the series of adjustments comprising comparing the plurality of coordinates of the actual specification to the plurality of coordinates from the manufacturing specification.
23. The method of claim 1, further comprising an observation system for observing the dispensing of the beneficial agent into the plurality of openings.
24. The method of claim 1, further comprising an observation system for mapping the medical device on the mandrel.
25. The method of claim 11, further comprising drying the mandrel to evaporate the solvent and then dispensing an additional beneficial agent into the plurality of openings.
26. The method of claim 11, further comprising baking the mandrel to evaporate the solvent and then dispensing an additional beneficial agent into the plurality of openings.
27. The method of claim 1, further comprising verifying the dispensing of the beneficial agent into the plurality of opening of the medical device.
28. The method of claim 27, wherein the verification step is performed using a refracted light beam.
29. The method of claim 27, wherein the verification step is performed using a camera.
30. The method of claim 10, further comprising removing the cylindrical device from the mandrel by inflating the resilient outer surface of the mandrel.
31. The method of claim 1, further comprising a plurality of bearings, the plurality of bearings providing a means for supporting the mandrel.
32. The method of claim 1, further comprising repeating the dispensing of the beneficial agent until the plurality of openings in the expandable medical device have been filled with the beneficial agent.
33. A method for loading a beneficial agent in an expandable medical device, the method comprising:
dispensing a beneficial agent through a dispenser into a first opening in an expandable medical device;
providing relative movement between the dispenser and the expandable medical device such that the dispenser is moved from alignment with the first opening in the expandable medical device to alignment with a second opening in the expandable medical device; and
dispensing the beneficial agent into the second opening in the expandable medical device.
34. The method of claim 33, further comprising repeating the relative movement between the dispenser and expandable medical device, and dispensing of the beneficial agent until the plurality of openings in the expandable medical device have been filled with the beneficial agent.
35. The method of claim 33, further comprising adjusting an amount of the beneficial agent dispensed into each of the openings based on a shape of each of the openings.
36. The method of claim 33, further comprising adjusting an amount of the beneficial agent dispensed into each of the openings based on a volume of each of the openings or a preprogrammed pattern of the openings.
37. The method of claim 33, wherein the expandable medical device is an expandable intraluminal prosthesis.
38. The method of claim 33, wherein the expandable medical device is a stent.
39. The method of claim 33, further comprising dissolving the beneficial agent in a solvent prior to dispensing.
40. The method of claim 33, further comprising mapping the expandable medical device on the mandrel to obtain an actual specification of the medical device including locations of the opening.
41. The method of claim 40, further comprising comparing the plurality of coordinates of the actual specification to the plurality of coordinates from the manufacturing specification.
42. The method of claim 41, further comprising adjusting the dispensing of the beneficial agent based on a series of adjustments, the series of adjustments comprising comparing the plurality of coordinates of the actual specification to the plurality of coordinates from the manufacturing specification.
43. The method of claim 33, further comprising an observation system to observe the dispensing of the beneficial agent into the plurality of openings.
44. The method of claim 33, further comprising a step of blocking a bottom side of the openings prior to dispensing.
45. An apparatus for loading a beneficial agent in an expandable medical device, the apparatus comprising:
a mandrel;
an expandable medical device having a plurality of openings, the expandable medical device mounted on the mandrel; and
a dispenser configured to dispense a beneficial agent into the plurality of openings in the expandable medical device.
46. The apparatus of claim 45, further comprising a plurality of bearings for receiving the mandrel.
47. The apparatus of claim 45, further comprising a central processing unit for controlling the dispensing of the beneficial agent into the openings of the expandable medical device.
48. The apparatus of claim 45, further comprising an observation system for dispensing the beneficial agent into the plurality of openings in the expandable medical device.
49. The apparatus of claim 48, wherein the observation system is used to map the mandrel including a plurality of expandable medical devices fixed thereto.
50. The apparatus of claim 48, further comprising a monitor for observing the dispensing of the beneficial agent into the plurality of openings of the expandable medical device.
51. The apparatus of claim 45, wherein an exterior surface of the mandrel is encapsulated with a rubber-like material.
52. The apparatus of claim 45, wherein the beneficial agent includes a solvent.
53. The apparatus of claim 45, wherein the dispenser is a piezoelectric micro-jetting dispenser.
54. The apparatus of claim 45, wherein the medical device is an expandable intraluminal prosthesis.
55. The apparatus of claim 45, wherein the medical device is a stent.
56. A method for loading a stent with a beneficial agent, the method comprising:
providing a stent with a plurality of holes; and
dispensing a beneficial agent through a piezo-electric microjet into the plurality of holes.
57. The method of claim 56, further comprising encapsulating the mandrel with a resilient material.
58. An apparatus for loading a beneficial agent in a medical device having a plurality of openings, the apparatus comprising:
a dispenser configured to dispense a beneficial agent into the plurality of openings in the medical device;
an observation system configured to locate and identify the plurality of openings; and
a central processing unit for controlling the dispensing of the beneficial agent into the openings of the medical device, wherein an amount and location of droplets of beneficial agent dispensed into each of the openings in the medical device is determined by the central processing unit based on information obtained from the observation system.
59. The apparatus of claim 58, further comprising a mandrel for mounting a plurality of medical devices.
60. The apparatus of claim 59, wherein the mandrel includes a resilient outer surface which seals a bottom side of the opening.
61. The apparatus of claim 58, wherein the plurality of openings have different volumes and the amount of beneficial agent dispensed is adjusted based on the volume of the opening.
62. The apparatus of claim 58, wherein the beneficial agent comprises a drug.
63. A system for controlling a delivery of a beneficial agent into a plurality of openings of a medical device, the system comprising:
an observation system for mapping a medical device to obtain an actual position of a plurality of openings of the medical device;
a central processing unit for comparing the actual position of the plurality of openings of the medical device to an anticipated position from a manufacturing specification; and
a dispenser for dispensing a fluid beneficial agent into the plurality of openings.
64. The system of claim 63, wherein the central processing unit compares the actual position of the medical device to the manufacturing specifications of the medical device on an opening by opening comparison.
65. The system of claim 63, wherein the central processing unit compares the actual position of the medical device to the manufacturing specification of the medical device on a medical device by medical device comparison.
66. The system of claim 63, wherein the medical device is on a mandrel.
67. The system of claim 63, wherein the fluid beneficial agent is delivered in droplets.
68. The system of claim 63, further comprising a motor providing relative movement between the dispenser and the medical device, such that the dispenser is moved from alignment with the first opening in the medical device to alignment with a second opening in the medical device.
69. The system of claim 63, wherein the medical device is an expandable intraluminal prosthesis.
70. The system of claim 63, wherein the medical device is a stent.
71. A system for controlling a delivery of a beneficial agent into an opening, the system comprising:
a mandrel having a plurality of expandable medical devices;
a dispenser configured to dispense a first layer and a second layer of a beneficial agent into a plurality of openings in the expandable medical device; and
a central processing unit for controlling the dispensing of the beneficial agent into the openings of the expandable medical device.
72. The system of claim 71, wherein the mandrel includes a resilient outer surface which seals a bottom side of the opening.
73. The system of claim 71, wherein the plurality of opening have different volumes and the amount of beneficial agent dispensed is adjusted based on the volume of the opening.
74. The system of claim 71, wherein the beneficial agent comprises a drug.
75. A method of removing stents from a mandrel, the method comprising:
radially expanding the stents by injecting air into at least a portion of the mandrel to inflate the mandrel and expand the stents;
deflating the mandrel; and
sliding the expanded stents off the mandrel.
76. The method claim 75, wherein the stents are radially constrained by a die during the inflation of the mandrel to prevent over expansion.
US10/447,587 2001-02-05 2003-05-28 Method and apparatus for loading a beneficial agent into an expandable medical device Abandoned US20040073294A1 (en)

