US20110001271A1 - Thermal Treatment Of An Implantable Medical Device - Google Patents

Thermal Treatment Of An Implantable Medical Device Download PDF

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Publication number
US20110001271A1
US20110001271A1 US12/879,938 US87993810A US2011001271A1 US 20110001271 A1 US20110001271 A1 US 20110001271A1 US 87993810 A US87993810 A US 87993810A US 2011001271 A1 US2011001271 A1 US 2011001271A1
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United States
Prior art keywords
polymer
temperature
coating
stent
stents
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
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US12/879,938
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English (en)
Inventor
Syed F. A. Hossainy
Yiwen Tang
Manish Gada
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Abbott Cardiovascular Systems Inc
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Advanced Cardiovascular Systems Inc
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Filing date
Publication date
Priority claimed from US09/390,855 external-priority patent/US6287628B1/en
Priority claimed from US09/390,069 external-priority patent/US6379381B1/en
Priority claimed from US09/470,559 external-priority patent/US6713119B2/en
Priority claimed from US09/715,510 external-priority patent/US6749626B1/en
Priority claimed from US09/750,595 external-priority patent/US6790228B2/en
Priority claimed from US10/108,004 external-priority patent/US20070032853A1/en
Priority claimed from US10/304,360 external-priority patent/US20030072868A1/en
Priority claimed from US10/603,794 external-priority patent/US7682647B2/en
Application filed by Advanced Cardiovascular Systems Inc filed Critical Advanced Cardiovascular Systems Inc
Priority to US12/879,938 priority Critical patent/US20110001271A1/en
Publication of US20110001271A1 publication Critical patent/US20110001271A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C71/00—After-treatment of articles without altering their shape; Apparatus therefor
    • B29C71/02—Thermal after-treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices

Definitions

  • U.S. patent application Ser. No. 10/603,794 is a continuation-in-part of U.S. patent application Ser. No. 09/750,595, and U.S. patent application Ser. No. 10/751,043 is a continuation of U.S. patent application Ser. No. 09/750,595, filed on Dec. 28, 2000, and which issued as U.S. Pat. No. 6,790,228 on Sep. 14, 2004.
  • U.S. patent application Ser. No. 09/750,595 is a continuation-in-part of U.S. patent application Ser. No. 09/470,559, filed on Dec. 23, 1999, which issued as U.S. Pat. No.
  • U.S. patent application Ser. No. 09/470,559 is a continuation-in-part of U.S. patent application Ser. No. 09/390,855, filed on Sep. 3, 1999 and issuing as U.S. Pat. No. 6,287,628 on Sep. 11, 2001, and U.S. patent application Ser. No. 09/470,559 is also a continuation-in-part of U.S. patent application Ser. No. 09/390,069, filed on Sep. 3, 1999 and issuing as U.S. Pat. No. 6,379,381 on Apr. 30, 2002.
  • U.S. patent application Ser. No. 09/750,595 is also a continuation-in-part of U.S. patent application Ser. No.
  • the invention relates to implantable medical devices, one example of which is a stent. More particularly, the invention relates to a method of thermally treating an implantable medical device that includes a polymer, for example, a polymeric coating on the device.
  • Percutaneous transluminal coronary angioplasty is a procedure for treating heart disease.
  • a catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery.
  • the catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion.
  • the balloon is inflated to a predetermined size to remodel the vessel wall.
  • the balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
  • a problem associated with the above procedure includes formation of intimal flaps or torn arterial linings, which can collapse and occlude the conduit after the balloon is deflated. Vasospasms and recoil of the vessel wall also threaten vessel closure. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may necessitate another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, a stent is implanted in the lumen to maintain the vascular patency.
  • Stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway.
  • stents are capable of being compressed so that they can be inserted through small lumens via catheters and then expanded to a larger diameter once they are at the desired location.
  • Mechanical intervention via stents has reduced the rate of restenosis as compared to balloon angioplasty.
  • restenosis is still a significant clinical problem with rates ranging from 20-40%. When restenosis does occur in the stented segment, its treatment can be challenging, as clinical options are more limited as compared to lesions that were treated solely with a balloon.
  • Stents are used not only for mechanical intervention but also as vehicles for providing biological therapy.
  • Biological therapy can be achieved by medicating the stents.
  • Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or even toxic side effects for the patient.
  • Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results.
  • One proposed method of medicating stents involves the use of a polymeric carrier coated onto the surface of the stent.
  • a composition including a solvent, a polymer dissolved in the solvent, and an active agent dispersed in the blend is applied to the stent by immersing the stent in the composition or by spraying the composition onto the stent.
  • the solvent is allowed to evaporate, leaving on the stent strut surfaces a coating of the polymer and the active agent impregnated in the polymer.
  • a stent coating can be exposed to significant stress, for example, radial expansion as the stent is deployed.
  • a potential shortcoming of the foregoing method of medicating stents is that the mechanical integrity of a polymeric drug coating can fail in the biological lumen, for example as a result of stress.
  • the polymeric coating may have poor adhesion to the surface of the stent.
  • the polymeric coating contains multiple layers of materials, the different layers may not attach well to each other and lack sufficient cohesiveness. Poor cohesion can result if there is inadequate interfacial compatibility between the surface of the stent and the polymer in the coating.
  • Another potential shortcoming of the foregoing method of medicating stents is that the release rate of the active agent may be too high to provide an efficacious treatment. This shortcoming may be especially pronounced with certain active agents. For instance, it has been found that the release rate of 40-O-(2-hydroxy)ethyl-rapamycin from a standard polymeric coating is greater than 50% in about 24 hours. Thus, there is a need for a coating that reduces the release rate of active agents in order to provide a more efficacious release rate profile.
  • release rate drift when stents are stored, the release rate from the stent coating can change during the storage time, known as “release rate drift.”
  • the present invention provides a method and coating to meet the foregoing as well as other needs.
  • a method of coating an implantable medical device including applying a composition to an implantable medical device, the composition including a polymer component and a solvent; and heating the polymer component to a temperature equal to or greater than the glass transition temperature of the polymer component.
  • the temperature is (a) equal to the glass transition temperature of the polymer component plus the melting temperature of the polymer component, divided by 2; (b) equal to 0.9 times the melting temperature of the polymer component, wherein the melting temperature of the polymer component is expressed in Kelvin; (c) less than the melting temperature of the polymer component; (d) greater than the melting temperature of the polymer component; or (e) equal to or greater than the crystallization temperature of the polymer component.
  • the polymer component is heated at a temperature equal to or greater than the glass transition temperature until a dry coating is formed on the device and optionally for a period of time thereafter, the dry coating comprising (a) less than about 10% residual solvent or water (w/w); (b) less than about 2% residual solvent or water (w/w); (c) less than about 1% residual solvent or water (w/w); or (d) 0% residual solvent or water (w/w).
  • the composition is free of any active agents, while in another embodiment, the composition further includes an active agent.
  • a method of manufacturing an implantable medical device including applying a semicrystalline polymer to an implantable medical device; and exposing the polymer to a temperature equal to or greater than the crystallization temperature of the polymer for a duration of time.
  • the polymer includes poly(lactic acid).
  • the polymer includes a block copolymer or a graft copolymer, wherein a moiety of the block copolymer or the graft copolymer is poly(lactic acid).
  • a method of manufacturing a stent having a body made at least in part from a polymer component comprising exposing the polymer component to a temperature equal to or greater than the glass transition temperature of the polymer component.
  • the stent is a biodegradable stent.
  • a method of manufacturing an implantable medical device including forming a first region including a first polymer on the device; forming a second region of a second polymer on the device, the second region including an active agent, the first region being over or under the second region; and heating (i) the first polymer to a temperature equal to or above the glass transition temperature of the first polymer, or (ii) the second polymer to a temperature equal to or above the glass transition temperature of the second polymer.
  • the first polymer has a glass transition temperature greater than the second polymer.
  • the second polymer has a glass transition temperature greater than the first polymer.
  • a method of manufacturing a stent coating including applying a composition to a stent, the composition including a polymer and a solvent; allowing some, most or all of the solvent to evaporate to form a coating; and exposing the coating to a temperature sufficient to increase the crystallinity of the polymer in at least a portion of the coating.
  • a method of manufacturing an implantable medical device including a polymer and a drug, where the method comprises treating the device to a temperature greater than ambient temperature for a duration of time, wherein the temperature and the duration of exposure are sufficient to decrease the release rate of the drug from the device after the device has been implanted into a biological lumen.
  • the device is made in whole or in part from the polymer.
  • the polymer is biodegradable.
  • the standard deviation of the mean release rate of the drug in a 24 hour period is lower than the standard deviation of the mean release rate for a group of devices which have not been exposed to the temperature.
  • a method of manufacturing a coating for an implantable medical device including exposing a polymeric coating on the device to a temperature greater than ambient temperature for a duration of time, wherein the temperature and the duration of exposure is sufficient to increase the adhesion of the polymeric coating to the device.
  • the polymeric coating is free from any active agents.
  • the polymeric coating includes an amorphous polymer.
  • the polymeric coating includes a bioabsorable polymer.
  • a method of forming a coating for an implantable medical device including (a) applying a first composition including a first polymer and a solvent on the device; (b) heating the first polymer to a temperature equal to or greater than about the glass transition temperature of the first polymer; (c) applying a second composition including a second polymer and a solvent over the first polymer; and (d) heating the second polymer to a temperature equal to or greater than about the glass transition temperature of the second polymer.
  • the heating of the first polymer is conducted after removal of some, most or all of the solvent in the first composition.
  • the heating of the second polymer is conducted after removal of some, most or all of the solvent in the second composition.
  • the first or the second composition but not both, additionally include an active agent.
  • FIGS. 1A-1H illustrate coatings deposited on an implantable medical substrate in accordance with various embodiments of the present invention
  • FIG. 2 is an illustration of a system for thermally treating stents
  • FIG. 3 is a graph of the relationship of heat capacity versus temperature for a polymer
  • FIG. 4 is graph of the relationship of elasticity versus temperature for a polymer
  • FIG. 5 is a graph of the relationship of specific volume versus temperature for a polymer
  • FIG. 6A illustrates a fluid on a solid substrate having a contact angle ⁇ 1 ;
  • FIG. 6B illustrates a fluid on a solid substrate having a contact angle ⁇ 2 ;
  • FIG. 7 graphically illustrates elution profiles for stents with a coating of ethylene vinyl alcohol copolymer impregnated with vinblastine made according to Example 4;
  • FIG. 8 graphically illustrates in vitro experimental data, in accordance with Example 15, showing affects of actinomycin D, mitomycin, and docetaxel on smooth muscle cell proliferation;
  • FIG. 9A is a picture of a histology slide of a coronary vessel from the control group in accordance with Example 16;
  • FIG. 9B is a picture of a histology slide of a coronary vessel from the actinomycin D group in accordance with Example 16;
  • FIG. 10A is a picture of a histology slide of a coronary vessel from the control group in accordance with Example 26;
  • FIG. 10B is a picture of a histology slide of a coronary vessel from the actinomycin D group in accordance with Example 26;
  • FIG. 11 is a graph showing the release rate of an active agent from stent coatings as referred to in Example 42;
  • FIG. 12 is a graph showing the release rate of an active agent from stent coatings as referred to in Example 53;
  • FIG. 13 is a chromatograph as referred to in Examples 68 and 69;
  • FIG. 14 is a graph showing the release rate of an active agent from stent coatings as referred to in Example 72;
  • FIGS. 15-19 are photographs as referred to in Example 103.
  • FIGS. 20-24 are graphs as referred to in Example 109.
  • the implantable medical device manufactured in accordance with embodiments of the present invention may be any suitable medical substrate that can be implanted in a human or veterinary patient.
  • the thermal treatment process can be directed to an implantable medical device having a body that includes a polymer, and optionally a drug.
  • the polymer is biodegradable, bioabsorbable or bioerodable.
  • the embodiments directed to a coating are equally applicable to a device, such as a stent, made from a polymer or a combination of polymers.
  • the thermal treatment process described herein includes exposing (i.e., heating) a polymer contained in a coating.
  • the polymer is exposed to a temperature sufficient to increase the adhesion of a coating to an implantable medical device.
  • the polymer is exposed to a temperature sufficient to decrease the release rate of an active agent from a drug coating on an implantable medical device.
  • “Polymer,” “poly,” and “polymeric” are inclusive of homopolymers, copolymers, terpolymers etc., including random, alternating, block, cross-linked, blends and graft variations thereof.
  • the active agent can be any substance capable of exerting a therapeutic or prophylactic effect.
  • FIGS. 1A-1H Some of the embodiments of polymeric coatings are illustrated by FIGS. 1A-1H .
  • the Figures have not been drawn to scale, and the thickness of the various layers have been over or under emphasized for illustrative purposes.
  • a body of a medical substrate 20 such as a stent, is illustrated having a surface 22 .
  • a primer layer 24 is deposited on surface 22 .
  • the polymer in primer layer 24 is free of any active agents, although incidental active agent migration into primer layer 24 can occur.
  • Primer layer 24 can include a poly(lactic acid).
  • a reservoir layer 26 having a polymer and an active agent 28 (e.g., 40-O-(2-hydroxy)ethyl-rapamycin, known by the trade name of everolimus, available from Novartis as CerticanTM) dispersed in the polymer is deposited on surface 22 .
  • Reservoir layer 26 can release the active agent when medical substrate 20 is inserted into a biological lumen.
  • reservoir layer 26 is deposited on primer layer 24 .
  • Primer layer 24 serves as an intermediary layer for increasing the adhesion between reservoir layer 26 and surface 22 .
  • Increasing the amount of active agent 28 admixed within the polymer can diminish the adhesiveness of reservoir layer 26 to surface 22 .
  • using an active agent-free polymer as an intermediary primer layer 24 allows for a higher active agent content for reservoir layer 26 .
  • the coating of the present invention can also have multiple primer and reservoir layers, the layers alternating between the two types of layers through the thickness of the coating.
  • medical substrate 20 can have primer layer 24 A deposited on surface 22 , followed by reservoir layer 26 A deposited on primer layer 24 A.
  • a second primer layer, primer layer 24 B can then be deposited on reservoir layer 26 A.
  • Reservoir layer 26 B is deposited over primer layer 24 B.
  • the different layers through the thickness of the coating can contain the same or different components.
  • primer layers 24 A and 24 B can contain the same or different polymers.
  • reservoir layers 26 A and 26 B can contain the same or different polymers and/or active agents.
  • the coating can also include a barrier layer.
  • medical substrate 20 is illustrated having reservoir layer 26 deposited on primer layer 24 .
  • a barrier layer or rate-reducing membrane 30 including a polymer is formed over at least a selected portion of reservoir layer 26 .
  • Barrier layer 30 functions to reduce the rate of release of active agent 28 from medical substrate 20 .
  • the coating can be constructed without a primer layer.
  • medical substrate 20 includes cavities or micro-pores 31 formed in the body for releasably containing active agent 28 .
  • Barrier layer 30 is disposed on surface 22 of medical substrate 20 , covering cavities 31 .
  • Barrier layer 30 can reduce the rate of release of active agent 28 from micropores 31 .
  • medical substrate 20 is illustrated having reservoir layer 26 deposited on surface 22 .
  • Barrier layer 30 is formed over at least a selected portion of reservoir layer 26 .
  • FIG. 1H illustrates, for example, medical substrate 20 having a first reservoir layer 26 A disposed on a selected portion of primer layer 24 .
  • First reservoir layer 26 A contains a first active agent, e.g., 40-O-(2-hydroxy)ethyl-rapamycin.
  • a second reservoir layer 26 B can also be disposed on primer layer 24 .
  • Second reservoir layer 26 B contains a second active agent, e.g., taxol.
  • First and second reservoir layers 26 A and 26 B are covered by first and second barrier layers 30 A and 30 B, respectively.
  • the particular components of reservoir layers 26 A and 26 B, and barrier layers 30 A and 30 B can be selected so that the release rate of the active agent from first reservoir layer 26 A is different or the same than the release rate of the active agent from second reservoir layer 26 B.
  • primer layer 24 can have any suitable thickness, examples of which can be in the range of about 0.1 to about 10 microns, more narrowly about 0.1 to about 1 micron.
  • Reservoir layer 26 can have any suitable thickness, for example, a thickness of about 0.1 microns to about 10 microns, more narrowly about 0.5 microns to about 6 microns.
  • the amount of the active agent to be included on medical substrate 20 can be further increased by applying a plurality of reservoir layers 24 on top of one another.
  • Barrier layer 30 can have any suitable thickness, for example, a thickness of about 0.1 to about 10 microns, more narrowly from about 0.25 to about 5 microns. The particular thickness of each layer is based on the type of procedure for which medical substrate 20 is employed, the amount of the active agent to be delivered, the rate at which the active agent is to be delivered, and the thickness of the other coating layers.
  • the method of the present invention includes exposing a polymer on a stent or a stent made from a polymer to a thermal treatment.
  • Treatment includes heating or exposing the polymer to a temperature and maintaining the temperature for a duration of time.
  • the duration of time can be less than a second, a second, minutes, or hours.
  • maintenance of temperature includes fluctuation in the temperature.
  • the temperature can be increased or decreased during treatment so long as it remains within the range of the selected temperature.
  • the thermal treatment is conducted on a composition applied to the stent, for example immediately after the composition has been applied to the stent while the composition on the stent is remains wet.
  • the composition for instance, can include a polymer (or polymers) and a solvent (or solvents), and optionally one or more active agents or drugs.
  • the thermal treatment can be terminated when the coating becomes dry or extended for a period of time subsequent to the drying of the coating.
  • the thermal treatment is conducted subsequent to the evaporation of the solvent, when the polymer is in a dry form.
  • the thermal treatment is conducted when the polymeric coating is a dry coating.
  • “Dry coating” is defined as a coating with less than about 10% residual fluid (e.g., solvent(s) or water) content (w/w). In one embodiment, the coating has less than about 2% residual fluid content (w/w), and more narrowly, less than about 1% residual fluid content (w/w). A coating can also have 0% residual fluid content (w/w).
  • the amount of residual fluids in the coating can be determined by a Karl Fisher, or ThermoGravimetric Analysis (TGA), study.
  • TGA ThermoGravimetric Analysis
  • a coated stent can be placed in the TGA instrument, and the weight change can be measured at 100° C. as an indication of water content, or measured at a temperature equal to the boiling temperature of the solvent used in the coating as an indication of the solvent content.
  • the stent can undergo the thermal treatment process at any appropriate stage of manufacture, such as before being packaged, or concurrently with or subsequent to the stent being secured onto a stent delivery device such as a catheter.
  • the stent coating can be exposed to the appropriate temperature as the stent is being crimped onto the delivery device, and then further coated with a polymeric drug coating material.
  • the heat source/emitter used to thermally treat the coating can be any apparatus that emits radiation capable of heating the polymeric coating.
  • the heat source can be a cauterizer tip, a RF source, or a microwave emitter.
  • the heat source can also be a blower that includes a heating device so that the blower can direct a warm gas onto the implantable device.
  • the gas can be inert (e.g., air, argon, nitrogen, etc.).
  • the heating device can be an electric heater incorporating heating coils or a system that includes a gas source and a computer controller to control the temperature of the gas directed at the stents.
  • a gas system for the thermal treatment process can include a gas source 40 , a flow controller 42 (e.g., a flow controller available from Eurotherm Control, Inc., Leesburg, Va.), an in-line heater 44 (e.g., an in-line heater available from Sylvania, Danvers, Mass.), a computer controller 46 , an air tight chamber 48 for holding a plurality of stents 50 and an exhaust 52 .
  • Computer controller 46 can be in communication with flow controller 42 and in-line heater 44 to control the amount of air and temperature, respectively, which is delivered to chamber 48 .
  • Exhaust 52 can provide a route for unwanted components (e.g., oxygen) to travel after being removed from the stent coatings.
  • In-line heater 44 can be used to precisely and gradually increase the temperature of the gas delivered by gas source 40 to the temperature used to conduct the thermal treatment.
  • a polymeric coating on a stent or a polymeric stent body is exposed to a temperature for a duration of time sufficient to improve the mechanical properties of the coating or the stent body.
  • the temperature can be above ambient temperature.
  • the temperature can also be below the melting temperature of the polymer.
  • a polymer in a primer layer can be exposed to the temperature to improve the mechanical properties of the primer layer.
