US20050220841A1 - Coating compositions for bioactive agents - Google Patents

Coating compositions for bioactive agents Download PDF

Info

Publication number
US20050220841A1
US20050220841A1 US11099911 US9991105A US2005220841A1 US 20050220841 A1 US20050220841 A1 US 20050220841A1 US 11099911 US11099911 US 11099911 US 9991105 A US9991105 A US 9991105A US 2005220841 A1 US2005220841 A1 US 2005220841A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
poly
bioactive
coating
composition
polymer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11099911
Inventor
David DeWitt
Michael Finley
Laurie Lawin
Harrison Malinoff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SurModics Inc
Original Assignee
SurModics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08Materials for coatings
    • A61L29/085Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials 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
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067Means for introducing or releasing pharmaceutical products into the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222Steroids, e.g. corticosteroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41Anti-inflammatory agents, e.g. NSAIDs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43Hormones, e.g. dexamethasone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602Type of release, e.g. controlled, sustained, slow
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings

Abstract

A coating composition and related method for use in applying a bioactive agent to a surface in a manner that will permit the bioactive agent to be released from the coating in vivo. The composition is particularly well suited for coating the surface of implantable medical device, such as a stent or catheter, in order to permit the device to release bioactive agent to the surrounding tissue over time. The composition includes a plurality of compatible polymers having different properties that can permit them to be combined together to provide an optimal combination of such properties as durability, biocompatibility, and release kinetics.