Priority Applications (27)

Application Number Priority Date Filing Date Title
US10/447,587 US20040073294A1 (en) 2002-09-20 2003-05-28 Method and apparatus for loading a beneficial agent into an expandable medical device
JP2004538367A JP4532276B2 (en) 2002-09-20 2003-09-22 Device for filling expandable medical devices with beneficial agents
BR0314849-1A BR0314849A (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandably medical device
CA2752146A CA2752146C (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
CA2499566A CA2499566C (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
US10/668,125 US20040127976A1 (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
CNB038244780A CN100482186C (en) 2002-09-20 2003-09-22 Method and apparatus for loading a benefical agent into an expandable medical device
PCT/US2003/029747 WO2004026182A2 (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
EP03754807.0A EP1539039B1 (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
KR1020057004788A KR101079561B1 (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
AU2003272615A AU2003272615B2 (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
US10/822,063 US20040220660A1 (en) 2001-02-05 2004-04-08 Bioresorbable stent with beneficial agent reservoirs
CA002525393A CA2525393A1 (en) 2003-05-28 2004-05-21 Methods of delivering anti-restenotic agents from a stent
JP2006533368A JP2007501095A (en) 2003-05-28 2004-05-21 Method for supplying anti-restenosis agent from stent
EP04753187A EP1628597A4 (en) 2003-05-28 2004-05-21 Methods of delivering anti-restenotic agents from a stent
AU2004247027A AU2004247027A1 (en) 2003-05-28 2004-05-21 Methods of delivering anti-restenotic agents from a stent
EP11008893A EP2433661A1 (en) 2003-05-28 2004-05-21 Anti-restenotic agents to be delivered from a stent
PCT/US2004/016315 WO2004110302A2 (en) 2003-05-28 2004-05-21 Methods of delivering anti-restenotic agents from a stent
US10/871,216 US20040238978A1 (en) 2002-09-20 2004-06-18 Method and apparatus for loading a benefical agent into an expandable medical device
US11/070,973 US7658758B2 (en) 2001-09-07 2005-03-02 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/252,824 US20060096660A1 (en) 2002-09-20 2005-10-18 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/325,223 US20060178734A1 (en) 2003-05-28 2006-01-04 Methods of delivering anti-restenotic agents from a stent
US11/747,907 US20080077233A1 (en) 2002-09-20 2007-05-13 Method and apparatus for loading a beneficial agent into an expandable medical device
AU2009202719A AU2009202719B2 (en) 2002-09-20 2009-07-06 Method and apparatus for loading a beneficial agent into an expandable medical device
JP2009283145A JP5038385B2 (en) 2002-09-20 2009-12-14 Method of filling an expandable medical device with a beneficial agent
US12/841,903 US8349390B2 (en) 2002-09-20 2010-07-22 Method and apparatus for loading a beneficial agent into an expandable medical device
US13/736,752 US9254202B2 (en) 2002-09-20 2013-01-08 Method and apparatus for loading a beneficial agent into an expandable medical device