  • the thermal treatment can be beneficial because the treatment can cause the primer layer to act as a more effective adhesive tie layer between the stent substrate and subsequently applied layers of polymer.
  • the heat treatment can cause the primer layer to act as a better adhesive tie layer between a metallic surface of the stent and a drug reservoir layer.
  • the thermal treatment process of a primer layer can improve adhesion of a drug-delivery coating on a stent by (1) improving the film formation of the primer layer (e.g., causing the polymeric primer layer to flow into imperfections (i.e., microcracks) in the stent substrate); (2) removing residual stresses in the coating; and/or (3) if the polymer is a semicrystalline polymer, increasing the crystallinity of the polymer.
  • the thermal treatment can also be beneficial because the treatment can improve the adhesion between multiple layers of coating material. Without being bound by any particular theory, it is believed that the thermal treatment process will improve adhesion by increasing polymer chain entanglement between the polymers of the different layers.
  • polymeric coatings having an active agent can be exposed to a temperature that is greater than ambient temperature and is sufficient to decrease the release rate of the active agent from the coating.
  • the coatings illustrated in FIGS. 1B-H can be exposed to the thermal treatment process to decrease the release rate of the active agent from the coatings.
  • an active agent such as 40-O-(2-hydroxy)ethyl-rapamycin
  • the coating can be exposed to a sufficient temperature effective to decrease the release rate of 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, by about 50% as compared to a control group, as demonstrated in Example 53 below.
  • the thermal treatment process can decrease the release rate of the active agent from the polymeric drug coating by redistributing the microphase distribution of the active agent in the coating, thereby causing the active agent to cluster.
  • the redistribution can decrease the surface area of the active agent clusters as the clusters are exposed to bodily fluids at the treatment site.
  • the thermal treatment can decrease the release rate of the active agent by (1) decreasing the free volume in an amorphous polymer; (2) increasing the crosslinking of the polymer in the coating; and (3) repairing minute imperfections in the coating such as cracks formed during the initial coating process.
  • an active agent has a greater diffusivity in the amorphous domain of a polymer as compared to the crystalline domain.
  • Most polymeric materials used for drug delivery stent coatings have some crystallinity and the degree of polymer crystallinity directly affects an active agent's diffusivity due to changes in free volume and the increase in the volume fraction of the crystalline phase.
  • the diffusion rate of the active agent from the polymer can be decreased because heating the polymer increases the percent crystallinity of the polymer.
  • thermal treatment process to treat a polymeric drug coating can increase the manufacturing consistency of drug delivery stents by reducing the variability of the release rate of active agents among stents.
  • the thermal treatment process can also reduce the release rate drift over time.
  • “Release rate drift” refers to the phenomenon in which the release rate of an active agent from a polymeric coating can change over time, for instance, while the stent is in storage. Release rate drift may occur because of changes in the morphology of a polymeric coating over a period of time, for example by exposure to degradation agents such as oxygen and moisture.
  • the standard deviation of the mean release rate of the active agent in a 24 hour period can be decreased so that the standard deviation is lower than the standard deviation of the mean release rate for a baseline group of stents (i.e., stents which have not been subjected to a thermal treatment process). It is believed that the thermal treatment process can increase manufacturing consistency by moving a polymeric stent coating closer to a thermodynamic equilibrium.
  • the polymer in the coating is a thermoplastic polymer.
  • the polymer in the coating is an amorphous polymer (e.g., D,L-poly(lactic acid)).
  • amorphous polymers refer to those polymers that are void of crystallinity. Amorphous polymers can be differentiated from semicrystalline or crystalline polymers by certain quantifiable characteristics. For example, as further described herein, amorphous polymers do not have a melting temperature (T m ) (while crystalline and semicrystalline polymers do have a T m ), and can have a sharp glass transition. It is believed that the heat treatment of an amorphous polymer in a coating can improve the polymeric film formation on the stent.
  • T m melting temperature
  • the polymer in the coating is a semicrystalline polymer (e.g., polyvinyl chloride or an ethylene vinyl alcohol copolymer).
  • semicrystalline polymers refer to those polymers that have at least some crystallinity.
  • Semicrystalline polymers can be differentiated from amorphous polymers by certain quantifiable characteristics. For example, as further described herein, semicrystalline polymers have a glass transition temperature (T g ) and a T m .
  • a polymeric coating including a semicrystalline polymer is exposed to the crystallization temperature (T c ) of the semicrystalline polymer or above the T c .
  • the polymer should have a T c greater than ambient temperature.
  • Crystallization temperature refers to the temperature at which a semicrystalline polymer has its highest percent crystallinity. Amorphous polymers do not exhibit a crystallization temperature.
  • the crystallization temperature of ethylene vinyl alcohol copolymer (44 mole % ethylene), for instance, is about 415° K.
  • Other examples of crystallization temperatures include 396° K for poly(ethylene terephthalate) as measured by differential scanning calorimetry (as reported by Parravicini et al., J. Appl.
  • composition components e.g., solvents
  • process parameters that are often used to coat stents do not allow for maximum crystallinity in the polymer matrix. If a highly volatile solvent is included in the composition, for example, then the polymer does not have sufficient time to fully crystallize before the solvent has evaporated from the coating. As noted above, it is believed that the primer layer can act as a more effective adhesive tie layer if the percent crystallinity of a semicrystalline polymer is increased by the heat treatment.
  • the release rate of a drug from the polymeric matrix can be reduced by increasing the percent of crystallinity of the polymeric coating (e.g., the reservoir and/or barrier layers.) “Percent crystallinity” refers to the percentage of the polymer material that is in a crystalline form. It is thought that the methods of the present invention can increase the percent crystallinity of the polymer by about 5 to 30, more narrowly about 20 to 30 percent crystallinity.
  • a second method involves the determination of the density of the crystalline portion via X-ray analysis of the crystal structure, and determining the theoretical density of a 100% crystalline material.
  • the density of the amorphous material can be determined from an extrapolation of the density from the melt to the temperature of interest. Then the percent crystallinity is given by:
  • ⁇ expt1 represents the experimental density
  • ⁇ amorph and ⁇ 100% cryst are the densities of the amorphous and crystalline portions, respectively.
  • a third method stems from the fact that X-ray diffraction depends on the number of electrons involved and is thus proportional to the density. Besides Bragg diffraction lines for the crystalline portion, there is an amorphous halo caused by the amorphous portion of the polymer. The amorphous halo occurs at a slightly smaller angle than the corresponding crystalline peak, because the atomic spacings are larger. The amorphous halo is broader than the corresponding crystalline peak, because of the molecular disorder.
  • This third method can be quantified by the crystallinity index, CI, where
  • a c and A a represent the area under the Bragg diffraction line and corresponding amorphous halo, respectively.
  • the thermal treatment process can be used to heat a polymeric coating on a stent to a temperature equal to or greater than a T g of a polymer included in the coating.
  • a polymer included in the coating both amorphous and semicrystalline polymers exhibit glass transition temperatures.
  • the polymeric coating can be exposed to a temperature equal to or greater than the T g and less than the T m of the polymer included in the coating.
  • the polymer is exposed to a temperature greater than the T m of the polymer included in the coating.
  • Amorphous polymers do not exhibit a T m .
  • the T g and T m of the polymer is greater than ambient temperature.
  • the polymer can include a crystalline component and an amorphous component.
  • the polymer is exposed to a temperature equal to or greater than the T g of one or both components.
  • the polymer is exposed to a temperature less than the T m of the crystalline component.
  • the polymer is exposed to a temperature greater than the T m of the crystalline component.
  • the polymeric coating is exposed to the annealing temperature of the polymer.
  • “Annealing temperature” refers to the temperature equal to (T g +T m )/2.
  • the annealing temperature for ethylene vinyl alcohol copolymer for instance, is about 383° K.
  • the polymeric coating can also be exposed, in another embodiment, to a temperature equal to 0.9 times the T m of the polymer, with the T m expressed in Kelvin (e.g., about 394° K for ethylene vinyl alcohol copolymer).
  • the T g is the temperature at which the amorphous domains of a polymer change from a brittle vitreous state to a plastic state at atmospheric pressure.
  • the T g corresponds to the temperature where the onset of segmental motion in the chains of the polymer occurs.
  • T g of a given polymer can be dependent on the heating rate and can be influenced by the thermal history of the polymer. Furthermore, the chemical structure of the polymer heavily influences the glass transition by affecting mobility. Generally, flexible main-chain components lower the T g ; bulky side-groups raise the T g ; increasing the length of flexible side-groups lowers the T g ; and increasing main-chain polarity increases the T g . Additionally, the presence of crosslinking polymeric components can increase the observed T g for a given polymer. For instance, FIG.
  • the T m of a polymer is the temperature at which the last trace of crystallinity in a polymer disappears as a sample is exposed to increasing heat.
  • the T m of a polymer is also known as the fusion temperature (T f ).
  • T f fusion temperature
  • the T m of a given polymer is influenced by the structure of the polymer.
  • the most influential inter- and intramolecular structural characteristics include structural regularity, bond flexibility, close-packing ability, and interchain attraction.
  • high melting points are associated with highly regular structures, rigid molecules, close-packing capability, strong interchain attraction, or two or more of these factors combined.
  • FIG. 3 illustrates the change in heat capacity (endothermic v. exothermic) of a semicrystalline polymer as the polymer is exposed to an increasing temperature, as measured by the differential scanning calorimetry (DSC) method.
  • DSC uses the relationship between heat capacity and temperature as the basis for determining the thermal properties of polymers and is further described below.
  • the crystallinity of the polymer begins to increase as the increasing temperature reaches the T g .
  • the increased molecular motion of the polymer allows the polymer chains to move around more to adopt a more thermodynamically stable relationship, and thereby increase the percent crystallinity of the polymer sample.
  • the T g is shown as point T g of first curve 60 , which is the temperature at which half of the increase in heat capacity ( ⁇ C p ) has occurred.
  • the percent crystallinity then increases rapidly after point T g and is maximized at the T c of the polymer, which is indicated at the point T c (the apex of second curve 62 ). As the temperature continues to increase, the temperature approaches the T m of the polymer, and the percent crystallinity decreases until the temperature reaches the melting temperature of the polymer (at point T m of curve 64 ). As noted above, T m is the temperature where the last trace of crystallinity in the polymer disappears.
  • the heat of crystallization, ⁇ H c , and the heat of fusion, ⁇ H f can be calculated as the areas under curves 62 and 64 . The heat of crystallization and heat of fusion must be equal, but with opposite signs.
  • test polymer means the polymer that is measured to determine the T g and/or the T m of the polymer.
  • Coating polymer means the polymer that is actually applied as a component of the stent coating, in other words, the one or more polymers applied as components of the primer layer, drug reservoir layer and barrier layer.
  • the factors include (1) the structure of the polymer (e.g., modification of side groups and dissimilar stereoregularity); (2) the molecular weight of the polymer; (3) the molecular-weight distribution (M w /M n ) of the polymer; (4) the crystallinity of the polymer; (5) the thermal history of the polymer; (6) additives or fillers that are included in the polymer; (7) the pressure applied to the polymer as the polymer is heated; (8) residual fluids in the polymer; (9) the rate that the polymer is heated; and (10) the method used to apply the polymer to the substrate (e.g., a controlled deposition process as compared to a spray coating process).
  • the factors include (1) the structure of the polymer (e.g., modification of side groups and dissimilar stereoregularity); (2) the molecular weight of the polymer; (3) the molecular-weight distribution (M w /M n ) of the polymer; (4) the crystallinity of the polymer; (5)
  • test polymer that is substantially the same as the coating polymer, and is tested under substantially the same conditions as the conditions used to conduct the thermal treatment of the polymeric coating.
  • the test polymer should have the same chemical structure as the coating polymer, and should have substantially the same molecular weight and molecular-weight distribution as the coating polymer. For example, if the polymer is a blend of copolymers or homopolymers, the test polymer should have substantially the same percentage of components as the coating polymer. At the same time, the test polymer should have substantially the same crystallinity as the coating polymer. Methods of determining cystallinity are discussed herein.
  • the composition used to form the test polymer should include the same compounds (e.g., additives such as therapeutic substances) and fluids (e.g., solvent(s) and water) that are mixed with the coating polymer.
  • the test polymer should have the same thermal history as the coating polymer.
  • the test polymer should be prepared under the same conditions as the coating polymer, such as using the same solvent, temperature, humidity and mixing conditions.
  • the heating rate used for measuring the transition temperature of the test polymer should be substantially similar to the heating rate used to conduct the thermal treatment of the polymeric coating.
  • the method used to apply the test polymer to the substrate should be the same as the method used to apply the polymeric coating to the stent.
  • the T g and T m of the test polymer can be measured experimentally by testing a bulk sample of the polymer.
  • a bulk sample of the polymer can be prepared by standard techniques, for example those that are outlined in the documentation accompanying the instruments used to measure the transition temperature of the polymer.
  • T g and T m can be measured experimentally by measuring any one of several basic thermodynamic, physical, mechanical, or electrical properties as a function of temperature. Methods of measuring glass transition temperatures and melting temperatures are understood by one of ordinary skill in the art and are discussed by, for example, L. H. Sperling, Introduction to Physical Polymer Science, Wiley-Interscience, New York (3 rd ed. 2001); and R. F. Boyer, in Encyclopedia of Polymer Science and Technology, Suppl. Vol. 2, N. M. Bikales, ed., Interscience, New York (1977).
  • the T g of a bulk sample can be observed by measuring the expansion of the polymer as the polymer is exposed to increasing temperature. This process is known as dilatometry.
  • dilatometry There are at least two ways of characterizing polymers via dilatometry. One way is to measure the linear expansivity of the polymer sample. Another method involves performing volume-temperature measurements, where the polymer is confined by a liquid and the change in volume is recorded as the temperature is raised. The usual confining liquid is mercury, since it does not swell organic polymers and has no transition of its own through most of the temperature range of interest. The results may be plotted as specific volume versus temperature as shown in FIG. 5 , which illustrates a representative example of a dilatometric study of branched poly(vinyl acetate).
  • T g the elbow in volume-temperature studies is not sharp (measurements of T g using dilatometric studies show a dispersion of about 20-30° C.), the two straight lines below and above the transition are extrapolated until they meet. The extrapolated meeting point is taken as the T g .
  • a representative example of an apparatus that can be used to measure a T g via dilatometric studies is the Dilatometer DIL 402 PC (available from Netzsch, Inc., Exton, Pa.).
  • Thermal methods can also be used to measure the T g of a bulk sample.
  • Two closely related methods are differential thermal analysis (DTA), and differential scanning calorimetry (DSC). Both methods yield peaks relating to endothermic and exothermic transitions and show changes in heat capacity.
  • DTA differential thermal analysis
  • DSC differential scanning calorimetry
  • Both methods yield peaks relating to endothermic and exothermic transitions and show changes in heat capacity.
  • a representative example of a DTA apparatus is the Rheometrics STA 1500 which provides simultaneous thermal analysis via DTA and DSC.
  • the DSC method In addition to the information that can be produced by a DTA, the DSC method also yields quantitative information relating to the enthalpic changes in the polymer (the heat of fusion of the temperature, ⁇ H f ).
  • the DSC method uses a servo system to supply energy at a varying rate to the sample and the reference, so that the temperatures of the two stay equal.
  • the DSC output plots energy supplied against average temperature. By this method, the areas under the peaks can be directly related to the enthalpic changes quantitatively.
  • the T g can be taken as the temperature at which one-half of the increase in the heat capacity, ⁇ C p , has occurred.
  • the increase in ⁇ C p is associated with the increased molecular motion of the polymer.
  • a method of separating a transient phenomenon such as a hysteresis peak from the reproducible result of the change in heat capacity is obtained via the use of modulated DSC.
  • a sine wave is imposed on the temperature ramp.
  • a real-time computer analysis allows a plot of not only the whole data but also its transient and reproducible components.
  • modulated DSC apparatuses are those in the Q SeriesTM DSC product line from TA Instruments, New Castle, Del.
  • a micro thermal analyzer such as the ⁇ TATM 2990 product from TA Instruments.
  • a micro thermal analyzer can have an atomic force microscope (AFM) that is used in conjunction with a thermal analyzer.
  • the instrument can be used to analyze individual sample domains identified from the AFM images.
  • the AFM measurement head can contain an ultra-miniature probe that functions as a programmable heat source and temperature sensor.
  • a micro thermal analyzer therefore, can provide information similar to that from traditional thermal analysis, but on a microscopic scale.
  • the ⁇ TATM 2990 can provide images of a sample in terms of its topography, relative thermal conductivity and relative thermal diffusivity.
  • the ⁇ TATM 2990 can also provide spatial resolution of about 1 ⁇ m with a thermal probe and atomic resolution with regular AFM probes.
  • Other advantages of the ⁇ TATM 2990 is that it can heat the polymer sample from ambient to about 500° C. at heating rates up to 1500° C./minute which allows for rapid thermal characterization (e.g., in less than 60 seconds), and it can hold the sample isothermically over a broad range of temperatures (e.g., ⁇ 70 to 300° C.), which allows for thermal characterization over a broad temperature range.
  • TSA torsional braid analysis
  • the T g of a bulk sample of a polymer can also be observed by utilizing electromagnetic methods.
  • Representative examples of electromagnetic methods for the characterization of transitions in polymers are dielectric loss (e.g., using the DEA 2970 dielectric analyzer, available from TA Instruments, New Castle, Del.) and broad-line nuclear magnetic resonance (NMR).
  • the thickness of the coating polymer is ultra thin (i.e., less than 1 micron)
  • Specialized techniques may be useful because it has recently been observed that the T g of a polymer can be influenced by the thickness of the polymer layer.
  • researchers, for example, have observed that polystyrene films on hydrogen-passivated Si had glass transition temperatures that were lower than the bulk value if the thickness of the films was less than 0.04 microns. See Forest et al., Effect of Free Surfaces on the T g of Thin Polymer Films, Physical Review Letters 77(10), 2002-05 (September 1996).
  • BLS Brillouin light scattering
  • the T g of an ultra thin polymer film can also be determined by using three complementary techniques: local thermal analysis, ellipsometry and X-ray reflectivity. See, e.g., Fryer et al., Dependence of the Glass Transition Temperature of Polymer Films on Interfacial Energy and Thickness, Macromolecules 34, 5627-34 (2001).
  • ellipsometry e.g., with a Rudolph AUTO ELTM nulling ellipsometer
  • X-ray reflectivity e.g., with a SCINTAG XDS 2000TM
  • the T g is determined by measuring changes in the thermal expansion of the film.
  • the T g is determined by measuring changes in the heat capacity and thermal conductivity of the film and the area of contact between a probe and the polymer surface.
  • Table 1 lists the T g for some of the polymers used in the embodiments of the present invention.
  • the cited temperature is the temperature as reported in the noted reference and is provided by way of illustration only and is not meant to be limiting.
  • polymer as used herein is inclusive of homopolymers, copolymers, terpolymers etc., including random, alternating, block, cross-linked, blends and graft variations thereof.
  • T g for some of these types of polymers.
  • some polymer blends that exhibit two phase systems can have more than one T g .
  • the selected temperature is determined as previously described.
  • the coating is a blend of ethylene vinyl alcohol copolymer and poly(vinyl alcohol)
  • the T g of the blend can be calculated by using a DSC method.
  • the lower T g is the designated T g .
  • the higher T g is the designated T g .
  • block and graft copolymers can have two separate glass transition temperatures. For some of these polymers, each T g can be close to the T g of the parent homopolymer.
  • Table 2 lists the glass transition temperatures for representative examples of block and graft copolymers that can be used in the present invention. As illustrated by Table 2, most of these block and graft copolymers exhibit two glass transition temperatures. The cited temperatures were reported in Black and Worsfold, J. Appl. Polym. Sci., 18, 2307 (1974). The researches from this reference used a thermal expansion technique to measure the temperatures, and are provided by way of illustration only.
  • the polymer if the polymer exhibits more than one T g , the polymer is exposed to a temperature equal to or greater than the lowest observed T g . It is believed that by exposing a polymer to a temperature equal to or greater than the lowest T g , the coating characteristics will be improved because at least some of the amorphous domains will be modified during the process. In another embodiment, if the polymer in the coating exhibits more than one T g , the polymer is exposed to a temperature equal to or greater than the highest observed T g . By exposing the polymer to the highest T g , it is believed that one can maximize the improvement in coating characteristics, for example, maximizing polymer adhesion and/or cohesion, or maximizing the drug release rate reduction.