Description

    RELATED APPLICATIONS
  • [0001]
    This application claims the benefit of U.S. Provisional Application Ser. No. 60/559,821, titled Coating Compositions for Bioactive Agents, filed Apr. 6, 2004, the contents of which are hereby incorporated by reference. This application is related to PCT Application Serial No. ______, filed Apr. 6, 2005, titled Coating Compositions for Bioactive Agents and identified by Attorney Docket No. 9896.166.7, as well as PCT Application Serial No. ______, filed Apr. 6, 2005, titled Coating Compositions for Bioactive Agents and identified by Attorney Docket No. 9896.166.8, the contents of both of which are hereby incorporated by reference.
  • TECHNICAL FIELD
  • [0002]
    In one aspect, the present invention relates to a method of treating implantable medical devices with coating compositions to provide for the controlled release of bioactive (e.g., pharmaceutical) agents from the surface of the devices under physiological conditions. In another aspect, the invention relates to the coating compositions, per se. In yet another aspect, the invention relates to devices or surfaces coated with such compositions. In yet another aspect, the present invention relates to the local administration of bioactive agents for the prevention and treatment of diseases, such as vascular and ocular diseases.
  • BACKGROUND OF THE INVENTION
  • [0003]
    Many surgical interventions require the placement of a medical device into the body. One prevalent surgical intervention often requiring such a device is percutaneous transluminal coronary angioplasty (“PTCA”). Many individuals suffer from circulatory disease caused by a progressive blockage of the blood vessels, which often leads to hypertension, ischemic injury, stroke, or myocardial infarction. Percutaneous transluminal coronary angioplasty is a medical procedure performed to increase blood flow through a damaged artery and is now the predominant treatment for coronary vessel stenosis. The increasing use of this procedure is attributable to its relatively high success rate and its minimal invasiveness compared with coronary bypass surgery. A limitation associated with PTCA is the abrupt closure of the vessel which can occur soon after angioplasty. Insertion of small spring-like medical devices called stents into such damaged vessels has proved to be a better approach to keep the vessels open as compared to systemic pharmacologic therapy.
  • [0004]
    While often necessary and beneficial for treating a variety of medical conditions, metal or polymeric devices (e.g., stents, catheters . . . ), after placement in the body, can give rise to numerous physiological complications. Some of these complications include: increased risk of infection; initiation of a foreign body response resulting in inflammation and fibrous encapsulation; and initiation of a detrimental wound healing response resulting in hyperplasia and restenosis. These problems have been particularly acute with the placement of stents in damaged arteries after angioplasty.
  • [0005]
    One promising approach is to provide the device with the ability to deliver bioactive agents in the vicinity of the implant. By doing so, some of the harmful effects associated with the implantation of medical devices can be diminished. Thus, for example, antibiotics can be released from the surface of the device to minimize the possibility of infection, and antiproliferative drugs can be released to inhibit hyperplasia. Another benefit to the local release of bioactive agents is the avoidance of toxic concentrations of drugs encountered when given systemically at sufficiently high doses to achieve therapeutic concentrations at the site where they are needed.
  • [0006]
    Although the potential benefit from using such bioactive agent-releasing medical devices is great, development of such medical devices has been slow. Progress has been hampered by many challenges, including: 1) the requirement, in some instances, for long term (i.e., at least several weeks) release of bioactive agents; 2) the need for a biocompatible, non-inflammatory device surface; 3) the demand for significant durability (and particularly, resistance to delamination and cracking), particularly with devices that undergo flexion and/or expansion when being implanted or used in the body; 4) concerns regarding the ability of the device to be manufactured in an economically viable and reproducible manner; and 5) the requirement that the finished device can be sterilized using conventional methods.
  • [0007]
    Implantable medical devices capable of delivering medicinal agents from hydrophobic polymer coatings have been described. See, for instance, U.S. Pat. No. 6,214,901; U.S. Pat. No. 6,344,035; U.S. Publication No. 2002-0032434; U.S. Publication No. 2002-0188037; U.S. Publication No. 2003-0031780; U.S. Publication No. 2003-0232087; U.S. Publication No. 2003-0232122; PCT Publication No. WO 99/55396; PCT Publication No. WO 03/105920; PCT Publication No. WO 03/105918; PCT Publication No. WO 03/105919 which collectively disclose, inter alia, coating compositions having a bioactive agent in combination with a polymer component such as polyalkyl(meth)acrylate or aromatic poly(meth)acrylate polymer and another polymer component such as poly(ethylene-co-vinyl acetate) for use in coating device surfaces to control and/or improve their ability to release bioactive agents in aqueous systems.
  • SUMMARY OF THE INVENTION
  • [0008]
    The present invention provides a coating composition, and related methods for preparing and using the coating composition to coat a surface with a bioactive agent, for instance to coat the surface of an implantable medical device in a manner that permits the surface to release the bioactive agent over time when implanted in vivo.
  • [0009]
    The coating composition of this invention comprises one or more bioactive agents in combination with a plurality of polymers, including: (a) a first polymer component comprising one or more polybutenes; and (b) a second polymer component comprising one or more polymers selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates), where “(meth)” will be understood by those skilled in the art to include such molecules in either the acrylic and/or methacrylic form (corresponding to the acrylates and/or methacrylates, respectively).