Applications Claiming Priority (2)

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US41248902P 2002-09-20 2002-09-20
US10/447,587 US20040073294A1 (en) 2002-09-20 2003-05-28 Method and apparatus for loading a beneficial agent into an expandable medical device

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US09/948,989 Continuation-In-Part US7208010B2 (en) 1998-03-30 2001-09-07 Expandable medical device for delivery of beneficial agent

Related Child Applications (7)

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US10/668,125 Continuation-In-Part US20040127976A1 (en) 2002-09-20 2003-09-22 Method and apparatus for loading a beneficial agent into an expandable medical device
US10/777,881 Continuation-In-Part US20040204756A1 (en) 2001-02-05 2004-02-11 Absorbent article with improved liquid acquisition capacity
US10/871,216 Continuation US20040238978A1 (en) 2002-09-20 2004-06-18 Method and apparatus for loading a benefical agent into an expandable medical device
US11/070,973 Continuation US7658758B2 (en) 2001-09-07 2005-03-02 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/252,824 Continuation US20060096660A1 (en) 2002-09-20 2005-10-18 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/747,907 Division US20080077233A1 (en) 2002-09-20 2007-05-13 Method and apparatus for loading a beneficial agent into an expandable medical device
US12/841,903 Division US8349390B2 (en) 2002-09-20 2010-07-22 Method and apparatus for loading a beneficial agent into an expandable medical device

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US10/447,587 Abandoned US20040073294A1 (en) 2001-02-05 2003-05-28 Method and apparatus for loading a beneficial agent into an expandable medical device
US10/871,216 Abandoned US20040238978A1 (en) 2002-09-20 2004-06-18 Method and apparatus for loading a benefical agent into an expandable medical device
US11/070,973 Active 2024-07-15 US7658758B2 (en) 2001-09-07 2005-03-02 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/252,824 Abandoned US20060096660A1 (en) 2002-09-20 2005-10-18 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/747,907 Abandoned US20080077233A1 (en) 2002-09-20 2007-05-13 Method and apparatus for loading a beneficial agent into an expandable medical device
US12/841,903 Expired - Lifetime US8349390B2 (en) 2002-09-20 2010-07-22 Method and apparatus for loading a beneficial agent into an expandable medical device
US13/736,752 Expired - Fee Related US9254202B2 (en) 2002-09-20 2013-01-08 Method and apparatus for loading a beneficial agent into an expandable medical device

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US10/871,216 Abandoned US20040238978A1 (en) 2002-09-20 2004-06-18 Method and apparatus for loading a benefical agent into an expandable medical device
US11/070,973 Active 2024-07-15 US7658758B2 (en) 2001-09-07 2005-03-02 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/252,824 Abandoned US20060096660A1 (en) 2002-09-20 2005-10-18 Method and apparatus for loading a beneficial agent into an expandable medical device
US11/747,907 Abandoned US20080077233A1 (en) 2002-09-20 2007-05-13 Method and apparatus for loading a beneficial agent into an expandable medical device
US12/841,903 Expired - Lifetime US8349390B2 (en) 2002-09-20 2010-07-22 Method and apparatus for loading a beneficial agent into an expandable medical device
US13/736,752 Expired - Fee Related US9254202B2 (en) 2002-09-20 2013-01-08 Method and apparatus for loading a beneficial agent into an expandable medical device

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US7658758B2 (en) 2010-02-09
CA2752146A1 (en) 2004-04-01
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CA2499566A1 (en) 2004-04-01
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US20110017346A1 (en) 2011-01-27
US20080077233A1 (en) 2008-03-27
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US20130127089A1 (en) 2013-05-23
US9254202B2 (en) 2016-02-09
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AU2009202719A1 (en) 2009-07-23
US20040238978A1 (en) 2004-12-02
WO2004026182A3 (en) 2004-07-15
US8349390B2 (en) 2013-01-08
US20070082120A1 (en) 2007-04-12
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US20060096660A1 (en) 2006-05-11
KR20050063768A (en) 2005-06-28

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