  • the polymer in the coating can be exposed to a temperature equal to or greater than the T g and less than the T m of the polymer.
  • a temperature equal to or greater than the T g and less than the T m of the polymer.
  • the T m can be observed by measuring visual, physical, and thermal properties as a function of temperature.
  • T m can be measured by visual observation by using microscopic techniques. For instance, the disappearance of crystallinity in a semicrystalline or crystalline polymer can be observed with a microscope, with the sample housed between crossed nicols (i.e., an optical material that functions as a prism, separating light rays that pass through it into two portions, one of which is reflected away and the other transmitted). As a polymer sample is heated, the sharp X-ray pattern characteristic of crystalline material gives way to amorphous halos at the T m .
  • crossed nicols i.e., an optical material that functions as a prism, separating light rays that pass through it into two portions, one of which is reflected away and the other transmitted.
  • T m Another way of observing the T m is to observe the changes in specific volume with temperature. Since melting constitutes a first-order phase change, a discontinuity in the volume is expected. The T m should give a discontinuity in the volume, with a concomitant sharp melting point. Because of the very small size of the crystallites in bulk crystallized polymers, however, most polymers melt over a range of several degrees. The T m is the temperature at which the last trace of crystallinity disappears. This is the temperature at which the largest and/or most “perfect” crystals are melting.
  • the T m can be determined by using thermomechanical analysis (TMA) that uses a thermal probe (e.g., available from Perkin Elmer, Norwalk, Conn.).
  • TMA thermomechanical analysis
  • the T m can also be determined with a thermal-based method.
  • DSC differential scanning calorimetry
  • the same process for DSC as described above for the determination of T g can be used to determine the T m .
  • the T m of the representative polymer is the peak of curve 64 .
  • Table 3 lists the T m for some of the polymers used in the embodiments of the present invention.
  • the cited temperature is the temperature as reported in the noted reference and is provided by way of illustration only and is not meant to be limiting.
  • T m can be observed while using the standard techniques to measure T m as described herein. For example, while using a DSC method of measuring T m , a double melting peak can be observed. It has been suggested that multiple observed melting points can be due to the presence of two or more distinct crystal or morphological structures in the initial sample. It has also been suggested that this phenomenon can be the results of annealing occurring during the measurement process (e.g., during a DSC process) whereby crystals of low perfection melt have time to recrystallize a few degrees above and to remelt. See, e.g., Sarasua et al., Crystallization and Melting Behavior of Polylactides, Macromolecules 31(12), 3895-3905 (1998). To the extent that more than one T m is observed, the embodiments using T m herein use the highest observed T m .
  • the thermal treatment process can be used to improve the mechanical properties of polymeric coatings having various coating structures, for instance, those structures illustrated in FIGS. 1A-1H .
  • the thermal treatment process can also be used to reduce the release rate of an active agent from polymeric coatings having various coating structures. Referring to FIGS. 1B-1H , for instance, reservoir layer 26 can be exposed to a temperature sufficient to reduce the release rate of active agent 28 from the coating.
  • barrier layer 30 can be treated in lieu of or in addition to the reservoir layer 26 .
  • primer layer 24 can be exposed to the thermal treatment process before a reservoir layer is applied to medical substrate 20 to improve the mechanical properties of the polymeric coating.
  • the thermal treatment process is used to treat a coating having multiple layers wherein at least one of the layers is a primer layer.
  • the coating including primer layer 24 and reservoir layer 26 can be heat treated.
  • the polymer in primer layer 24 is exposed to a temperature equal to or greater than the T g of the polymer. In another embodiment, the polymer in primer layer 24 is exposed to a heat treatment at a temperature range equal to or greater than about the T g and optionally less than about the T m of the polymer. The device should be exposed to the heat treatment for any suitable duration of time that would allow for the formation of the primer coating on the surface of the device.
  • primer layer 24 includes a thermoplastic polymer, such as ethylene vinyl alcohol copolymer, polycaprolactone, poly(lactide-co-glycolide), or poly(hydroxybutyrate).
  • a thermoplastic polymer such as ethylene vinyl alcohol copolymer, polycaprolactone, poly(lactide-co-glycolide), or poly(hydroxybutyrate).
  • Table 4 lists the T g and T m for some of the polymers that can be used for primer layer 24 .
  • the cited exemplary temperature and time for exposure are provided by way of illustration and are not meant to be limiting.
  • the thermal treatment process is used to treat a coating having reservoir layer 26 .
  • the polymer in reservoir layer 26 is exposed to a temperature equal to or greater than the T g of the polymer in reservoir layer 26 .
  • the polymer in reservoir layer 26 can also be exposed to a temperature equal to or greater than the T g and, optionally, less than the T m of the polymer.
  • the polymer can be exposed to (1) the T c of the polymer; (2) the annealing temperature of the polymer; (3) a temperature equal to 0.9 times the T m of the polymer; or (4) a temperature equal to or greater than the T m of the polymer.
  • the process can also be aimed at exposing the polymer(s) of primer layer 24 to a temperature equal to or greater than the T g , equal to the T c , the annealing temperature, a temperature equal to 0.9 times the T m or equal to or greater than the T m of the polymer(s). If, however, the T g of the primer layer is excessively high or higher than the T m of reservoir layer 26 , such high temperatures may adversely affect the active agents.
  • the thermal treatment process can also be directed to a polymeric coating having a polymeric reservoir layer 26 covered at least in part by barrier layer 30 as illustrated by FIGS. 1E-1H .
  • reservoir layer 26 can be deposited on primer layer 24 and covered by barrier layer 30 .
  • the polymer in barrier layer 30 can be exposed to a temperature equal to or greater than the T g of the polymer in barrier layer 30 .
  • a polymer included in barrier layer 30 can also be exposed to a temperature equal to or greater than the T g and, optionally, less than the T m of the polymer.
  • the polymer can be exposed to (1) the T m of the polymer; (2) the annealing temperature of the polymer or (3) a temperature equal to 0.9 times the T m of the polymer. If barrier layer 30 is covering a reservoir layer 26 , reservoir layer 26 can also be heated to a temperature equal to or greater than the T g of a polymer in reservoir layer 26 , equal to the T c of a polymer in reservoir layer 26 , the annealing temperature of a polymer in reservoir layer 26 , equal to 0.9 times the T m of the polymer, or equal to or greater than the T m of the polymer.
  • the thermal treatment process can be conducted so that polymers in the different layers are heat treated simultaneously.
  • the polymers in reservoir layer 26 and barrier layer 30 can be simultaneously exposed to a temperature equal to or greater than the T g of the polymers in the two layers.
  • the polymers in reservoir layer 26 and barrier layer 30 can also be simultaneously exposed to (1) a temperature equal to or greater than the T g and less than the T m of the polymers; (2) the T c of the polymers; (3) the annealing temperature of the polymers; (4) a temperature equal to 0.9 times the T m of the polymers or (5) a temperature equal to or greater than the T m of the polymers.
  • the polymers in reservoir layer 26 and barrier layer 30 can be simultaneously exposed to the appropriate temperature if, for instance, the polymer in reservoir layer 26 has the same or substantially the same thermal properties as the polymer in barrier layer 30 .
  • the polymer in reservoir layer 26 can have about the same T c or T g as the polymer in barrier layer 30 .
  • the polymers in reservoir layer 26 and barrier layer 30 can also be simultaneously exposed to the appropriate temperature if the temperature used to conduct the thermal treatment is sufficiently high to surpass the selected temperature (e.g., annealing temperature, T c , etc.) for each polymer.
  • the thermal treatment process can also be conducted to selectively treat the various polymeric layers.
  • the coating illustrated by FIG. 1C can be constructed so that the polymer in primer layer 24 has different thermal properties than the polymer in reservoir layer 26 .
  • the polymeric coating is exposed to a temperature greater than the T g of the polymer in reservoir layer 26 , but less than the T g of the polymer in primer layer 24 .
  • This process can also be used if the annealing temperature or T c of the polymer in primer layer 24 is greater than the annealing temperature or T c of the polymer in reservoir layer 26 .
  • the polymer in primer layer 24 has a T g that is lower than the T g of the polymer in reservoir layer 26 , the polymeric coating is exposed to a temperature greater than the T g of the polymer in primer layer 24 , but less than the T g of the polymer in reservoir layer 26 .
  • This process can also be used if the annealing temperature or T c of the polymer in primer layer 24 is lower than the annealing temperature or T c of the polymer in reservoir layer 26 .
  • the coating illustrated by FIG. 1E can be constructed so that the polymer in reservoir layer 26 has different thermal properties than the polymer in barrier layer 30 .
  • the polymeric coating is exposed to a temperature greater than the T g of the polymer in barrier layer 30 , but less than the T g of the polymer in reservoir layer 26 .
  • This process can also be used if the annealing temperature or T c of the polymer in reservoir layer 26 is greater than the annealing temperature or T c of the polymer in barrier layer 30 .
  • the polymeric coating is exposed to a temperature greater than the T g of the polymer in reservoir layer 26 , but less than the T g of the polymer in barrier layer 30 .
  • This process can also be used if the annealing temperature or T c of the polymer in reservoir layer 26 is lower than the annealing temperature or T c of the polymer in barrier layer 30 .
  • the heat source can be directed to only certain portions of the stent or only for certain durations so that the diffusion rates of the active agent from the polymer differs in various portions of the coating.
  • the polymeric material in barrier layer 30 B can be exposed to a thermal treatment, whereas the polymeric material in barrier layer 30 A is not.
  • the release rate of the active agent from the polymeric material in barrier 30 B can be lower than the release rate of the active agent from the polymeric material in barrier 30 A.
  • the release rate difference can result because, for example, the polymer of barrier layer 30 B will have a higher percent crystallinity than the polymeric material in barrier layer 30 A.
  • the stent can have two or more segments along the longitudinal axis of the stent, such as a first segment, a second segment and a third segment.
  • the radiation could be directed substantially only at the first segment and the third segment, for instance, by using a cauterizer tip.
  • the radiation could be set higher for the first and third segments, or the radiation could be directed at the first and third segments for a longer duration than the second segment.
  • the polymer along the first segment and the third segment would have a greater percent crystallinity than the polymer along the second segment. Therefore, the diffusion rates of the active agent from the polymer matrix along the first segment and the third segment would be less than the diffusion rate along the second segment.
  • the first and third segments can be on the opposing end portions of the stent, the second segment being the middle region of the stent.
  • the time that the coating is exposed to radiation can be limited so that the percent crystallinity is not maximized throughout the entire thickness of the coating.
  • the shallower regions of the coating will have a higher percent crystallinity than the deeper regions.
  • the degree of crystallinity decreases as a function of the depth of the coating.
  • the coating is defined as having four regions, with the fourth region as the deepest, by controlling the thermal treatment, the first or shallowest region would have a higher percent crystallinity, followed by the second, third and lastly fourth region, which would have the lowest degree of crystallinity.
  • the selected duration of the thermal treatment of the polymeric coating can depend on the selected exposure temperature, and the thermal characteristics of the polymer in the coating, among other environmental factors such as the humidity.
  • the duration of the thermal treatment for instance, can be from about 30 seconds to about 48 hours.
  • the polymer in a thermal treatment of a coating having ethylene vinyl alcohol copolymer and actinomycin D, the polymer can be exposed to a temperature of about 473° K for about 2 minutes, or about 353° K for about 2 hours.
  • the exposure temperature should not adversely affect the characteristics of the polymer or the active agent present in the coating.
  • additives can be mixed with the polymer before or during the coating process to shift the thermal profile of the polymer (i.e., decrease the T g and T m of the polymer).
  • a plasticizer which is usually a low molecular weight nonvolatile molecule, can be dissolved with the polymer before the application process.
  • the plasticizer can be an active agent.
  • a representative example of an additive is dioctyl phthalate.
  • the selected duration of the thermal treatment of the reservoir layer and/or barrier layer can depend on the selected exposure temperature, the thermal characteristics of the polymer in the coating, the thermal stability of the active agent and the desired release rate, among other factors.
  • the stent can be sterilized by various methods.
  • the particular procedure used to sterilize the coating can also be modified to conduct the thermal treating process.
  • an electron beam or a gas sterilization procedure can be used to conduct the thermal treating process and to sterilize the coating that has been formed on the stent.
  • Representative examples of gas sterilization procedures include those using ethylene oxide, steam/autoclaving, hydrogen peroxide and peracetic acid.
  • the sterilization processes can be modified so that the temperature produced during the process is sufficient to have the desired effect on the coating, for example, to decrease the release rate of the active agent from the polymeric coating, but not significantly degrade the active agent.
  • the exposure temperature is at least a function of dose, dose rate, heat capacity of the coating material and the degree of insulation of the product.
  • a primer layer can serve as a functionally useful intermediary layer between the surface of the device and an active agent-containing or reservoir coating, or between multiple layers of reservoir coatings.
  • the primer layer provides an adhesive tie between the reservoir coating and the device—which, in effect, would also allow for the quantity of the active agent in the reservoir coating to be increased without compromising the ability of the reservoir coating to be effectively contained on the device during delivery and, if applicable, expansion of the device.
  • the primer layer can be formed by applying a polymer or prepolymer to the stent by conventional methods.
  • a polymer or a prepolymer can be applied by applying the polymer directly onto the stent substrate such as by powder coating or by vapor deposition.
  • an unsaturated prepolymer e.g., an unsaturated polyester or acrylates
  • the polymer or prepolymer can also be applied by depositing a polymer composition onto the stent.
  • the polymer composition can be prepared by combining a predetermined amount of a polymer or a prepolymer and a predetermined amount of a solvent or a combination of solvents.
  • solvent is defined as a liquid substance or composition that is compatible with the components of the composition and is capable of dissolving the component(s) at the concentration desired in the composition.
  • the mixture can be prepared in ambient pressure and under anhydrous atmosphere. If necessary, a free radical or UV initiator can be added to the composition for initiating the curing or cross-linking of a prepolymer. Heating and stirring and/or mixing can be employed to effect dissolution of the polymer into the solvent.
  • the composition can then be applied by convention methods such as by spraying the stent substrate with the composition or dipping the substrate into the composition.
  • the polymers used for the primer material should have a high capacity of adherence to the surface of an implantable device, such as a metallic surface of a stent, or a high capacity of adherence to a polymeric surface such as the surface of a stent made of polymer, or a previously applied layer of polymeric material.
  • Stainless steel such as 316L is a commonly used material for the manufacturing of a stent.
  • Stainless steel includes a chromium oxide surface layer which makes the stent corrosion resistant and confers, in large part, biocompatibility properties to the stent.
  • the chromium oxide layer presents oxide, anionic groups, and hydroxyl moieties, which are polar. Consequently, polymeric materials with polar substituents and cationic groups can adhere to the surface.
  • suitable polymeric materials include polyisocyanates, unsaturated polymers, high amine content polymers, acrylates, polymers with high content of hydrogen bonding groups, silane coupling agents, titanates and zirconates.
  • polyisocyanates include triisocyanurate, alphatic polyisocyanate resins based on hexamethylene diisocyanate, aromatic polyisocyanate prepolymers based on diphenylmethane diisocyanate, polyisocyanate polyether polyurethanes based on diphenylmethane diisocyanate, polymeric isocyanates based on toluene diisocyanate, polymethylene polyphenyl isocyanate, and polyester polyurethanes.
  • unsaturated polymers include polyester diacrylates, polycaprolactone diacrylates, polyester diacrylates, polytetramethylene glycol diacrylate, polyacrylates with at least two acrylate groups, polyacrylated polyurethanes, and triacrylates.
  • unsaturated prepolymers a free radical or UV initiator can be added to the composition for the thermal or UV curing or cross-linking process.
  • examples of free radicals initiators are benzoyl peroxide; bis(2,4-dichlorobenzoyl)peroxide; dicumyl peroxide; 2,5-bis(tert-butyl peroxy)-2,5-dimethyl hexane; ammonium persulfate, and 2,2′-azobisisobutyronitrile.
  • each initiator requires a different temperature to induce decomposition.
  • examples of initiators include 2,2-dimethoxy-2-phenylacetophenone; 1-hydroxycyclohexyl phenyl ketone; benzoin ethyl ether; and benzophenone. These initiators can be activated by illumination with a medium pressure Hg bulb that contains wavelengths between 250 and 350 nm.
  • high amine content polymers include polyethyleneamine, polyallylamine, and polylysine.
  • acrylates include copolymers of ethyl acrylate, methyl acrylate, butyl methacrylate, methacrylic acid, acrylic acid, and cyanoacrylates.
  • high content of hydrogen bonding group polymers include polyethylene-co-polyvinyl alcohol, epoxy polymers based on the diglycidylether of bisphenol A with amine crosslinking agents, epoxy polymers cured by polyols and lewis acid catalysts, epoxy phenolics, epoxy-polysulfides, ethylene vinyl acetate, melamine formaldehydes, polyvinylalcohol-co-vinyl acetate polymers, resorcinol-formaldehydes, urea-formaldehydes, polyvinylbutyral, polyvinylacetate, alkyd polyester resins, acrylic acid modified ethylene vinyl acetate polymers, methacrylic acid modified ethylene vinyl acetate polymers, acrylic acid modified ethylene acrylate polymers, methacrylic acid modified ethylene acrylate polymers, anhydride modified ethylene acrylate butylene, and anhydride modified ethylene vinyl acetate polymers.
  • silane coupling agents include 3-aminopropyltriethoxysilane and (3-glydidoxypropyl)methyldiethoxysilane.
  • titanates include tetra-iso-propyl titanate and tetra-n-butyl titanate.
  • zirconates include n-propyl zirconate and n-butyl zirconate.
  • polymers for the primer layer include ethylene vinyl alcohol copolymer; poly(butylmethacrylate); copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; poly(hydroxyvalerate); poly(epsilon-caprolactone); poly(lactide-co-glycolide); poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester; polyanhydride; poly(glycolic acid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester; polyphosphoester urethane; poly(amino acids); cyanoacrylates; poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-
  • Ethylene vinyl alcohol is functionally a very suitable choice of polymer.
  • Ethylene vinyl alcohol copolymer refers to copolymers comprising residues of both ethylene and vinyl alcohol monomers.
  • ethylene vinyl alcohol copolymer may also be a terpolymer so as to include small amounts of additional monomers, for example less than about five (5) mole percentage of styrenes, propylene, or other suitable monomers.
  • the copolymer comprises a mole percent of ethylene of from about 27% to about 47%. Typically, 44 mole percent ethylene is suitable.
  • Ethylene vinyl alcohol copolymer is available commercially from companies such as Aldrich Chemical Company, Milwaukee, Wis., or EVAL Company of America, Lisle, Ill., or can be prepared by conventional polymerization procedures that are well known to one of ordinary skill in the art.
  • the copolymer possesses good adhesive qualities to the surface of a stent, particularly stainless steel surfaces, and has illustrated the ability to expand with a stent without any significant detachment of the copolymer from the surface of the stent.
  • the polymer in the primer layer is a biologically degradable polymer.
  • biologically degradable biologically erodable
  • biologicalcally absorbable biologically resorbable polymers
  • biologically resorbable polymers that are capable of being completely degraded, dissolved, and/or eroded over time when exposed to bodily fluids such as blood and are gradually resorbed, absorbed and/or eliminated by the body.
  • the processes of breaking down and eventual absorption and elimination of the polymer can be caused, for example, by hydrolysis, metabolic processes, bulk or surface erosion, and the like.
  • biologically degradable biologically degradable
  • biologically erodable biologically resorbable
  • biologically absorbable stent coatings and/or polymers forming such stent coatings
  • biologically degradable biologically erodable
  • biologically resorbable biologically absorbable
  • a stent that is made in whole or in part from a biodegradable polymer or a combination of biodegradable polymers is subjected to the thermal treatment in accordance to the various embodiments of the invention.
  • the biologically degradable, erodable, absorbable and/or resorbable polymers that can be used for making the primer layer includes at least a poly(lactic acid).
  • Poly(lactic acid) includes poly(D,L-lactic acid) (DLPLA), poly(D-lactic acid) (DPLA) and poly(L-lactic acid) (LPLA).
  • the stereochemical composition of the poly(lactic acid) can dramatically affect the properties of the poly(lactic acid).