  • [0010]
    Applicants have discovered a group of first polymers that when used in combination with one or more second polymers can each meet or exceed the variety of criteria required of a preferred composition of this invention, including in terms of its formulation, delivery, and/or coated characteristics.
  • [0011]
    With regard to its formulation, a coating composition of this invention is, in some embodiments, provided in the form of a true solution by the use of one or more solvents. Such solvents, in turn, are not only capable of dissolving the polymers and bioactive agent in solution, as compared to dispersion or emulsion, but they are also sufficiently volatile to permit the composition to be effectively applied to a surface (e.g., as by spraying) and quickly removed (e.g., as by drying) to provide a stable and desirable coated composition. In turn, the coated composition is itself homogeneous, with the first and second polymers effectively serving as cosolvents for each other, and bioactive agent substantially equally sequestered within them both.
  • [0012]
    In some embodiments, the ability to form a true solution using the claimed polymer combinations is preferred when considering the inclusion of potentially significant amounts of bioactive agent with the polymer blend. In various embodiments of the present invention, the coating composition is not only in the form of a true solution, but one in which bioactive agent is present at saturated or supersaturated levels. Without intending to be bound by theory, it appears that it is by virtue of the ability to achieve such solutions, that release of the bioactive agent from the coated composition is best accomplished and facilitated. In turn, it appears that the release of bioactive agent from such a system is due, at least in part, to its inherent instability within the coated composition itself, coupled with its physical/chemical preference for surrounding tissues and fluids. In turn, those skilled in the art will appreciate the manner in which the various ingredients and amounts in a composition of this invention can be adjusted to provide desired release kinetics and for any particular bioactive agent, solvent and polymer combination.
  • [0013]
    In some embodiments, with regard to its delivery, a composition of this invention meets or exceeds further criteria in its ability to be sterilized, stored, and delivered to a surface in a manner that preserves its desired characteristics, yet using conventional delivery means, such as spraying. In various embodiments, such delivery involves spraying the composition onto a device surface in a manner that avoids or minimizes phase separation of the polymer components.
  • [0014]
    Finally, and with regard to its coated characteristics, a composition of this invention permits polymer ratios to be varied in a manner that provides not only an optimal combination of such attributes as biocompatibility, durability, and bioactive agent release kinetics, but also that may provide a coated composition that is homogeneous, and hence substantially optically clear upon microscopic examination. Even more surprisingly, various compositions of this invention will provide these and other features, with or without optional pretreatment of a metallic surface. The ability to achieve or exceed any of these criteria, let alone most if not all of them, was not expected.
  • [0015]
    In turn, compositions of the present invention provide properties that are comparable or better than those obtained with previous polymer blend compositions. This, in turn, provides a variety of new and further opportunities, including with respect to both the type and concentration of bioactive agents that can be coated, as well as the variety of medical devices, and surfaces, themselves. In turn, the present invention also provides a combination that includes a medical device coated with a composition of this invention, as well as a method of preparing and using such a combination.
  • BRIEF DESCRIPTION OF THE FIGURES
  • [0016]
    FIG. 1 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in Example 1.
  • DETAILED DESCRIPTION
  • [0017]
    Without intending to be bound by theory, it appears that suitable first polymers for use in a composition of this invention provide an optimal combination of such properties as glass transition temperature (Tg) and diffusion constant for the particular bioactive agent of choice. Along with melting temperature (Tm), Tg is an important parameter of a given polymer (including copolymer), and particularly amorphous polymers, that can be used to characterize its properties over a wide temperature range. A polymer is typically brittle at temperatures below its Tg, and flexible at temperatures above. Both Tm and Tg can be affected by such things as polymer structure and backbone flexibility, molecular weight, attractive forces, and pressure. For random copolymers and compatible polymer blends, only a single Tg is observed, usually lying intermediate between the Tg of the corresponding pure homopolymers. Different Tg's are exhibited for incompatible polymer blends, and between the microdomains of block copolymers with mutually incompatible blocks. Tg can be measured by any suitable technique, e.g., dilatometry, refractive index, differential scanning calorimetry, dynamic mechanical measurement, and dielectric measurement.
  • [0018]