  • LPLA can be a semicrystalline polymer that can have a T g of about 67° C., and a T m of about 180° C.
  • DLPLA can be an amorphous polymer that can have a T g of about 58° C. or lower.
  • the amorphous form of PLA may have certain performance advantages as a component of stent coatings; for example, it has been found that DLPLA is more readily absorbable under biological conditions than LPLA.
  • Poly(lactic acid) has the formula H—[O—CH(CH 3 )—C(O)] n —OH and can be obtained by ring-opening polymerization of lactide (a cyclic dimer of lactic acid), as demonstrated schematically by reaction (I), where lactide is compound (A) and poly(lactic acid) is compound (B):
  • the molecular weight of poly(lactic acid) can be for example about 30,000 to about 300,000 Daltons.
  • the molecular weight is proportional to the value of the integer n in the compound (B), which can be for example about 416 to about 4,166.
  • n in the compound (B) can be for example about 416 to about 4,166.
  • polymers containing moieties derived from poly(lactic acid) can be also used in addition to or instead of, poly(lactic acid), for making the primer layer.
  • One type of alternative polymers based on poly(lactic acid) includes derivatives of poly(lactic acid), for example, hydrolyzed or carboxylated poly(lactic acid), or a blend thereof. Using the hydrolyzed or carboxylated poly(lactic acid) is expected to result in the increased rate of degradation of the coating.
  • the hydrolyzed poly(lactic acid) is a polymeric product comprising a mixture of the original (unhydrolized) poly(lactic acid) (B) and oligomeric and/or polymeric products of the hydrolysis thereof.
  • the products of hydrolysis can include a complex mixture of oligomers of lactic acid, monomeric lactic acid and other products that can include hydroxylated species.
  • the mixture can contain about 1 mass % to about 20 mass % original poly(lactic acids) (B) having the molecular weight as indicated above, and the balance, the products of hydrolysis thereof.
  • the oligomeric and/or polymeric products of hydrolysis of poly(lactic acid) can have an average molecular weight of about 1,000 to about 20,000 Daltons.
  • poly(lactic acid) can be hydrolyzed under the condition that can be selected by those having ordinary skill in the art.
  • the process of hydrolysis is polymer-analogous transformation and can be carried out until the mixture of poly(lactic acid) and the products of hydrolysis thereof are obtained, the mixture having a desired ratio between poly(lactic acid) and the products of hydrolysis thereof.
  • the desired ratio can be also determined by those having ordinary skill in the art.
  • the carboxylated poly(lactic acid) comprises poly(lactic acid) terminated with a carboxyl group and can be obtained by ring-opening polymerization of lactide (A), in the presence of a butylene acid (HO—R—COOH) serving as a ring opening catalyst as demonstrated schematically by reaction (II), where the carboxylated poly(lactic acid) is compound (C):
  • the ring-opening catalyst in reaction (II) can be any suitable butylene acid that can be selected by those having ordinary skill in the art.
  • butylene acid that can be used is hydroacetic (glycolic) acid.
  • the carboxylated poly(lactic acid) can be a fully carboxylated poly(lactic acid), i.e., can be a 100% product (C).
  • the molecular weight of the fully carboxylated poly(lactic acid) can be about 1,000 to about 20,000 Daltons.
  • the fully carboxylated poly(lactic acid) can be obtained from Birmingham Polymers, Inc. of Birmingham, Ala.
  • the carboxylated poly(lactic acid) can also be in a mixture with original poly(lactic acid) (B).
  • the mixture can contain between about 1 mass % to about 20 mass % original poly(lactic acid) (B) having the molecular weight as indicated above, and the balance, the carboxylated poly(lactic acid) (C).
  • poly(lactic acid) that can be used for the primer layer
  • graft copolymers and block copolymers, such as AB block-copolymers (“diblock-copolymers”) or ABA block-copolymers (“triblock-copolymers”), or mixtures thereof.
  • the molecular weight of blocks A can be about 300 to about 40,000 Daltons, more narrowly, about 8,000 to about 30,000 Daltons, for example, about 15,000 Daltons.
  • the molecular weight of blocks B can be about 50,000 to about 250,000 Daltons, more narrowly, about 80,000 to about 200,000 Daltons, for example, about 100,000 Daltons.
  • block-copolymer and “graft copolymer” are defined in accordance with the terminology used by the International Union of Pure and Applied Chemistry (IUPAC).
  • Block-copolymer refers to a copolymer containing a linear arrangement of blocks. The block is defined as a portion of a polymer molecule in which the monomeric units have at least one constitutional or configurational feature absent from the adjacent portions.
  • “Graft copolymer” refers to a polymer composed of macromolecules with one or more species of block connected to the main chain as side chains, these side chains having constitutional or configuration features that differ from those in the main chain.
  • ABS block-copolymer is defined as a block-copolymer having moieties A and B arranged according to the general formula - ⁇ [A-] m -[B] n ⁇ — x , where each of “m,” “n,” and “x” is a positive integer, and m ⁇ 2, and n ⁇ 2.
  • ABA block-copolymer is defined as a block-copolymer having moieties A and B arranged according to the general formula - ⁇ [A-] m -[B] n -[A-] p ⁇ - x , where each of “m,” “n,” “p,” and “x” is a positive integer, and m ⁇ 2, and n ⁇ 2, and p ⁇ 2.
  • the blocks of the ABA and AB block-copolymers need not be linked on the ends, since the values of the integers determining the number of A and B blocks are such as to ensure that the individual blocks are usually long enough to be considered polymers in their own right.
  • the ABA block copolymer can be named poly A-block-co-poly B block-co-poly block-copolymer
  • the AB block copolymer can be named poly A-block-co-poly B block-copolymer.
  • Blocks “A” and “B,” can be larger than the three-block size and can be alternating or random.
  • the term “copolymer” encompasses for the purposes of this disclosure a polymer with two or more constituent monomers and does not imply a polymer of only two monomers.
  • the block polymers or graft polymers of the present invention include a biologically compatible moiety.
  • ABA and AB block-copolymers can be used to contain the block(s) of poly(lactic acid), and block(s) of a biologically compatible moiety, providing the AB or ABA block-copolymer with blood compatibility.
  • moiety A is poly(lactic acid) and moiety B is the biocompatible moiety.
  • moiety B is poly(lactic acid), and moiety A is the biocompatible moiety.
  • the biocompatible moieties are selected in such a way so that to make the entire ABA and AB block-copolymers biologically degradable.
  • suitable biocompatible moieties include poly(alkylene glycols), for example, poly(ethylene-glycol) (PEG), poly(ethylene oxide), poly(propylene glycol) (PPG), poly(tetramethylene glycol), or poly(ethylene oxide-co-propylene oxide); lactones and lactides, for example, ⁇ -caprolactone, ⁇ -butyrolactone, ⁇ -valerolactone, or glycolide; poly(N-vinyl pyrrolidone); poly(acrylamide methyl propane sulfonic acid) and salts thereof (AMPS and salts thereof); poly(styrene sulfonate); sulfonated dextran; polyphosphazenes; poly(orthoesters); poly(tyrosine carbonate); hyaluronic acid; hyaluronic acid having a stearoyl or palmitoyl substituent group; copolymers of PEG with hyaluronic acid or with
  • a molecular weight of a suitable biocompatible polymeric moiety can be below 40,000 Daltons to ensure the renal clearance of the compound, for example, between about 300 and about 40,000 Daltons, more narrowly, between about 8,000 and about 30,000 Daltons, for example, about 15,000 Daltons. Lactones and lactides mentioned above can also replace a part or all of DLPLA in the block-copolymer, if desired.
  • AB block copolymer poly(D,L-lactic acid)-block-poly(ethylene-glycol) (DLPLA-PEG).
  • DLPLA-PEG poly(D,L-lactic acid)-block-poly(ethylene-glycol)
  • the DLPLA-PEG block-copolymer shown by formula (III) can have a total molecular weight of about 30,000 to about 300,000 Daltons, for example, about 60,000 Daltons as measured by the gel-permeation chromatography (GPC) method in tetrahydrofuran.
  • the molecular weight of the PEG blocks can be about 500 to about 30,000 Daltons, for example, about 550 Daltons, and the molecular weight of the DLPLA blocks can be about 1,500 to about 20,000 Daltons, for example, about 1,900 Daltons.
  • “n” is an integer that can have a value of about 21 to about 278, and “m” is an integer that can have a value of about 11 to about 682.
  • ABA block copolymer poly(D,L-lactic acid)-block-poly(ethylene-glycol)-block-poly(D,L-lactic acid) (DLPLA-PEG-DLPLA).
  • DLPLA-PEG-DLPLA poly(D,L-lactic acid)-block-poly(ethylene-glycol)-block-poly(D,L-lactic acid)
  • the DLPLA-PEG-DLPLA block-copolymer shown by formula (IV) can have a total molecular weight of about 30,000 to about 300,000 Daltons, for example, about 60,000 Daltons as measured by a GPC method in tetrahydrofuran.
  • the molecular weight of the PEG blocks can be about 500 to about 30,000 Daltons, for example, about 7,500 Daltons; and the molecular weight of the DLPLA blocks can be about 1,500 to about 20,000 Daltons, for example, one terminal DLPLA block can have the molecular weight of about 3,400 Daltons, and the other terminal DLPLA block can have the molecular weight of about 10,000 Daltons.
  • n is an integer that can have a value of about 21 to about 278
  • m is an integer that can have a value of about 11 to about 682
  • p is an integer that can have a value of about 21 to about 278.
  • the positions of the moieties can be switched to obtain a BAB block-copolymer, poly(ethylene-glycol)-block-poly(D,L-lactic acid)-block-poly(ethylene-glycol) (PEG-DLPLA-PEG).
  • PEG-DLPLA-PEG poly(ethylene-glycol)-block-poly(D,L-lactic acid)-block-poly(ethylene-glycol)
  • the PEG-DLPLA-PEG block-copolymer shown by formula (V) can have a total molecular weight of about 30,000 to about 300,000 Daltons, for example, about 60,000 Daltons as measured by the GPC method in tetrahydrofuran.
  • the molecular weight of the PEG block can be about 500 to about 30,000 Daltons, for example, about 7,500 Daltons; and the molecular weight of the DLPLA blocks can be about 1,500 to about 20,000 Daltons.
  • “n” is an integer that can have a value of about 21 to about 278;
  • m is an integer that can have a value of about 11 to about 682, and
  • p is an integer that can have a value of about 11 to about 682.
  • Block-copolymers shown by formulae (III-V) can be synthesized by standard methods known to those having ordinary skill in the art, for example, copolycondensation of PEG with DLPLA. The process of copolycondensation can be catalyzed by an acid or a base, if necessary.
  • hydrolyzed block copolymers of PEG and DPLA can be used for making the stent coatings. Both AB and ABA and BAB block-copolymers discussed above can be used to obtain the hydrolyzed block copolymers of PEG and DPLA.
  • the hydrolyze block copolymers of PEG and DPLA are polymeric products comprising a mixture of block copolymers of PEG and DPLA and products of partial hydrolysis thereof. The mixture can contain about 1 mass % to about 20 mass % unhydrolyzed block copolymers of PEG and DPLA and the balance, the products of hydrolysis thereof.
  • the block-copolymers can be hydrolyzed under the conditions that can be selected by those having ordinary skill in the art.
  • the process of hydrolysis can be carried out until the mixture of the block-copolymer and the products of partial hydrolysis thereof is obtained, the mixture having a desired ratio between the block-copolymer and the products of partial hydrolysis thereof.
  • the desired ratio can be also determined by those having ordinary skill in the art.
  • the biologically degradable polymer in the primer layer includes:
  • PCL poly(caprolactone)
  • poly(lactide-co-glycolide) (e) poly(lactide-co-glycolide) (PLGA);
  • (k) AB and ABA block-copolymers of PEG with poly(butylene terephthalate) (PBT), e.g., poly(ethylene-glycol)-block-poly(butylene terephthalate) (PEG-PBT), poly(ethylene-glycol)-block-poly(butylene terephthalate)-block-poly(ethylene-glycol) (PEG-PBT-PEG), or poly(butylene terephthalate)-block-poly(ethylene-glycol)-block poly(butylene terephthalate) (PBT-PEG-PBT); and
  • (l) AB and ABA block-copolymers of PEG with PCL e.g., poly(ethylene-glycol)-block-poly(caprolactone) (PEG-PCL), poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol) (PEG-PCL-PEG), or poly(caprolactone)-block-poly(ethylene-glycol) block-poly(caprolactone) (PCL-PEG-PCL).
  • PEG-PCL poly(ethylene-glycol)-block-poly(caprolactone)
  • PEG-PCL-PEG poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol)
  • PCL-PEG-PCL poly(caprolactone)-block-poly(ethylene-glycol) block-poly(caprolactone)
  • PEG-PBT and PEG-PBT-PEG block copolymers are known under a trade name POLYACTIVE and are available from IsoTis Corp. of Holland. These polymers can be obtained, for example, by trans-esterification of dibutylene terephthalate with PEG.
  • POLYACTIVE the ratio between the units derived from ethylene glycol and the units derived from butylene terephthalate can be about 0.67:1 to about 9:1.
  • the molecular weight of the units derived from ethylene glycol can be about 300 to about 4,000 Daltons, and the molecular weight of the units derived from butylene terephthalate can be about 50,000 to about 250,000, for example, about 100,000 Daltons.
  • DLPLA-PEG-DLPLA, PEG-DLPLA-PEG, PEG-PBT, PEG-PBT-PEG, PBT-PEG-PBT, PEG-PCL, PEG-PCL-PEG, and PCL-PEG-PCL block copolymers all contain fragments with ester bonds.
  • Ester bonds are known to be water-labile bonds. When in contact with slightly alkaline blood, ester bonds are subject to catalyzed hydrolysis, thus ensuring biological degradability of the block-copolymer.
  • One product of degradation of every block polymer belonging to the group DLPLA-PEG-DLPLA, PEG-DLPLA-PEG, PEG-PBT, PEG-PBT-PEG, PBT-PBG-PBT, PEG-PCL, PEG-PCL-PEG, and PCL-PEG-PCL is expected to be PEG, which is highly biologically compatible.
  • the solvent should be mutually compatible with the polymer and should be capable of placing the polymer into solution at the concentration desired in the solution.
  • Useful solvents should also be able to expand the chains of the polymer for maximum interaction with the surface of the device, such as a metallic surface of a stent.
  • solvent can include, but are not limited to, dimethylsulfoxide (DMSO), dimethyl acetamide (DMAC), chloroform, acetone, water (buffered saline), xylene, acetone, methanol, ethanol, 1-propanol, tetrahydrofuran, 1-butanone, dimethylformamide, dimethylacetamide, cyclohexanone, ethyl acetate, methylethylketone, propylene glycol monomethylether, isopropanol, N-methyl pyrrolidinone, toluene and mixtures thereof.
  • mixtures of solvents include:
  • acetone and cyclohexanone e.g., 80:20, 50:50, or 20:80 by mass mixture
  • acetone and xylene e.g., a 50:50 by mass mixture
  • 1,1,2-trichloroethane and chloroform e.g., an 80:20 by mass mixture.
  • the polymer can comprise from about 0.1% to about 35%, more narrowly about 2% to about 20% by weight of the total weight of the composition, and the solvent can comprise from about 65% to about 99.9%, more narrowly about 80% to about 98% by weight of the total weight of the composition.
  • a specific weight ratio is dependent on factors such as the material from which the implantable device is made and the geometrical structure of the device.
  • a fluid can be added to the composition to enhance the wetting of the composition for a more uniform coating application.
  • a suitable fluid typically has a high capillary permeation.
  • Capillary permeation or wetting is the movement of a fluid on a solid substrate driven by interfacial energetics.
  • Capillary permeation is quantitated by a contact angle, defined as an angle at the tangent of a droplet in a fluid phase that has taken an equilibrium shape on a solid surface.
  • a low contact angle means a higher wetting liquid.
  • a suitably high capillary permeation corresponds to a contact angle less than about 90°.
  • FIG. 6A illustrates a fluid droplet 70 A on a solid substrate 72 , for example a stainless steel surface.
  • Fluid droplet 70 A has a high capillary permeation that corresponds to a contact angle ⁇ 1 , which is less than about 90°.
  • FIG. 6B illustrates a fluid droplet 70 B on solid substrate 72 , having a low capillary permeation that corresponds to a contact angle ⁇ 2 , which is greater than about 90°.
  • the wetting fluid typically, should have a viscosity not greater than about 50 centipoise, narrowly about 0.3 to about 5 centipoise, more narrowly about 0.4 to about 2.5 centipoise. The wetting fluid, accordingly, when added to the composition, reduces the viscosity of composition.
  • the wetting fluid should be mutually compatible with the polymer and the solvent and should not precipitate the polymer.
  • the wetting fluid can also act as the solvent.
  • Useful examples of the wetting fluid include, but are not limited to, tetrahydrofuran (THF), dimethylformamide (DMF), 1-butanol, n-butyl acetate, dimethyl acetamide (DMAC), and mixtures and combinations thereof.
  • the polymer can comprise from about 0.1% to about 35%, more narrowly from about 2% to about 20% by weight of the total weight of the composition;
  • the solvent can comprise from about 19.9% to about 98.9%, more narrowly from about 58% to about 84% by weight of the total weight of the composition;
  • the wetting fluid can comprise from about 1% to about 80%, more narrowly from about 5% to about 40% by weight of the total weight of the composition.
  • the specific weight ratio of the wetting fluid depends on the type of wetting fluid employed and type of and the weight ratio of the polymer and the solvent.
  • tetrahydrofuran used as the wetting fluid can comprise, for example, from about 1% to about 44%, more narrowly about 21% by weight of the total weight of the solution.
  • Dimethylformamide used as the wetting fluid can comprise, for example, from about 1% to about 80%, more narrowly about 8% by weight of the total weight of the solution.
  • 1-butanol used as the wetting fluid can comprise, for example, from about 1% to about 33%, more narrowly about 9% by weight of the total weight of the solution.
  • N-butyl acetate used as the wetting fluid can comprise, for example, from about 1% to about 34%, more narrowly about 14% by weight of the total weight of the solution.
  • DMAC used as the wetting fluid can comprise, for example, from about 1% to about 40%, more narrowly about 20% by weight of the total weight of the solution.
  • Table 5 illustrates some examples of suitable combinations for the primer composition:
  • thermoset polymer an initiator may be required.
  • epoxy systems consisting of diglycidyl ether of bisphenol A resins can be cured with amine curatives, thermoset polyurethane prepolymers can cured with polyols, polyamines, or water (moisture), and acrylated urethane can be cured with UV light. Examples 27 and 28 provide illustrative descriptions. If baked, the temperature can be above the T g of the selected polymer.
  • Example 29 provides a brief description.
  • the composition containing the active agent can be prepared by first forming a polymer solution by adding a predetermined amount of a polymer to a predetermined amount of a compatible solvent.
  • the polymer can be added to the solvent at ambient pressure and under anhydrous atmosphere. If necessary, gentle heating and stirring and/or mixing can be employed to effect dissolution of the polymer into the solvent, for example 12 hours in a water bath at about 60° C.
  • the active agent can then be dispersed in the blended composition of the polymer and the solvent.
  • the active agent can be mixed with the polymer solution so that the active agent forms a true solution or becomes saturated in the blended composition. If the active agent is not completely soluble in the composition, operations including mixing, stirring, and/or agitation can be employed to effect homogeneity of the residues.
  • the active agent can also be first added to a solvent that is capable of more readily dissolving the active agent prior to admixing with the polymer composition. The active agent can also be added so that the dispersion is in fine particles.
  • the polymer can comprise from about 0.1% to about 35%, more narrowly from about 0.5% to about 20% by weight of the total weight of the composition, the solvent can comprise from about 59.9% to about 99.8%, more narrowly from about 79% to about 99% by weight of the total weight of the composition, and the active agent can comprise from about 0.1% to about 40%, more narrowly from about 1% to about 9% by weight of the total weight of the composition. Selection of a specific weight ratio of the polymer and solvent is dependent on factors such as, but not limited to, the material from which the device is made, the geometrical structure of the device, the type and amount of the active agent employed, and the release rate desired.
  • polymers that can be combined with the active agent for the reservoir layer include the polymers noted above for the primer layer.
  • Ethylene vinyl alcohol copolymer for example, is functionally a very suitable choice of polymer because ethylene vinyl alcohol copolymer allows for good control capabilities of the release rate of the active agent.
  • an increase in the amount of the ethylene comonomer content decreases the rate that the active agent is released from the copolymer matrix.
  • the release rate of the active agent typically decreases as the hydrophilicity of the copolymer decreases.
  • An increase in the amount of the ethylene comonomer content increases the overall hydrophobicity of the copolymer, especially as the content of vinyl alcohol is concomitantly reduced.
  • release rate and the cumulative amount of the active agent that is released is directly proportional to the total initial content of the agent in the copolymer matrix. Accordingly, a wide spectrum of release rates can be achieved by modifying the ethylene comonomer content and the initial amount of the active agent.
  • PBMA poly(butylmethacrylate)
  • ethylene-vinyl acetate copolymers can also be especially suitable polymers for the reservoir layer.
  • the polymer in the reservoir coating is a mixture of PBMA and an ethylene-vinyl acetate copolymer.
  • the polymer in the reservoir layer is a biologically biodegradable polymer, such as one of the polymers listed above for formation of the primer layer.
  • the biological degradation, erosion, absorption and/or resorption of a biologically degradable, absorbable and/or resorbable polymer are expected to cause the release rate of the drug due to the gradual disappearance of the polymer that is included in the reservoir layer.
  • the stent coating can be engineered to provide either fast or slow release of the drug, as desired.
  • fast release may be recommended for stent coatings loaded with antimigratory drugs which often need to be released within 1 to 2 weeks.
  • slow release may be needed (up to 30 days release time).
  • solvents include the solvents listed above for the primer layer.
  • the active agent may be any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. Exposure of the composition to the active agent should not adversely alter the active agent's composition or characteristic. Accordingly, the particular active agent is selected for compatibility with the blended composition.
  • active agents include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I 1 , actinomycin X 1 , and actinomycin C 1 .
  • the bioactive agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances.
  • antineoplastics and/or antimitotics examples include paclitaxel, (e.g., TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., TAXOTERE®, from Aventis S.A., Frankfurt, Germany), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., ADRIAMYCIN® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., MUTAMYCIN® from Bristol-Myers Squibb Co., Stamford, Conn.).
  • paclitaxel e.g., TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.
  • docetaxel e.g., TAXOTERE®, from Aventis S.A., Frankfurt,
  • antiplatelets examples include aspirin, sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as ANGIOMAXTM (bivalirudin, Biogen, Inc., Cambridge, Mass.).
  • ANGIOMAXTM bivalirudin, Biogen, Inc., Cambridge, Mass.
  • cytostatic or antiproliferative agents examples include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g., CAPOTEN® and CAPOZIDE® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g., PRINIVIL® and PRINZIDE® from Merck & Co., Inc., Whitehouse Station, N.J.), calcium channel blockers (such as nifedipine), colchicine, proteins, peptides, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name MEVACOR® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF)
  • an antiallergic agent is permirolast potassium.
  • Other therapeutic substances or agents which may be appropriate agents include cisplatin, insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin, alpha-interferon, genetically engineered epithelial cells, anti-inflammatory agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antivirals, anticancer drugs, anticoagulant agents, free radical scavengers, estradiol, antibiotics, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, ABT-578, clobetasol, cytostatic agents, prodrugs thereof, co-drugs thereof, and a combination thereof.
  • Rapamycin can be a very suitable choice of active agent. Additionally, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), or a functional analog or structural derivative thereof, can be an especially functional choice of active agent. Examples of analogs or derivatives of 40-O-(2-hydroxy)ethyl-rapamycin include but are not limited to 40-O-(3-hydroxy)propyl-rapamycin and 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.
  • 40-O-(2-hydroxy)ethyl-rapamycin binds to the cytosolic immunophyllin FKBP12 and inhibits growth factor-driven cell proliferation, including that of T-cells and vascular smooth muscle cells.
  • the actions of 40-O-(2-hydroxy)ethyl-rapamycin occur late in the cell cycle (i.e., late G1 stage) compared to other immunosuppressive agents such as tacrolimus or cyclosporine which block transcriptional activation of early T-cell-specific genes.
  • 40-O-(2-hydroxy)ethyl-rapamycin can act as a potent anti-proliferative agent, it is believed that 40-O-(2-hydroxy)ethyl-rapamycin can be an effective agent to treat restenosis by being delivered to a local treatment site from a polymeric coated implantable device such as a stent.
  • the release rate of 40-O-(2-hydroxy)ethyl-rapamycin can be advantageously controlled by various methods and coatings as described herein.
  • the release rate of the 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof can be less than about 50% in 24 hours.
  • the ratio of 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, to polymer by weight in the reservoir layer can be about 1:2.8 to about 1:1.
  • the 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, in the reservoir layer can be in the amount of about 50 ⁇ g to about 500 ⁇ g, more narrowly about 90 ⁇ g to about 350 ⁇ g, and the polymer is in the amount of about 50 ⁇ g to about 1000 ⁇ g, more narrowly about 90 ⁇ g to about 500 ⁇ g.
  • the dosage or concentration of the active agent required to produce a therapeutic effect should be less than the level at which the active agent produces unwanted toxic effects and greater than the level at which non-therapeutic effects are obtained.
  • the dosage or concentration of the active agent required to inhibit the desired cellular activity of the vascular region can depend upon factors such as the particular circumstances of the patient; the nature of the trauma; the nature of the therapy desired; the time over which the ingredient administered resides at the vascular site; and if other bioactive substances are employed, the nature and type of the substance or combination of substances.
  • Therapeutically effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art.
  • the release rate of the active agent may be too high to be clinically useful.
  • the percentage of 40-O-(2-hydroxy)ethyl-rapamycin released from a stent coating without a barrier layer in 24 hours was determined to be 58.55% as measured in a porcine serum release rate procedure.
  • the release rate from the coating of Example 58 may be too high for a treatment using 40-O-(2-hydroxy)ethyl-rapamycin as the active agent.
  • a barrier layer can reduce the rate of release or delay the time at which the active agent is released from the reservoir layer.
  • the barrier layer can be applied on a selected region of the reservoir layer to form a rate reducing member.
  • the barrier layer can be applied to the reservoir layer prior to or subsequent to the heat treatment.
  • the composition for the barrier layer can be free or substantially free of active agents. Incidental migration of the active agent into the barrier layer can occur during or subsequent to the formation of the barrier layer.
  • compounds such as poly(ethylene glycol), heparin, heparin derivatives having hydrophobic counterions, or polyethylene oxide can be added to the barrier layer, or disposed on top of the barrier layer. The addition can be by blending, mixing, conjugation, bonding, etc.
  • the choice of polymer for the barrier layer can be the same as the selected polymer for the primer layer and/or reservoir layer.
  • the use of the same polymer, as described for some of the embodiments, significantly reduces or eliminates any interfacial incompatibilities, such as lack of cohesion, which may exist in the employment of two different polymeric layers.
  • Polymers that can be used for a barrier layer include the examples of polymers listed above for the primer layer and/or reservoir layer.
  • Representative examples of polymers for the barrier layer also include polytetrafluoroethylene, perfluoro elastomers, ethylene-tetrafluoroethylene copolymer, fluoroethylene-alkyl vinyl ether copolymer, polyhexafluoropropylene, low density linear polyethylenes having high molecular weights, ethylene-olefin copolymers, atactic polypropylene, polyisobutene, polybutylenes, polybutenes, styrene-ethylene-styrene block copolymers, styrene-butylene-styrene block copolymers, styrene-butadiene-styrene block copolymers, and ethylene methacrylic acid copolymers of low methacrylic acid content.
  • Ethylene vinyl alcohol copolymer is functionally a very suitable choice of polymer for the barrier layer.
  • Fluoropolymers are also a suitable choice for the barrier layer composition.
  • polyvinylidene fluoride otherwise known as KYNARTM, available from Atofina Chemicals, Philadelphia, Pa.
  • KYNARTM polyvinylidene fluoride
  • DMAC methylethylketone
  • cyclohexanone can optionally be combined with ethylene vinyl alcohol copolymer to form the barrier layer composition.
  • solution processing of fluoropolymers is possible, particularly the low crystallinity varieties such as CYTOPTM available from Asahi Glass and TEFLON AFTM available from DuPont.
  • PBMA and ethylene-vinyl acetate copolymers can also be especially suitable polymers for the barrier layer.
  • PBMA for example, can be dissolved in a solution of xylene, acetone and HFE FLUX REMOVERTM (Techspray, Amarillo, Tex.).
  • the polymer in the barrier layer can be a mixture of PBMA and an ethylene-vinyl acetate copolymer.
  • the barrier layer can also be styrene-ethylene/butylene-styrene block copolymer.
  • Styrene-ethylene/butylene-styrene block copolymer e.g., KRATONTM G-series
  • non-polar solvents such as, but not limited to, toluene, xylene, and decalin.
  • polymers for the rate-limiting membrane include, but are not limited to, ethylene-anhydride copolymers; and ethylene-acrylic acid copolymers having, for example, a mole % of acrylic acid of from about 2% to about 25%.
  • the ethylene-anhydride copolymer available from Bynel adheres well to ethylene vinyl alcohol copolymer and thus would function well as a barrier layer over a reservoir layer made from ethylene vinyl alcohol copolymer.
  • the copolymer can be dissolved in organic solvents, such as dimethylsulfoxide and DMAC.
  • Ethylene vinyl acetate polymers can be dissolved in organic solvents, such as toluene and n-butyl acetate.
  • Ethylene-acrylic acid copolymers can be dissolved in organic solvents, such as methanol, isopropyl alcohol, and dimethylsulfoxide.
  • a cross-linked silicone elastomer is a cross-linked silicone elastomer. Loose silicone and silicone with very low cross-linking are thought to cause an inflammatory biological response. However, it is believed that a thoroughly cross-linked silicone elastomer, having low levels of leachable silicone polymer and oligomer, is an essentially non-inflammatory substance.
  • Silicone elastomers such as Nusil MED-4750TM, MED-4755TM, or MED2-6640TM, having high tensile strengths, for example between 1200 psi and 1500 psi, will likely have the best durability during crimping, delivery, and expansion of a stent as well as good adhesion to a reservoir layer, e.g., ethylene vinyl alcohol copolymer or the surface of an implantable device.
  • a reservoir layer e.g., ethylene vinyl alcohol copolymer or the surface of an implantable device.
  • the composition for a rate-reducing membrane or diffusion barrier layer can be prepared by the methods used to prepare a polymer solution as described above.
  • the polymer can comprise from about 0.1% to about 35%, more narrowly from about 1% to about 20% by weight of the total weight of the composition, and the solvent can comprise from about 65% to about 99.9%, more narrowly from about 80% to about 98% by weight of the total weight of the composition. Selection of a specific weight ratio of the polymer and solvent is dependent on factors such as, but not limited to, the type of polymer and solvent employed, the type of underlying reservoir layer, and the method of application.
  • finishing layer that is especially biocompatible on the surface of the coating that is exposed to the biological lumen when inserted into a patient.
  • the finishing layer can be formed on the surface of the coating subsequent to the thermal treatment.
  • biocompatible polymers or biocompatible agents for the finishing layer include, but are not limited to polyethylene oxide, poly(ethylene glycol), hyaluronic acid, polyvinyl pyrrolidone, heparin, heparin derivatives such as those having hydrophobic counterions, and phosphylcholine.
  • the primer composition can first be applied to the stent.
  • Application of the composition can be by any conventional method, such as by spraying the composition onto the prosthesis, using a controlled deposition system or by immersing the prosthesis in the composition.
  • a representative example of a spray coating device is the EFD 780S device with VALVEMATETM 7040 control system (manufactured by EFD Inc., East Buffalo, R.I.).
  • a representative example of a controlled deposition system is described in U.S. Pat. No. 6,395,326 to Castro et al. Briefly, the controlled deposition system can include a dispenser that is configured to follow the pattern of the stent structures to deposit a coating directed on the surface of the stent.
  • dispensers include an ink jet printhead type dispenser.
  • a dispenser that can be used is a microinjector capable of injecting small volumes ranging from about 2 to about 70 mL, such as NANOLITERTM 2000 available from World Precision Instruments or Pneumatic PICOPUMPSTM PV830 with Micropipette available from Cell Technology System.
  • wiping refers to physical removal of excess coating from the surface of the stent
  • centrifugation refers to rapid rotation of the stent about an axis of rotation
  • blowing refers to application of air at a selected pressure to the deposited coating. Any excess coating can also be vacuumed off the surface of the device.
  • the solvent in the composition on the stent should be removed before the application of the reservoir layer composition.
  • the solvent can be allowed to evaporate or evaporation can be induced by heating the device at a predetermined temperature for a predetermined period of time.
  • the heating can be conducted in an anhydrous atmosphere and at ambient pressure.
  • the heating can also be conducted under a vacuum condition.
  • the thermal treatment according to the various embodiments of the invention can be used before or after removal of the solvent or a significant amount of the solvent from the primer layer. A dry or wet coating of the primer layer can therefore be subjected to the thermal treatment temperature for a duration of time that improves the properties of the primer layer.
  • the composition containing the active agent can be applied to a designated region of the primer coating or the surface of the device.
  • the solvent can be removed from the composition by allowing the solvent to evaporate or heating the stent.
  • the thermal treatment according to the various embodiments of the invention can be used before or after removal of the solvent or a significant amount of the solvent from the reservoir layer. A dry or wet coating of the reservoir layer can therefore be subjected to the thermal treatment temperature for a duration of time that improves the properties of the reservoir layer or the underlying primer layer (if a primer layer is included).
  • the diffusion barrier layer can be formed on a designated region of the active agent-containing coating subsequent to the evaporation of the solvent and the drying of the polymer for the active agent-containing coating.
  • the above-described processes can be similarly repeated for the formation of the diffusion barrier layer.
  • the thermal treatment according to the various embodiments of the invention can be used before or after removal of the solvent or a significant amount of the solvent from the barrier layer.
  • a dry or wet coating of the barrier layer can therefore be subjected to the thermal treatment temperature for a duration of time that improves the properties of the barrier layer or the underlying layer(s).
  • a coating with ethylene vinyl alcohol copolymer can have about 2% residual content of water (w/w). These residual components may adversely react with the polymer during the thermal treatment process if they are not removed beforehand.
  • the stents can advantageously be processed to remove essentially all of the water and/or free oxygen that may have been absorbed by the composition during the coating process.
  • the stents for example, can be placed in a dessicator and then heated in a convection oven to remove any residual water.
  • the stents can also be placed in a vacuum oven or in a gas chamber before undergoing the thermal treatment process. If a gas chamber is used, the chamber can be in communication with a gas source that provides an inert gas such as nitrogen or argon that can remove the water and free oxygen in the coating. The duration required for the process to remove residual water can be determined by a Karl Fisher, or TGA study.
  • implantable medical devices for the present invention include self-expandable stents, balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINETM and ENDOTAKTM, available from Guidant Corporation, Santa Clara, Calif.).
  • the underlying structure of the device can be of virtually any design. In one embodiment, the underlying structure is made from a metallic material or an alloy.
  • the device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy ((ELGILOYTM), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITETM (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
  • cobalt chromium alloy (ELGILOYTM), stainless steel (316L), high nitrogen stainless steel,
  • the underlying structure is made of a biostable polymer, or a bioabsorbable, bioerodable or biodegradable polymer.
  • the underlying structure can be made of a polymer such as, but not limited to, polyanhydrides such as poly(L-lactic acid), poly(D-lactic acid), poly(D,L-lactic acid), poly(L-lactic acid-co-L-aspartic acid), poly(D,L-lactic acid-co-L-aspartic acid) and poly(maleic acid-co-sebacic acid); poly(amino acid); polyesters such as poly(caprolactone), poly(glycolic acid), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(hydroxybutyrate-valerate), poly(4-hydroxy-L-proline ester), and poly(1,10-decanediol-1,10-decanediol dilactide); polyorthoesters; polycyanoacrylates; and polyphos
  • the device is a bioabsorbable stent which is intended to uphold luminal patency for a duration of time until the stent is partially or completely eliminated by the body.
  • a bioabsorbable stent can include an agent in the body of the stent or can have a coating layer(s) as described herein.
  • a bioabsorbable stent can be subjected to the thermal treatments of the invention.
  • the active agent can be applied to a device, e.g., a stent, retained on the device during delivery and released at a desired control rate and for a predetermined duration of time at the site of implantation.
  • a stent having the above-described coating layers is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways.
  • a stent having the above-described coating layers is particularly useful for treating occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis. Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
  • an angiogram is first performed to determine the appropriate positioning for stent therapy.
  • Angiography is typically accomplished by injecting a radiopaque contrasting agent through a catheter inserted into an artery or vein as an x-ray is taken.
  • a guidewire is then advanced through the lesion or proposed site of treatment.
  • Over the guidewire is passed a delivery catheter, which allows a stent in its collapsed configuration to be inserted into the passageway.
  • the delivery catheter is inserted either percutaneously, or by surgery, into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance.
  • a stent having the above-described coating layers may then be expanded at the desired area of treatment.
  • a post insertion angiogram may also be utilized to confirm appropriate positioning.
  • Multi-LinkTM stents (available from Guidant Corporation) were cleaned by placement in an ultrasonic bath of isopropyl alcohol solution for 10 minutes. The stents were dried and plasma cleaned in a plasma chamber. An ethylene vinyl alcohol copolymer solution was made. Ethylene vinyl alcohol copolymer (herein, “EVOH”) is commonly known by the generic name EVOH or by the trade name EVAL®. The EVOH solution was made with 1 gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7. The mixture was placed in a warm water shaker bath at 60° C. for 24 hours. The solution was cooled and vortexed.
  • EVAL® Ethylene vinyl alcohol copolymer
  • the cleaned Multi-LinkTM stents were dipped in the EVOH solution and then passed over a hot plate, for about 3-5 seconds, with a temperature setting of about 60° C.
  • the coated stents were heated for 6 hours in an air box and then placed in an oven at 60° C., under vacuum condition, and for 24 hours.
  • the coated stents were expanded on a 4.0 mm angioplasty balloon.
  • the coatings remained intact on the stents.
  • the coatings were transparent giving the Multi-LinkTM stents a glossy-like shine.
  • Multi-LinkTM stents were cleaned by placement in an ultrasonic bath of isopropyl alcohol solution for 10 minutes. The stents were dried and plasma cleaned in a plasma chamber. An EVOH solution was made with 1 gram of EVOH and 4 grams of DMSO, making an EVOH:DMSO ratio of 1:4. Dexamethasone was added to the 1:4 EVOH:DMSO solution. Dexamethasone constituted 9% by weight of the total weight of the solution. The solution was vortexed and placed in a tube. The cleaned Multi-LinkTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3-5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured for 6 hours in an air box and then placed in a vacuum oven at 60° C. for 24 hours.
  • the above-recited step was repeated twice.
  • the average weight of the coating was 0.0003 gram, having an estimated dexamethasone content of 75 ⁇ g per stent.
  • the coated stents were expanded on a 4.0 mm angioplasty balloon. The coatings remained intact on the stents. Verification of coverage and physical properties of the coatings were visualized using a scanning electron microscope.
  • the coatings were transparent, giving the Multi-LinkTM stents a glossy-like shine.
  • Multi-Link DuetTM stents are cleaned by placement in an ultrasonic bath of isopropyl alcohol solution for 10 minutes.
  • the stents are dried and plasma cleaned in a plasma chamber.
  • the EVOH solution is made with 1 gram of EVOH and 4 grams of DMSO, making an EVOH:DMSO ratio of 1:4.
  • Dexamethasone is added to the 1:4 EVOH:DMSO solution.
  • Dexamethasone constitutes 9% by weight of the total weight of the solution.
  • the solution is vortexed and placed in a tube.
  • the cleaned Multi-LinkTM stents are attached to mandrel wires and dipped into the solution.
  • the coated stents are passed over a hot plate, for about 3-5 seconds, with a temperature setting of about 60° C.
  • the coated stents are cured for 6 hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.
  • the single layered dexamethasone/EVOH coated stents are dipped into the 1:4 ratio EVOH:DMSO solution, free from dexamethasone.
  • the stents are passed over the hot plate, cured, and placed in the oven as previously described.
  • the top coating will provide a barrier layer for controlling the release of dexamethasone from the drug coated layer.
  • the coated stents can be expanded on a 4.0 mm angioplasty balloon. It is predicted that the coatings will remain intact on the stents.
  • the coatings will be transparent, giving the Multi-LinkTM stents a glossy-like shine.
  • Multi-LinkTM stents were cleaned by placement in an ultrasonic bath of isopropyl alcohol solution for 10 minutes. The stents were dried and plasma cleaned in a plasma chamber. An EVOH solution was made with 1 gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7. Vinblastine was added to the 1:7 EVOH:DMSO solution. Vinblastine constituted 2.5% by weight of the total weight of the solution. The solution was vortexed and placed in a tube. The cleaned Multi-LinkTM stents were attached to mandrel wires and dipped into the solution. The coated stents were passed over a hot plate, for about 3-5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured for 6 hours in an air box then placed in a vacuum oven at 60° C. for 24 hours. The above process was repeated twice, having a total of three layers. The average weight of the coating was 0.00005 gram, with an estimated vinblastine concentration of 12 microgram per stent.
  • Some of the stents were sterilized by electron beam radiation.
  • the sterilized and unsterilized vinblastine coated stents were tested for a 24 hour elution period by placing one sterilized and one unsterilized stent in 5 ml of phosphated saline solution (pH 7.4) at room temperature with rotational motion. The amount of vinblastine eluted was evaluated by High Performance Liquid Chromatography (HPLC) analysis. The results of this test are given below and plotted in FIG. 7 . The data indicates that electron beam radiation procedure does not interfere in the release of vinblastine from EVOH.
  • Multi-LinkTM stents were cleaned by placement in an ultrasonic bath of isopropyl alcohol solution for 10 minutes. The stents were dried and plasma cleaned in a plasma chamber. An EVOH solution was made with 1 gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7. Cephalotaxin was added to the 1:7 EVOH:DMSO solution. Cephalotaxin constituted 5% by weight of the total weight of the solution. The solution was vortexed and placed in a tube. The cleaned Multi-LinkTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3-5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured for 6 hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.
  • the above process was repeated twice, having a total of three layers.
  • the average weight of the coating was 0.00013 gram, with an estimated cephalotaxin concentration of 33 ⁇ g.
  • the stents were sterilized by electron beam radiation.
  • Cephalotaxin/EVOH coated stents and EVOH-coated control stents were implanted in the coronary arteries of 4 pigs, generally in accordance to the procedure set forth in “Restenosis After Balloon Angioplasty-A Practical Proliferative Model in Porcine Coronary Arteries” by Robert S. Schwartz, et al., Circulation 82(6):2190-2200, December 1990, and “Restenosis and the Proportional Neointimal Response to Coronary Artery Injury: Results in a Porcine Model” by Robert S. Schwartz et al, J Am Coll Cardiol; 19:267-74 Feb. 1992. Results of the porcine artery study indicated that there was no significant difference between the uncoated, EVOH coated and cephalotaxin coated stents in the amount of neointimal proliferation resulting from arterial injury.
  • Multi-Link DuetTM stents (available from Guidant Corporation) were cleaned by placement in an ultrasonic bath of isopropyl alcohol solution for 20 minutes, then air dried.
  • An EVOH stock solution was made with 1 gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7.
  • the mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • a co-solvent was added to the EVOH solution to promote wetting of the struts of the Multi-Link DuetTM stents.
  • One gram of tetrahydrofuran (THF) was mixed with 1.2 grams of the EVOH:DMSO solution.
  • the cleaned Multi-Link DuetTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents were then heated in a laboratory oven at 90° C. for 4 hours.
  • the thin EVOH coating adhered to stainless steel without peeling or cracking EVOH forms a superior primer base coat for other polymers that do not adhere well to stainless steel.
  • Multi-Link DuetTM stents were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH solution was made with 1 gram of EVOH and 5 grams of DMSO, making an EVOH:DMSO ratio of 1:5.
  • the mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • the dissolved EVOH:DMSO solution was mixed with 24.6 grams of THF and 19.56 grams of DMSO. The solution was mixed then placed in the reservoir of an air pressured atomizing sprayer.
  • Multi-Link DuetTM stents were sprayed while the stents rotated between 30 to 120 rpm.
  • the spray time was dependent upon the flow rate of the sprayer. A flow rate between 1 to 20 mg/second required a stent to be sprayed between 1 to 30 seconds.
  • the polymer coated Multi-Link DuetTM stents were heated in a forced air convection oven for 12 hours. The coatings were transparent, giving the Multi-Link DuetTM stents a glossy-like shine.
  • Multi-Link DuetTM stents were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution was made having an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • Various co-solvents were examined to determine which co-solvent would promote a thicker coating. These co-solvents were THF, DMF, 1-butanol, and n-butyl acetate.
  • the formulation for the co-solvents was as follows.
  • a second layer of coating was applied to coated Multi-Link DuetTM stents and the stents were heated in the same manner as above. No difference was seen between the stents coated with the various co-solvents (e.g., greater weight of coating or physical appearance). All coated stents were transparent, giving the Multi-Link DuetTM stents a glossy-like shine. No webbing or bridging of the coating was seen between the struts of the coated Multi-Link DuetTM stents. The weight of the coatings was between 0.2 to 0.27 mg/stent.
  • Multi-Link DuetTM stents are cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution is made having an EVOH:DMSO ratio of 1:4. The mixture is placed in a warm water shaker bath at 60° C. for 12 hours. The solution is mixed, then cooled to room temperature.
  • a 9% by weight dexamethasone solution is formulated as follows: 2.96 grams of the EVOH:DMSO solution is mixed with 0.29 gram of dexamethasone, then 0.9 gram of THF is added.
  • the cleaned Multi-Link DuetTM stents are attached to mandrel wires and dipped into the solution.
  • the coated stents are passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents are cured in a forced air convection oven for 2 hours.
  • a second layer of coating is applied and cured in the above manner. It is predicted that the coatings will be transparent, giving the Multi-Link DuetTM stents a glossy-like shine.
  • Multi-Link DuetTM stents are cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution is made having an EVOH:DMSO ratio of 1:4. The mixture is placed in a warm water shaker bath at 60° C. for 12 hours. The solution is mixed, then cooled to room temperature.
  • a 9% by weight dexamethasone solution is formulated as follows: 2.96 grams of the EVOH:DMSO solution is mixed with 0.29 gram of dexamethasone, then 0.9 gram of THF is added.
  • the cleaned Multi-Link DuetTM stents are attached to mandrel wires and dipped into the solution.
  • the coated stents are passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents are cured in a forced air convection oven for 2 hours.
  • a second layer of coating is applied and cured in the above manner. It is predicted that the coatings will be transparent, giving the Multi-Link DuetTM stents a glossy-like shine.
  • Multi-Link DuetTM stents were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution was made having an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • a 4.75% by weight actinomycin D solution was formulated as follows: 600 milligrams of the EVOH:DMSO solution was mixed with 40 milligrams of actinomycin D, then 200 milligrams of THF was added.
  • the cleaned Multi-Link DuetTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured in a forced air convection oven for 2 hours.
  • a second layer of coating was applied and cured in the above manner.
  • Multi-Link DuetTM stents were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution was made having an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • a 3.60% by weight actinomycin D solution was formulated as follows: 600 milligrams of the EVOH:DMSO solution was mixed with 40 milligrams of actinomycin D, then 480 milligrams of DMF was added.
  • the cleaned Multi-Link DuetTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured in a forced air convection oven for 2 hours.
  • a second layer of coating was applied and cured in the above manner.
  • Multi-Link DuetTM stents were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution was made having an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • a 6.45% by weight actinomycin D solution was formulated as follows: 680 milligrams of the EVOH:DMSO solution was mixed with 80 milligrams of actinomycin D, then 480 milligrams of DMF was added.
  • the cleaned Multi-Link DuetTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured in a forced air convection oven for 2 hours.
  • a second layer of coating was applied and cured in the above manner.
  • Multi-Link DuetTM stents are cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution is made having an EVOH:DMSO ratio of 1:40.
  • the mixture is placed in a warm water shaker bath at 60° C. for 12 hours.
  • the solution is mixed, then cooled to room temperature.
  • a 0.60% by weight actinomycin D solution can be formulated as follows: 4920 milligrams of the EVOH:DMSO solution is mixed with 40 milligrams of actinomycin D, then 2000 milligrams of THF is added.
  • the cleaned Multi-Link DuetTM stents can be sprayed upon by the above formulation.
  • the coated stents are cured in a forced air convection oven for 2 hours.
  • a second layer of coating is applied and cured in the above manner.
  • SMC Medial smooth muscle cells
  • the IC 50 (concentration at which 50% of the cells stop proliferating) of actimomycin D was 10 ⁇ 9 M as compared to 5 ⁇ 10 ⁇ 5 M for mitomycin and 10 ⁇ 6 M for docetaxel. Actinomycin D was the most potent agent to prevent SMC proliferation as compared to other pharmaceutical agents.
  • Porcine coronary models were used to assess the degree of the inhibition of neointimal formation in the coronary arteries of a porcine stent injury model by actinomycin D, delivered with a microporous balloon catheter (1 ⁇ 10 6 pores/mm 2 with sizes ranging from 0.2-0.8 micron).
  • the preclinical animal testing was performed in accordance with the NIH Guide for Care and Use of Laboratory Animals. Domestic swine were utilized to evaluate effect of the drug on the inhibition of the neointimal formation. Each testing procedure, excluding the angiographic analysis at the follow-up endpoints, was conducted using sterile techniques. During the study procedure, the activated clotting time (ACT) was monitored regularly to ensure appropriate anticoagulation. Base line blood samples were collected for each animal before initiation of the procedure. Quantitative coronary angiographic analysis (QCA) and intravascular ultrasound (IVUS) analysis was used for vessel size assessment.
  • QCA Quantitative coronary angiographic analysis
  • IVUS intravascular ultrasound
  • the vessels at the sites of the delivery were denuded by inflation of the PTCA balloons to 1:1 balloon to artery ratio and moving the balloons back and forth 5 times.
  • the drug was delivered to the denuded sites at 3.5 atm (3.61 Kg/sq cm) for 2 minutes using the microporous balloon catheters before stent deployment.
  • the average volume of delivery was about 3.3+/ ⁇ 1.2 ml.
  • stents were deployed at the delivery site such that final stent to artery ratio was 1.1:1.
  • angiographic assessments were performed. Coronary artery blood flow was assessed and the stented vessels were evaluated to determine minimal lumen diameter. The animals were euthanized following this procedure at the endpoint. Following euthanasia, the hearts were pressure perfusion fixed with formalin and prepared for histological analysis, encompassing light microscopy, and morphometry. Morphometric analysis of the stented arteries included assessment of the position of the stent struts and determination of vessel/lumen areas, percent (%) stenosis, injury scores, intimal and medial areas and intima/media ratios. Percent stenosis is quantitated by the following equation:
  • IEL is the internal elastic lamia.
  • the control group of animals received delivery of water instead of the drug.
  • the test group of animals received actinomycin D in two different concentration of 10 ⁇ 5 M and 10 ⁇ 4 M.
  • the results of the study are tabulated in Table 6.
  • the percent stenosis in the treated groups (32.3+/ ⁇ 11.7) was significantly decreased as compared to the control groups (48.8+/ ⁇ 9.8).
  • FIGS. 9A and 9B illustrate sample pictures of the histology slides of the coronary vessels from the control and the Dose 1 group, respectively.
  • actinomycin D is useful for the treatment of hyper-proliferative vascular disease. Specifically, actinomycin D is useful for the inhibition of smooth muscle cell hyperplasia, restenosis and vascular occlusion in a mammal, particularly occlusions following a mechanically mediated vascular trauma or injury.
  • Multi-Link DuetTM stents (13 mm in length) were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution was made having an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • a 5.06% by weight actinomycin D solution was formulated as follows: 40 milligrams of actinomycin D was dissolved in 150 milligrams of THF, then 600 milligrams of the EVOH:DMSO was added.
  • the cleaned Multi-Link DuetTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured in a forced air convection oven at 60° C. for 1 hour.
  • a second layer of coating was applied in the above manner and cured in a forced air convection oven at 60° C. for 4 hours.
  • An average coating weight of about 260 micrograms and an average actinomycin D loading of about 64 micrograms was achieved.
  • Multi-Link DuetTM stents (13 mm in length) were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution was made having an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • a 3.75% by weight actinomycin D solution was formulated as follows: 60 milligrams of actinomycin D was dissolved in 310 milligrams of DMF, then 1.22 grams of EVOH:DMSO solution was added.
  • the cleaned Multi-Link DuetTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured in a forced air convection oven at 60° C. for 1 hour.
  • a second layer of coating was applied in the above manner and cured in a forced air convection oven at 60° C. for 4 hours.
  • An average coating weight of about 270 micrograms with an average actinomycin D content of about 51 micrograms was achieved.
  • Multi-Link DuetTM stents were cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution was made having an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm water shaker bath at 60° C. for 12 hours. The solution was mixed, then cooled to room temperature.
  • a 6.1% by weight actinomycin D solution was formulated as follows: 100 milligrams of actinomycin D was dissolved in 310 milligrams of DMF, then 1.22 grams of EVOH:DMSO was added.
  • the cleaned Multi-Link DuetTM stents were attached to mandrel wires and dipped into the solution.
  • the coated stents were passed over a hot plate, for about 3 to 5 seconds, with a temperature setting of about 60° C.
  • the coated stents were cured in a forced air convection oven at 60° C. for 1 hour.
  • a second layer of coating was applied in the above manner and cured in a forced air convection oven at 60° C. for 4 hours.
  • An average coating weight of about 250 micrograms and an average actinomycin D loading of about 75 micrograms was achieved.
  • Multi-Link DuetTM stents are cleaned in an ultrasonic bath of isopropyl alcohol for 20 minutes, then air dried.
  • An EVOH stock solution is made having an EVOH:DMSO ratio of 1:40. The mixture is placed in a warm water shaker bath at 60° C. for 12 hours. The solution is mixed, then cooled to room temperature.
  • a 0.60% by weight actinomycin D solution can be formulated as follows: 4920 milligrams of the EVOH:DMSO solution is mixed with 40 milligrams of actinomycin D, then 2000 milligrams of THF is added.
  • the cleaned Multi-Link DuetTM stents can be sprayed upon by the above formulation.
  • the coated stents are cured in a forced air convection oven 60° C. for 15 minutes. Additional layers of the coating are applied and cured in the above manner.
  • the final curing step for the coated stents is conducted for about 4 hours.
  • a stainless steel stent can be spray coated with a formulation of EVOH and a drug, as previously described in any of the above examples.
  • a diffusion barrier composition can be formulated with 2 grams of EVOH blended with 20 grams of dimethylsulfoxide. 2.2 grams of fumed silica can be added and dispersed with a high shear process. With constant agitation, 50 grams of tetrahydrofuran and 30 grams of dimethylformamide are admixed with the blend. The stent, having the EVOH coating, can be immersed in the diffusion barrier composition to form a layer.
  • a stainless steel stent can be spray coated with a formulation of EVOH and a drug, as previously described in any of the above examples.
  • a diffusion barrier formulation can be made by dissolving 8 grams of EVOH into 32 grams of dimethylsulfoxide. To this is added 14 grams of rutile titanium dioxide and 7 grams more of dimethylsulfoxide. The particles can be dispersed using a ball mill. The final solution is diluted with 39 grams of tetrahydrofuran, added slowly with constant agitation. It is predicted that the diffusion barrier will reduce the rate at which the drug is released from the stent.
  • a stainless steel stent can be coated with a formulation of EVOH and a drug, as previously described in any of the above examples.
  • a diffusion barrier formulation can be made by dissolving 8 grams of EVOH in 32 grams of dimethylsulfoxide. 10.5 grams of solution precipitated hydroxyapatite can be added to the blend. The particles can be dispersed using a rotor stator mixer. With constant agitation, 30 grams of tetrahydrofuran can be added. The stent can be coated by immersion followed by centrifugation.
  • a stent can be coated with a formulation of EVOH and a drug, as previously described in any of the above examples. 8 grams of EVOH can be added 50 grams of dimethylsulfoxide and the polymer can be dissolved by agitation and heat. Four grams of lamp black can be added and dispersed in a ball mill. 60 grams of dimethyl sulfoxide and 110 grams of tetrahydrofuran are slowly added while stirring. The stent can be spray coated.
  • a stent can be coated with a formulation of EVOH and a drug, as previously described in any of the above examples.
  • Colloidal gold can be prepared by reduction of tetrachloroauric acid with sodium citrate in aqueous solution. The solution can be exchanged by rinsing with tetrahydrofuran. Eight grams of EVOH can be dissolved in 32 grams of dimethylsulfoxide. To this is added a solution of 77 grams of colloidal gold in 32 grams of tetrahydrofuran. The stent can be coated by a dip coating process.
  • FIGS. 10A and 10B illustrate sample pictures of the histology slides of the coronary vessels from the control group 64 RCA (Right Coronary Group) and the actinomycin D loaded stent group 68 LAD (Left Anterior Descending), respectively.
  • the stent used was an Advanced Cardiovascular Systems Multi-Link DuetTM (stainless steel).
  • FIG. 10B the positive remodeling of EEL 80 , caused by the application of actinomycin D, creates a gap between stent struts 82 and EEL 80 .
  • Thrombus deposits illustrated by reference number 84 , are formed in the gap over time.
  • the use of a self-expandable stent eliminates the formation of the gap as the stent self-expands in response to the positive remodeling of IEL. Thrombus deposits can be, accordingly, eliminated.
  • Actinomycin D induces the positive remodeling of the vessel walls, more particularly positive remodeling of the external elastic lamina (EEL) of a blood vessel wall.
  • Positive remodeling is generally defined as the ability of the vessel walls to structurally adapt, by increasing in lumen size, to chronic stimuli.
  • a positively remodeled lumen wall has a greater diameter or size as compared to a lumen wall which has not been subjected to the remodeling effect. Accordingly, the flow of blood through the remodeled site is increased—flow which would have otherwise been reduced because of, for example, the presence of plaque build-up or migration and proliferation of cells.
  • the index of remodeling is defined by the ratio of the area circumscribed by the EEL of the lesion site to the area circumscribed by the EEL of a reference site.
  • the internal elastic lamina in response, can also increases in area or diameter.
  • Actinomycin D, or analogs or derivative thereof not only can inhibit abnormal or inappropriate migration and/or proliferation of smooth muscle cells, which can lead to restenosis, but can also induce positive remodeling of the blood vessel walls. Thus the widening of the diseased region becomes more pronounced.
  • thermoset resin 1.67 grams of Epon 828 (Shell) resin can be added to 98 grams of propylene glycol monomethyl ether and 0.33 grams of Jeffamine T-430 (Huntsman). After application, the stent can be baked for 2 hours at 80 C and 2 hours at 160 C.
  • Epon 828 Shell
  • Jeffamine T-430 Jeffamine T-430
  • a 0.25% (w/w) solution of tetra-n-butyl titanate can be made in anhydrous ethyl acetate.
  • the solution can be applied by spraying to a surface of a stainless steel stent.
  • the stent can be heated at 100° C. for two hours.
  • Coated stents tested through simulated delivery to a target lesion for testing the mechanical integrity of the coating were tested through simulated delivery to a target lesion for testing the mechanical integrity of the coating.
  • the test was performed to observe the coating integrity after a simulated delivery to a tortuosity without a lesion.
  • the primer layer improved coating adhesion to the stents that resulted in fewer defects after a simulated use.
  • Group B had a number defects. Although the coating surface for Group B was poor to begin with, and the defects were not too severe.
  • the adhesion of 0.67% actinomycin-D (in 5% EVAL 1:1 THF:DMSO solution) coating on stents with two different surface treatments was compared to control samples.
  • the specific surface treatments consisted of: (1) argon plasma treatment; and (2) argon plasma treatment with a primer layer of 5% EVOH in 1:1 DMSO:DMF solution applied with the dip-spin process, i.e., centrifugation process, and followed by heat treatments at 120° C. for two hours and 60° C. for 10 hours.
  • the test method used to test adhesion of coatings on stents was a wet flow test, expanding the stents in a TECOFLEXTM tubing at 37° C. of water or saline.
  • Water or saline is then flushed through the stents for 18 hours to simulate blood flow through the stents.
  • the stents were then removed from the TECOFLEXTM with a “stent catcher” and observed under optical microscope for defects.
  • Peel defects are defined as areas where the coating separated from the stent. The number of peel defects were counted on the stents' OD/sidewall on rings 3, 5, and 7. The flow field was on the ID of the stents' surface. Some of the damage to the OD surface could have been aggravated by the TECOFLEXTM tubing. The number of peel defects observed on groups C and F (EVOH primer) was clearly lower than the other two test groups, regardless of flow rate. The increased flow rate did not induce more peel defects.
  • the objective of this experiment was to test the adhesive properties of an actinomycin-D containing coating on stainless steel stents having an EVOH primer layer.
  • the coated stents were tested in a wet flow test condition of saline heated to 37° C.
  • the number of “peel defects” on a select number of stent rings was observed.
  • a “peel defect” is defined as a location on the stent surface devoid of coating, i.e., bare metal or underlying coating layer that is visible under optical magnification of less than 100 ⁇ .
  • the objective of this study was to test the adhesive properties of an actinomycin-D containing coating on stainless steel stents having an EVOH primer layer.
  • the coated stents were tested under wet flow conditions of saline heated to 37° C.
  • the number of “peel defects” on a select number of stent rings was observed.
  • a “peel defect” is defined as a location on the stent surface devoid of coating, i.e., bare metal or an underlying coating layer that is visible under optical magnification of no more than 100 ⁇ .
  • OD Defects/Ring
  • ID Control 2.67 3.00 Dip/Plasma 0.67 0.47 Dip/No Plasma 0.87 0.80 Spray/Plasma 0.47 0.80 Spray/No Plasma 0.67 0.73
  • the objective of this experiment was to test the adhesive properties of an Actinomycin-D containing coating to stainless steel stents having an EVOH primer layer. More specifically, this experiment attempted to illustrate the effect of different bake times on the final result.
  • the coated stents were tested under wet flow conditions of saline heated to 37° C. The number of “peel defects” on a select number of stent rings was observed.
  • the control group with no primer layer had significantly more peel defects as compared to the treatment groups with a primer layer.
  • the objective of this experiment was to test the adhesive properties of an actinomycin-D containing coating on stainless steel stents having an EVOH primer layer. More specifically, different solvent systems (e.g., THF and DMF) were evaluated. The coated stents were tested under wet flow conditions of saline heated to 37° C. The number of “peel defects” on a select number of stent rings was observed.
  • solvent systems e.g., THF and DMF
  • the objective of this experiment was to test the adhesive properties of an actinomycin-D containing coating on stainless steel stents having an EVOH primer layer made from a DMSO:THF solution applied to the stents.
  • the coated stents were tested under wet flow conditions of saline heated to 37° C. The number of “peel defects” on a select number of stent rings was observed.
  • a solution of 1.9% (w/w) EVOH and 0.7% (w/w) 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 68.2% (w/w) dimethylacetamide and 29.2% (w/w) ethanol was spray coated onto the stents to a thickness with a target of 175 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin on each stent.
  • the stents were then baked at 50° C. for 2 hours.
  • a barrier layer was formed by spraying the stents with a 4% (w/w) solution of EVOH in a mixture of 76% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to compare the target coating formulation with the final coating formulation.
  • the results are as follows:
  • For the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 43 ⁇ 3 ⁇ g of polymer.
  • the target drug:polymer ratio was 1:2.857
  • the target dry weight for the entire reservoir coating was 675 ⁇ g
  • the average actual dry weight was 683 ⁇ 19 ⁇ g.
  • the average total drug content of the stent coatings was determined by the process described in Example 38.
  • the average drug content was 133 ⁇ g or 152 ⁇ g/cm 2 .
  • the target dry weight of polymer was 300 ⁇ g and the measured average dry weight was 320 ⁇ 13 ⁇ g.
  • a drug-coated stent was placed in a volumetric flask.
  • An appropriate amount of the extraction solvent acetonitrile with 0.02% BHT as protectant was added (e.g., in a 10 ml volumetric flask, with about 9 ml solvent added).
  • the flask was sonicated for a sufficient time to extract all of the drug from the reservoir region.
  • the solution in the flask was filled to mark with the solvent solution.
  • the drug solution was the analyzed by HPLC.
  • the HPLC system consisted of a Waters 2690 system with an analytical pump, a column compartment (set at 40° C.), an auto-sampler, and a 996 PDA detector.
  • the column was an YMC Pro C18 (150 mm ⁇ 4.6 I.D., 3 ⁇ m particle size), maintained at a temperature of 40° C.
  • the mobile phase consisted of 75% acetonitrile and 25% 20 mMolar ammonium acetate.
  • the flow rate was set on 1 ml/min.
  • the HPLC release rate results were quantified by comparing the results with a reference standard. The total drug content of the stent was then calculated.
  • a barrier layer was formed by spraying the stents with a 4% (w/w) solution of EVOH in a mixture of 76% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to compare the target coating formulation with the final coating formulation.
  • the results are as follows:
  • For the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 43 ⁇ 3 ⁇ g of polymer.
  • the target drug:polymer ratio was 1:1.75
  • the target dry weight for the entire reservoir coating was 757 ⁇ g
  • the average actual dry weight was 752 ⁇ 23 ⁇ g.
  • the average total drug content of the stent coatings was determined by the process described in Example 38.
  • the average drug content was 205 ⁇ g or 235 ⁇ g/cm 2 .
  • the target dry weight of polymer was 200 ⁇ g and the measured average dry weight was 186 ⁇ 13 ⁇ g.
  • a barrier layer was formed by spraying the stents with a 4% (w/w) solution of EVOH in a mixture of 76% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to compare the target coating formulation with the final coating formulation.
  • the results are as follows:
  • For the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 41 ⁇ 2 ⁇ g of polymer.
  • the target drug:polymer ratio was 1:1.6, the target dry weight for the entire reservoir coating was 845 ⁇ g and the average actual dry weight was 861 ⁇ 16 ⁇ g.
  • the average total drug content of the stent coatings was determined by the process described in Example 38. The average drug content was 282 ⁇ g or 323 ⁇ g/cm 2 .
  • the target dry weight of polymer was 125 ⁇ g and the measured average dry weight was 131 ⁇ 9 ⁇ g.
  • This Example 41 is referred to as the “Release Rate Profile Procedure.”
  • a drug-coated stent was placed on a stent holder of a Vankel Bio-Dis release rate tester (Vankel, Inc., Cary, N.C.).
  • the stent was dipped into an artificial medium which stabilizes the 40-O-(2-hydroxy)ethyl-rapamycin in the testing solution, including a phosphate buffer saline solution (10 mM, pH 7.4) with 1% TRITON X-100 (Sigma Corporation), for a designated amount of time (e.g., 3 hours).
  • the solution was analyzed for the amount of drug released from the stent coating using an HPLC process.
  • the HPLC system consisted of a Waters 2690 system with an analytical pump, a column compartment (set at 40° C.), an auto-sampler, and a 996 PDA detector.
  • the column was an YMC Pro C18 (150 mm ⁇ 4.6 I.D., 3 ⁇ m particle size), maintained at a temperature of 40° C.
  • the mobile phase consisted of 75% acetonitrile and 25% 20 mMolar ammonium acetate. The flow rate was set on 1 ml/min. After the drug solution was analyzed by HPLC the results were quantified by comparing the release rate results with a reference standard.
  • the stent was then dipped in a fresh medium solution for the necessary amount of time (e.g., another 3 hours) and the drug released in the solution was analyzed again according to the HPLC procedure described above. The procedure was repeated according to the number of data points required. The release rate profile could then be generated by plotting cumulative drug released in the medium vs. time.
  • a comparison of the release rates for the stents from Examples 37, 39 and 40 is graphically shown in FIG. 11 .
  • Example 43 is referred to as the “3 day In Vivo Release Rate Procedure” or the “9 day In Vivo Release Rate Procedure,” depending on the number of days the stents are inserted into the experimental animal.
  • the stents harvested from the experimental animals were tested using an HPLC procedure to determine how much drug remained on the stents.
  • a drug-coated stent removed from the experimental animal was placed in a volumetric flask.
  • An appropriate amount of the extraction solvent acetonitrile with 0.02% BHT as protectant was added (e.g., in a 10 ml volumetric flask, with about 9 ml solvent added).
  • the flask was sonicated for a sufficient time to extract all of the drug from the reservoir region. Then, the solution in the flask was filled to mark with the solvent solution.
  • the HPLC system consisted of a Waters 2690 system with an analytical pump, a column compartment (set at 40° C.), an auto-sampler, and a 996 PDA detector.
  • the column was an YMC Pro C18 (150 mm ⁇ 4.6 I.D., 3 ⁇ m particle size), maintained at a temperature of 40° C.
  • the mobile phase consisted of 75% acetonitrile and 25% 20 mMolar ammonium acetate.
  • the flow rate was set on 1 ml/min.
  • the HPLC release rate results were quantified by comparing the results with a reference standard.
  • the total drug released in vivo was the difference between the average drug loaded on the stents and the amount of drug remaining on the stents after the stent implantation into the experimental animal.
  • the release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents with coatings produced by the process under Example 37 were tested using a 3 day in vivo process as described in Example 43.
  • stents from Example 37 were implanted into experimental animals and then the stents were tested by HPLC to determine how much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into the blood vessel.
  • HPLC analysis 21.8 ⁇ g of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days, or 16.4% of the total drug content of the coating.
  • the release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents with coatings produced by the process under Example 39 were tested using a 3 day in vivo process as described in Example 43.
  • stents from Example 39 were implanted into experimental animals and then the stents were tested by HPLC to determine how much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into the blood vessel. According to the HPLC analysis, 7.8 ⁇ g of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days, or 3.8% of the total drug content of the coating.
  • the release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents with coatings produced by the process under Example 40 were tested using a 3 day in vivo process as described in Example 43.
  • stents from Example 40 were implanted into experimental animals and then the stents were tested by HPLC to determine how much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into the blood vessel. According to the HPLC analysis, 50.8 ⁇ g of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days, or 18% of the total drug content of the coating.
  • the release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents with coatings produced by the process under Example 39 were tested using a 9 day in vivo process as described in Example 43.
  • stents from Example 39 were implanted into experimental animals and then the stents were tested by HPLC to determine how much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into the blood vessel. According to the HPLC analysis, 29.7% of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 9 days.
  • the release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents with coatings produced by the process under Example 40 were tested using a 9 day in vivo process as described in Example 43.
  • stents from Example 40 were implanted into experimental animals and then the stents were tested by HPLC to determine how much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into the blood vessel. According to the HPLC analysis, 39.4% of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 9 days.
  • a 13 mm PIXEL stent (available from Guidant Corporation) was coated.
  • the stent had a yellowish-gold coating that included EVOH and actinomycin D.
  • the ends of the stent were heated with a cauterizer tip for fifteen (15) seconds at a current setting of 2.2 Amps, which corresponded to a temperature of about 106° C. at a distance of about 0.006 inches from the stent.
  • the stent was submerged in a 50% (w/w) methanol:water bath. After twenty-four (24) hours, the stent was observed to have drug present at the stent end rings as indicated by a yellowish hue. The middle section of the stent, however, was clear, indicating that the drug had been released through the polymer. This process was repeated on 40 stents yielding similar results for all the stents.
  • PIXEL stents 13 mm PIXEL stents were coated.
  • the stents had yellowish-gold coatings that included EVOH and actinomycin D.
  • the stents were separated into three experimental groups, and the ends of the stents were heated with a cauterizer tip according to the parameters shown in Table 10 for each group. After the stents were exposed to heat from the cauterizer tip, the stent was submerged in a 50% (w/w) methanol:water bath. After twenty-four (24) hours, the stents were observed as summarized in Table 10.
  • 8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to compare the target coating formulation with the final coating formulation.
  • the results are as follows: For the primer layer, there was a target dry weight of 26 ⁇ g of polymer, and a measured average dry weight of 28 ⁇ 3 ⁇ g of polymer. For the reservoir layer, the target drug:polymer ratio was 1:1.25, and the measured average drug content was 128 ⁇ g. For the barrier layer, the measured average dry weight was 84 ⁇ g.
  • 8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to compare the target coating formulation with the final coating formulation.
  • the results are as follows: For the primer layer, there was a target dry weight of 26 ⁇ g of polymer, and a measured average dry weight of 28 ⁇ 2 ⁇ g of polymer. For the reservoir layer, the target drug:polymer ratio was 1:1.5, and the measured average drug content was 130 ⁇ g. For the barrier layer, the measured average dry weight was 81 ⁇ g.
  • stents were then heat treated by exposing the stents to a heat of 80° C. for 2 hours.
  • Example 51 A comparison of the release rates for the stents from Examples 51-52 is graphically shown in FIG. 12 .
  • the results unexpectedly show that the stent coatings that were exposed to thermal treatment in Example 52 have a significantly lower release rate than the stent coatings of Example 51.
  • This Example 54 is referred to as the “Porcine Serum Release Rate Procedure.”
  • a drug-coated stent was placed on a stent holder of a Vankel Bio-Dis release rate tester.
  • the stent was dipped into porcine serum, with 0.1% sodium azide added, for 24 hrs.
  • the stent was removed from the porcine serum and the drug solution analyzed by an HPLC procedure to determine how much drug was released into the porcine serum.
  • the HPLC system consisted of a Waters 2690 system with an analytical pump, a column compartment (set at 40° C.), an auto-sampler, and a 996 PDA detector.
  • the column was an YMC Pro C18 (150 mm ⁇ 4.6 I.D., 3 ⁇ m particle size), maintained at a temperature of 40° C.
  • the mobile phase consisted of 75% acetonitrile and 25% 20 mMolar ammonium acetate.
  • the flow rate was set on 1 ml/min.
  • the HPLC release rate results were quantified by comparing the results with a reference standard.
  • PENTA stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 45 ⁇ 1 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1, and the measured average drug content was 151 ⁇ g as determined by Example 38.
  • the measured average dry weight was 234 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 32.6 ⁇ g, or 21.6% of the total.
  • PENTA stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 44 ⁇ 3 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.8, and the measured average drug content was 97 ⁇ g as determined by Example 38.
  • the measured average dry weight was 184 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 24.1 ⁇ g, or 24.8% of the total.
  • PENTA stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 41 ⁇ 1 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.8, and the measured average drug content was 227 ⁇ g as determined by Example 38.
  • the measured average dry weight was 181 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 27.5 ⁇ g, or 12.1% of the total.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 44 ⁇ 2 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.8, and the measured average drug content was 221 ⁇ g as determined by Example 38.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 129.4 ⁇ g, or 58.55% of the total.
  • PENTA stents 13 mm, were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 42 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.5, and the measured average drug content was 184 ⁇ g as determined by Example 38.
  • the measured average dry weight was 81 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 70.1 ⁇ g, or 38.1% of the total.
  • PIXEL stents 8 mm, were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 45 ⁇ 1 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.75, and the measured average drug content was 200 ⁇ g as determined by Example 38.
  • the measured average dry weight was 180 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 39.0 ⁇ g, or 19.5% of the total.
  • PIXEL stents 8 mm, were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 41 ⁇ 4 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1, and the measured average drug content was 167 ⁇ g as determined by Example 38.
  • the measured average dry weight was 184 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 6.0 ⁇ g, or 3.6% of the total.
  • PIXEL stents 8 mm, were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 26 ⁇ g of polymer, and a measured average dry weight of 24 ⁇ 2 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.25, and the measured average drug content was 120 ⁇ g as determined by Example 38.
  • the measured average dry weight was 138 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 11.0 ⁇ g, or 9.2% of the total.
  • PENTA stents Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours.
  • a barrier layer was formed by spraying the stents with a solution of 1% (w/w) polybutylmethacrylate (“PBMA”), 5.7% (w/w) acetone, 50% (w/w) xylene and 43.3% (w/w) HFE FLUX REMOVER (Techspray, Amarillo, Tex.). Another 2 hour bake at 50° C. was performed to remove the solvent.
  • PBMA polybutylmethacrylate
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 44 ⁇ 4 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1, and the measured average drug content was 183 ⁇ g as determined by Example 38.
  • the measured average dry weight was 168 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 21.6 ⁇ g, or 11.8% of the total.
  • PENTA stents Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours.
  • a barrier layer was formed by spraying the stents with a solution of 1% (w/w) PBMA, 5.7% (w/w) acetone, 50% (w/w) xylene and 43.3% (w/w) HFE FLUX REMOVER. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 41 ⁇ 2 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.8, and the measured average drug content was 102 ⁇ g as determined by Example 38.
  • the measured average dry weight was 97 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 9.1 ⁇ g, or 8.9% of the total.
  • Eight (8) mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours.
  • a barrier layer was formed by spraying the stents with a solution of 1% (w/w) PBMA, 5.7% (w/w) acetone, 50% (w/w) xylene and 43.3% (w/w) HFE FLUX REMOVER (Techspray, Amarillo, Tex.). Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 26 ⁇ g of polymer, and a measured average dry weight of 27 ⁇ 2 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.25, and the measured average drug content was 120 ⁇ g as determined by Example 38.
  • the measured average dry weight was 68 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 22.0 ⁇ g, or 18.3% of the total.
  • Example 39 A select number of stents from Example 39 were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 22.8 ⁇ g, or 11.1% of the total.
  • Example 40 A select number of stents from Example 40 were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 57.0 ⁇ g, or 20.2% of the total.
  • Two stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide to form a primer layer.
  • a primer layer there was a target dry weight of 100 ⁇ g of polymer, and the measured dry weights were 93 ⁇ g and 119 ⁇ g, respectively.
  • the two stents were then coated with an EVOH-40-O-(2-hydroxy)ethyl-rapamycin blend at a drug:polymer ratio of 2:1 to produce a reservoir layer. After application, it was determined that the reservoir layers had weights of 610 ⁇ g and 590 ⁇ g, respectively.
  • the coatings contained about 407 ⁇ g and 393 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin, respectively.
  • Polymeric barrier layers were also applied to the stents and it was determined that the weights of the barrier layers were 279 ⁇ g and 377 ⁇ g, respectfully.
  • the stents from this Example were then sterilized using an ethylene oxide sterilization process.
  • the stents were placed in a chamber and exposed to ethylene oxide gas for 6 hours at 130-140° F., with a relative humidity of 45-80%.
  • the stents were then aerated for about 72 hours at 110-130° F.
  • FIG. 13 is a chromatograph showing the peak purity the 40-O-(2-hydroxy)ethyl-rapamycin in one of the coatings, labeled “ETO,” as compared to a reference standard for 40-O-(2-hydroxy)ethyl-rapamycin, labeled “Ref. Std.”
  • Two stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide to form a primer layer.
  • a primer layer there was a target dry weight of 100 ⁇ g of polymer, and the measured dry weights were 99 ⁇ g and 94 ⁇ g, respectively.
  • the two stents were then coated with an EVOH-40-O-(2-hydroxy)ethyl-rapamycin blend at a drug:polymer ratio of 2:1 to produce a reservoir layer. After application, it was determined that the reservoir layers had weights of 586 ⁇ g and 588 ⁇ g, respectively.
  • the coatings contained about 391 ⁇ g and 392 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin, respectively.
  • Polymeric barrier layers were also applied to the stents and it was determined that the weights of the barrier layers were 380 ⁇ g and 369 ⁇ g, respectfully.
  • the stents from this Example were then sterilized using an e-beam sterilization process.
  • the stents were placed in a stent container which was run through an e-beam chamber. While moving through the e-beam chamber via a conveyor belt, the stent container was exposed to an e-beam with a constant energy level so that the stent container received between 33.11 and 46.24 Kgy. The stent therefore at any point along the length of the stent received at a minimum 25 Kgy.
  • FIG. 13 is a chromatograph showing the peak purity the 40-O-(2-hydroxy)ethyl-rapamycin in one of the coatings, labeled “e-beam,” as compared to a reference standard for 40-O-(2-hydroxy)ethyl-rapamycin, labeled “Ref. Std.”
  • PENTA stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 44 ⁇ 3 ⁇ g of polymer.
  • the drug:polymer ratio was 1:2, and the measured average drug content was 245 ⁇ g as determined by Example 38.
  • the measured average dry weight was 104 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 23.5 ⁇ g, or 9.6% of the total.
  • PENTA stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. A solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w) dimethylacetamide and 30% (w/w) ethanol was spray coated onto the stents. The stents were then baked at 50° C. for 2 hours. A barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • a select number of stents were analyzed to quantify the coating components.
  • the primer layer there was a target dry weight of 40 ⁇ g of polymer, and a measured average dry weight of 45 ⁇ 3 ⁇ g of polymer.
  • the drug:polymer ratio was 1:1.5, and the measured average drug content was 337 ⁇ g as determined by Example 38.
  • the measured average dry weight was 169 ⁇ g.
  • Example 54 After the coatings were formed on the stents, a select number of stents were tested for the drug release rate from the coatings according to the procedure described in Example 54. It was determined that the average drug released in 24 hours was 37.1 ⁇ g, or 11.0% of the total.
  • Stents from Example 70 and stents from Example 71 were sterilized according to the process described in Example 68.
  • the released rates of the drug in the stent coatings of sterilized stents and non-sterilized were then tested according to the process described in Example 41.
  • the results of the release rate test are graphically shown in FIG. 14 .
  • a 13 mm PENTA stent can be coated by spraying a solution of EVOH, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 300 ⁇ g of EVOH and 300 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and pentane. A second 2 hour bake at 50° C. can be performed to remove the solvent to yield a barrier coating with 320 ⁇ g of EVOH.
  • a 13 mm PENTA stent can be coated by spraying a solution of EVOH and DMAC onto the stent.
  • the solvent is removed by baking at 140° C. for 2 hours to yield a primer coating with 100 ⁇ g of EVOH.
  • a reservoir layer can be applied by spraying a solution of EVOH, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 200 ⁇ g of EVOH and 400 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 350 ⁇ g of EVOH.
  • a 13 mm PENTA stent can be coated by spraying a solution of EVOH, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 500 ⁇ g of EVOH and 250 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and pentane. A second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 300 ⁇ g of EVOH.
  • a 13 mm PENTA stent can be coated by spraying a solution of EVOH, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 475 ⁇ g of EVOH and 175 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and pentane. A second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 300 ⁇ g of EVOH.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 400 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 300 ⁇ g of EVOH.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 400 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of PBMA and HFE FLUX REMOVER.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 150 ⁇ g of PBMA.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 200 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 200 ⁇ g of EVOH.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 200 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can formed by spraying the stent with a solution of PBMA and HFE FLUX REMOVER.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 150 ⁇ g of PBMA.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 200 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 200 ⁇ g of EVOH.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 200 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of PBMA and HFE FLUX REMOVER.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 100 ⁇ g of PBMA.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 270 ⁇ g of EVOH and 150 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 150 ⁇ g of EVOH.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 170 ⁇ g of EVOH and 150 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of PBMA and HFE FLUX REMOVER.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 75 ⁇ g of PBMA.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 150 ⁇ g of EVOH and 150 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 200 ⁇ g of EVOH.
  • a finishing layer can then applied by spraying the stent with a solution of EVOH, polyethylene oxide (molecular weight of 17.5 K) (“PEO”) and dimethylacetamide.
  • the stent is baked at 50° C. for 2 hours to remove the solvent to yield a finishing coating with 83 ⁇ g of EVOH and 17 ⁇ g of PEO.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 270 ⁇ g of EVOH and 150 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 150 ⁇ g of EVOH.
  • a finishing layer can then applied by spraying the stent with a solution of EVOH, PEO and dimethylacetamide.
  • the stent is baked at 50° C. for 2 hours to remove the solvent to yield a finishing coating with 83 ⁇ g of EVOH and 17 ⁇ g of PEO.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 200 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 100 ⁇ g of EVOH.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 200 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH, KYNAR and HFE FLUX REMOVER.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 50 ⁇ g of EVOH and 50 ⁇ g of KYNAR.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 350 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer is formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 200 ⁇ g of EVOH.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 350 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of PBMA and HFE FLUX REMOVER.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 100 ⁇ g of PBMA.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 350 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 200 ⁇ g of EVOH.
  • An 8 mm PIXEL stent is coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 350 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of EVOH and a mixture of dimethylacetamide and pentane.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 100 ⁇ g of EVOH.
  • a finishing layer can then be applied by spraying the stent with a solution of EVOH, PEO and dimethylacetamide.
  • the stent is baked at 50° C. for 2 hours to remove the solvent to yield a finishing coating with 83 ⁇ g of EVOH and 17 ⁇ g of PEO.
  • An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide and ethanol onto the stent.
  • the stent is then baked at 50° C. for 2 hours to yield a reservoir coating with 350 ⁇ g of EVOH and 200 ⁇ g of 40-O-(2-hydroxy)ethyl-rapamycin.
  • a barrier layer can be formed by spraying the stent with a solution of PBMA and HFE FLUX REMOVER.
  • a second 2 hour bake at 50° C. is performed to remove the solvent to yield a barrier coating with 75 ⁇ g of PBMA.
  • a finishing layer can then be applied by spraying the stent with a solution of PBMA, PEO and dimethylacetamide.
  • the stent is baked at 50° C. for 2 hours to remove the solvent to yield a finishing coating with 62.5 ⁇ g of PBMA and 12.5 ⁇ g of PEO.
  • the purpose of this study was to evaluate 40-O-(2-hydroxy)ethyl-rapamycin in its ability to prevent excessive neointimal proliferation following stenting in a 28-day porcine coronary artery stent model.
  • two formulations of 40-O-(2-hydroxy)ethyl-rapamycin and EVOH were coated onto Multi-Link PENTATM stents.
  • These two formulations of drug eluting stents were compared to a polymer control and a bare stent control in terms of safety and efficacy in a 28 day in vivo porcine model.
  • pigs Thirteen (13) pigs were evaluated in this study. Eleven (11) pigs were used for the 28-day chronic study in order to evaluate the vascular response to the drug eluting stents.
  • Three stents were implanted in each animal. Stents were deployed in the right coronary artery (RCA), the left anterior descending artery (LAD), and the left circumflex coronary artery (LCX) for the 28-day duration. All stents were deployed at a 1.1:1 stent:artery ratio allowing slight to moderate injury in order to assess the drugs ability to prevent excessive neointimal proliferation following stenting.
  • Each stented vessel underwent follow up angiography and histo-pathological evaluation in order to assess the chronic vascular cellular response and to assess if the drug has any effect in reducing neointimal proliferation compared to controls.
  • Ticlopidine 500 mg PO
  • Aspirin 325 mg PO
  • the pigs were euthanized immediately following the follow-up angiography.
  • the hearts were removed, perfused with saline and pressure perfusion fixed with formalin before being placed into a labeled container with formalin and submitted for pathological evaluation.
  • Sections of the treated coronary arteries were sent to a contracted pathology site.
  • Five cross sections of the stented vessel were prepared including one section of each vessel ends and three sections of the stented area.
  • the tissue was stained with haemoatoxylin and eosin and with an elastin stain.
  • a morphometric analysis of the stented arteries was performed which included an assessment of stent strut position and determination of vessel/lumen areas, percent stenosis, injury scores, intimal and medial areas and intima/media ratios.
  • 13 mm PIXEL-D stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. The target primer layer weight was 58.2 ⁇ g.
  • a solution of EVOH and actinomycin D in a mixture of 75% (w/w) dimethylacetamide and 25% (w/w) ethanol was spray coated onto the stents. The ratio of EVOH to actinomycin D was 9 to 1.
  • the stents were then baked at 50° C. for 2 hours.
  • the target weight for the reservoir layer was 90 ⁇ g.
  • a barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent. The target weight for the barrier layer was 218 ⁇ g.
  • stents were then subjected to a standard grip process in order to mount the stent onto a catheter.
  • the stents were separated into four test groups. Group 1 served as the control group and were mounted at room temperature; Group 2 was exposed to a temperature of about 82.2° C. (180° F.) for about 2 minutes; Group 3 was exposed to a temperature of about 93.3° C. (200° F.) for about 2 minutes; and Group 4 was exposed to a temperature of about 121.1° C. (250° F.) for about 2 minutes.
  • PIXEL-D stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours. The target primer layer weight was 40 ⁇ g.
  • a solution of EVOH and actinomycin D in a mixture of 75% (w/w) dimethylacetamide and 25% (w/w) ethanol was spray coated onto the stents. The ratio of EVOH to actinomycin D was 9 to 1, and a target total dose of 7.9 ⁇ g.
  • the stents were then baked at 50° C. for 2 hours.
  • the target weight for the reservoir layer was 79 ⁇ g.
  • a barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent. The target weight for the barrier layer was 135 ⁇ g.
  • a select number of stents were then subjected to different thermal treatment processes.
  • One process included subjecting stents to a two hour thermal treatment before the mounting process.
  • a select number of coated stents were placed in a convection oven and subjected to a temperature of about 80° C. for about 2 hours.
  • the other process included subjecting stents to a two minute thermal treatment during the mounting procedure.
  • Group 1 was the control group and was mounted at room temperature;
  • Group 2 was exposed to a temperature of about 82.2° C. (180° F.) for about 2 minutes; and
  • Group 3 was exposed to a temperature of about 121.1° C. (250° F.) for about 2 minutes.
  • Table 16 shows the number of stents used in each of the test groups.
  • Stents from Group 2 including stents from the two hour treatment group and the non-two hour treatment group, were tested to determine if the total content of the active agent was affected by the two hour thermal treatment process. The results demonstrated that the thermal treatment process did not affect the total content.
  • the average total content for the stents that were subjected to the two hour treatment was 9.3 ⁇ g/cm 2 ⁇ 0.6
  • the average total content for the stents that were not subjected to the two hour treatment was 8.8 ⁇ g/cm 2 ⁇ 0.6.
  • 13 mm PIXEL-D stents were coated by spraying a 2% (w/w) solution of EVOH and 98% (w/w) dimethylacetamide. The solvent was removed by baking at 140° C. for 2 hours.
  • a solution of EVOH and actinomycin D in a mixture of 75% (w/w) dimethylacetamide and 25% (w/w) ethanol was spray coated onto the stents. The ratio of EVOH to actinomycin D was 9 to 1.
  • the stents were then baked at 50° C. for 2 hours.
  • a barrier layer was formed by spraying the stents with a solution of EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C. was performed to remove the solvent.
  • test groups were subjected to different conditions to study the effect of (1) exposure temperatures (40° C., 50° C. or 80° C.); (2) exposure time (2 or 7 hours); and (3) storage time (0 or 30 days). Table 18 summarizes the different test parameters.
  • the stents were sterilized using an e-beam process. During the e-beam process, the stents were exposed to 35 kGy of radiation using a one pass process.
  • DLPLA for this Example was provided by Birmingham Polymers, Inc., 756 Tom Martin Drive, Birmingham, Ala. 35211-4467 (Manufacture Lot # DO1O78). According to the manufacture, the DLPLA has an inherent viscosity of 0.55-0.75, a T g of 55° C.-60° C., and lacks a T m (i.e., is amorphous). The viscosity was tested and was determined to be 0.67 dL/g in CHCl 3 .
  • PENTA stents available from Guidant were coated by spraying a solution having 1% (w/w) DLPLA, 1% (w/w) everolimus, 78.4% (w/w) 1,1,2-trichloroethane and 19.6% (w/w) chloroform.
  • the apparatus used to coat the stents for this Example and Examples 99-102 was an EFD 780S spray device with VALVEMATE 7040 control system (manufactured by EFD Inc., East Buffalo, R.I.).
  • the solvent was removed by baking at about 120° C. for about 1 hour.
  • the target drug coating weight after removal of the solvent was 300 ⁇ g.
  • the stents were then sterilized using an e-beam process set at 35 KGy.
  • a solution of 1% (w/w) DLPLA (0.67 dL/g in CHCl 3 , 1% (w/w) everolimus, 76.8% (w/w) 1,1,2-trichloroethane and 19.2% (w/w) chloroform was spray coated onto the stents.
  • the stents were then baked at about 50° C. for about 1 hour.
  • the target weight for the reservoir layer after removal of the solvent was 300 ⁇ g.
  • the stents were then sterilized using an e-beam process set at 35 KGy.
  • a solution of 1% (w/w) DLPLA (0.67 dL/g in CHCl 3 ), 1% (w/w) everolimus, 76.8% (w/w) 1,1,2-trichloroethane and 19.2% (w/w) chloroform was spray coated onto the stents.
  • the stents were then baked at about 50° C. for about 1 hour.
  • the target weight for the reservoir layer after removal of the solvent was 300 ⁇ g.
  • a barrier layer was formed by spraying the stents with a solution of 2% (w/w) POLYACTIVE in a mixture of 78.4% (w/w) 1,1,2-trichloroethane and 19.6% (w/w) chloroform.
  • POLYACTIVE is a trade name of a family of poly(ethylene glycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol) copolymers (PEG-PBT-PEG) and is available from IsoTis Corp. of Holland As indicated by the manufacturer, the grade of POLYACTIVE used for this Example and Example 102 had about 45 molar % units derived from PBT and about 55 molar % units derived from PEG.
  • the molecular weight of the PEG units was indicated to be about 300 Daltons.
  • a 1 hour bake at 50° C. was performed to remove the solvent.
  • the target weight for the barrier layer after removal of the solvent was 150 ⁇ g.
  • the stents were then sterilized using an e-beam process set at 35 KGy.
  • a solution of 1% (w/w) DLPLA (0.67 dL/g in CHCl 3 ), 1% (w/w) everolimus, 76.8% (w/w) 1,1,2-trichloroethane, and 19.2% (w/w) chloroform was spray coated onto the stents.
  • the stents were then baked at about 50° C. for about 1 hour.
  • the target weight for the reservoir layer after removal of the solvent was 300 ⁇ g.
  • the stents were then sterilized using an e-beam process set at 35 KGy.
  • a solution of 1% (w/w) DLPLA (0.67 dL/g in CHCl 3 ), 1% everolimus, 76.8% (w/w) 1,1,2-trichloroethane and 19.2% (w/w) chloroform was spray coated onto the stents.
  • the stents were then baked at about 50° C. for about 1 hour.
  • the target weight for the reservoir layer after removal of the solvent was 300 ⁇ g.
  • a barrier layer was formed by spraying the stents with a solution of 2% (w/w) POLYACTIVE in a mixture of 78.4% (w/w) 1,1,2-trichloroethane and 19.6% (w/w) chloroform. Another 1 hour bake at 50° C. was performed to remove the solvent. The target weight for the barrier layer after removal of the solvent was 150 ⁇ g. The stents were then sterilized using an e-beam process set at 35 KGy.
  • Sample stents from Examples 98-102 were subjected to a wet expansion test to determine the mechanical integrity of the coatings. The following procedure was used to determine the mechanical integrity of the coatings for each stent.
  • the stent was mounted on a balloon catheter.
  • the stent and the balloon were placed in a beaker containing de-ionized water at about 37° C.
  • a pressure of about 8 atm was applied to a balloon for about 1 minute.
  • the stent-catheter assembly was then taken out from the beaker, followed by deflating of the balloon and the retraction of the catheter.
  • the catheter was refracted, the stent was detached from the catheter and dried in air at room temperature for at least eight hours (i.e., over night) before the coating was studied for defects.
  • the stent coating was observed by using a scanning electron microscope (SEM).
  • FIGS. 15-19 are SEM photographs of representative stent coatings.
  • FIG. 15 provides illustrative results from the stents of Example 98, and shows polymer peeling at the high strain area of the stent structure.
  • FIG. 16 provides illustrative results from the stents of Example 99, and shows a smooth surface with no cracking or other damage at the high strain area of the stent structure.
  • FIG. 17 provides illustrative results from the stents of Example 100, and shows a smooth surface with no cracking or other damage at the high strain area of the stent structure.
  • FIG. 18 provides illustrative results from the stents of Example 101, and shows a smooth surface with no cracking or other damage at the high strain area of the stent structure.
  • FIG. 19 provides illustrative results from the stents of Example 102, and shows a smooth surface with no cracking or other damage at the high strain area of the stent structure.
  • a solution containing DLPLA and acetone was applied to stainless steel stents using a controlled deposition system. After the solution was applied, the stents were allowed to dry at room temperature. The target weight for the coating after removal of the solvent was 200 ⁇ g. The stents were then sterilized using an e-beam process set at 25 KGy.
  • a solution containing everolimus/DLPLA (1:1) was applied to stainless steel stents using a controlled deposition system. After the solution was applied, the stents were allowed to dry at room temperature. The target weight for the drug coating after removal of the solvent was 400 ⁇ g. The stents were then sterilized using an e-beam process set at 25 KGy.
  • a solution containing DLPLA and acetone was applied to VisionTM stents (available from Guidant) using a spray coating system. After the solution was applied, the stents were heat treated at 50° C. for 2 hours. The target weight for the coating after removal of the solvent was 200 ⁇ g. The stents were then sterilized using an e-beam process set at 25 KGy.
  • a solution containing everolimus/DLPLA (1:1) and acetone was applied to VisionTM stents using a spray coating system. After the solution was applied, the stents were heat treated at 50° C. for 2 hours. The target weight for the drug coating after removal of the solvent was 400 ⁇ g. The stents were then sterilized using an e-beam process set at 25 KGy.
  • Stents from Examples 104-107 were subjected to dry expanded, wet expanded or simulated use testing. It was found that the coatings of Examples 106 and 107 had fewer coating defects than Examples 104 and 105. This finding indicates that the thermal treatment of the coatings improved the mechanical properties of the coatings.
  • a DSC apparatus was used to study the thermal properties of DLPLA pellets and polymeric coatings that included DLPLA.
  • a Mettler-Toledo 822e DSC equipped with an Intracooler ( ⁇ 70° C.) and STARe software with ISOStep (modulated DSC) was used for this Example.
  • the stents were flattened longitudinally and folded into a zigzag pattern in order for the expanded stents to fit into the DSC pans.
  • the thermal properties of DLPLA pellets were studied using the above mentioned DSC for two runs. As illustrated in FIG. 20 , the pellets exhibited a T g of about 46° C.
  • a stainless steel stent was provided (“Stent A”).
  • a coating was formed on a stainless steel stent by applying a DLPLA and acetone solution to the stent using a controlled deposition system (“Stent B”). The solution was allowed to dry at room temperature for 48 to 96 hours.
  • a coating was formed on another stainless steel stent by applying an everolimus/DLPLA and acetone solution to the stent using a controlled deposition system (“Stent C”). The solution was allowed to dry at room temperature for 48 to 96 hours.
  • Stents A, B and C were studied using the above mentioned DSC for two runs. During the first run, the samples were heated slightly above the T g of the polymeric component to remove the relaxation peak. The results from the first run are illustrated in FIG. 21 . During the second run, as shown illustrated in FIG. 22 , the polymeric coatings of both Stent B and Stent C exhibited a T g for the polymer at about 46° C. The T m of the drug was shown to be about 83° C.
  • a VISIONTM stent was provided (“Stent D”).
  • a coating was formed on a VisionTM stent to include everolimus/DLPLA (“Stent E”).
  • Stents D and E were studied using the above mentioned DSC for two runs. During the first run, the samples were heated slightly above the T g of the polymeric component to remove the relaxation peak. The results from the first run are illustrated in FIG. 23 .
  • the polymeric coating of Stent E exhibited a T g for the polymer at about 36° C.
  • the T m of the drug was shown to be about 67° C.
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US09/390,069 US6379381B1 (en) 1999-09-03 1999-09-03 Porous prosthesis and a method of depositing substances into the pores
US09/470,559 US6713119B2 (en) 1999-09-03 1999-12-23 Biocompatible coating for a prosthesis and a method of forming the same
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US09/715,510 US6749626B1 (en) 2000-03-31 2000-11-17 Actinomycin D for the treatment of vascular disease
US09/750,595 US6790228B2 (en) 1999-12-23 2000-12-28 Coating for implantable devices and a method of forming the same
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US10/304,360 US20030072868A1 (en) 2000-12-28 2002-11-25 Methods of forming a coating for a prosthesis
US10/603,794 US7682647B2 (en) 1999-09-03 2003-06-25 Thermal treatment of a drug eluting implantable medical device
US10/751,043 US20040162609A1 (en) 1999-12-23 2004-01-02 Coating for implantable devices and a method of forming the same
US10/856,984 US7807211B2 (en) 1999-09-03 2004-05-27 Thermal treatment of an implantable medical device
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