    Various second polymers (e.g., poly(n-butyl methacrylate)) of the present composition generally provide a Tg in the range of room to body temperature (e.g., from about 20° C. to about 40° C.), and hence tend to be somewhat stiffer polymers, in turn, providing a slower diffusion constant for a number of the bioactive agents. Applicants have discovered the manner in which certain new polymers can be used as a first polymer component, to essentially balance, or temper the desired properties of the second polymer. Such first polymers will generally provide a lower glass transition temperature (e.g., below room temperature, and in some embodiments, in the range of about 0° C. or less), together with a relatively high diffusion constant for the bioactive agent. By appropriately combining the two polymers with bioactive agent, those skilled in the art, given the present description, will be able to vary both the selection and ratios of first and second polymers, in order to determine an optimal combination of physical and mechanical properties, including bioactive agent diffusion and release kinetics, as well as durability and tenacity of the coating itself upon a particular surface, that best fits their particular needs.
  • [0019]
    Hence the first polymer of this invention will generally provide an optimal combination of glass transition temperature (e.g., at or lower than that of the second polymer), compatibility with the bioactive agent of choice, acceptable solubility in the solvents of choice, as well as commercial availability and cost.
  • [0020]
    The term “coating composition”, as used herein, will refer to one or more vehicles (e.g., solutions, mixtures, emulsions, dispersions, blends, etc.) used to effectively coat a surface with bioactive agent, first polymer component and/or second polymer component, either individually or in any suitable combination.
  • [0021]
    The term “coated composition” will refer to the effective combination, upon the surface of a device, of bioactive agent, first polymer component and second polymer component, whether formed as the result of one or more coating vehicles or in one or more layers and/or steps.
  • [0022]
    Unless defined otherwise, the term “coating” will refer to the effective combination of bioactive agent, first polymer component and second polymer component, independent of the device surface, and whether formed as the result of one or more coating vehicles or in one or more layers.
  • [0023]
    Unless otherwise indicated, the term “molecular weight” and all polymeric molecular weights described herein are “weight average” molecular weights (“Mw”). As used herein “weight average molecular weight” or Mw, is an absolute method of measuring molecular weight and is particularly useful for measuring the molecular weight of a polymer preparation. The weight average molecular weight (Mw) can be defined by the following formula: M w = i N i M i 2 i N i M i
    wherein N represents the number of moles of a polymer in the sample with a mass of M, and Σi is the sum of all NiMi (species) in a preparation. The Mw can be measured using common techniques, such as light scattering or ultracentrifugation. Discussion of Mw and other terms used to define the molecular weight of polymer preparations can be found in, for example, Allcock, H. R. and Lampe, F. W., Contemporary Polymer Chemistry; pg 271 (1990).
  • [0024]
    As described and exemplified herein, a resultant composition can be coated using a plurality of individual steps or layers, including for instance, an initial layer having only bioactive agent (or bioactive agent with one or both of the polymer components), over which are coated one or more additional layers containing suitable combinations of bioactive agent, first polymer component and/or second polymer component, the combined result of which is to provide a coated composition of the invention. In turn, and in various embodiments, the invention further provides a method of reproducibly controlling the release (e.g., elution) of a bioactive agent from the surface of a medical device implanted in vivo. Those skilled in the art will appreciate the manner in which the combined effect of these various layers can be used and optimized to achieve various effects in vivo. In addition, the surface to which the composition is applied can itself be pretreated in a manner sufficient to improve attachment of the composition to the underlying (e.g., metallic) surface. Examples of such pretreatments include the use of compositions such as Parylene™ coatings, as described herein. Additional examples of such pretreatments include silane coupling agents, photografted polymers, epoxy primers, polycarboxylate resins, and physical roughening of the surface. It is further noted that the pretreatment compositions may be used in combination with each other or may be applied in separate layers to form a pretreatment coating on the surface of the medical device.
  • [0025]
    While not intending to be bound by theory, the release kinetics of the bioactive agent in vivo are thought to generally include both a short term (“burst”) release component, within the order of minutes to hours after implantation, and a longer term release component, which can range from on the order of hours to days or even months or years of useful release.
  • [0026]
    Additionally, the ability to coat a device in the manner of the present invention provides greater latitude in the composition of various coating layers, e.g., permitting more or less of the second polymer component (i.e., poly(alkyl(meth)acrylate) and/or poly(aromatic(meth)acrylate)) to be used in coating compositions used to form different layers (e.g., as a topcoat layer). This, in turn, provides the opportunity to further control release and elution of the bioactive agent from the overall coating.
  • [0027]
    The coating composition and method can be used to control the amount and rate of bioactive agent (e.g., drug) release from one or more surfaces of implantable medical devices. In various embodiments, the method employs a mixture of hydrophobic polymers in combination with one or more bioactive agents, such as a pharmaceutical agent, such that the amount and rate of release of agent(s) from the medical device can be controlled, e.g., by adjusting the relative types and/or concentrations of hydrophobic polymers in the mixture. For a given combination of polymers, for instance, this approach permits the release rate to be adjusted and controlled by simply adjusting the relative concentrations of the polymers in the coating mixture. This provides an additional means to control rate of bioactive agent release besides the conventional approach of varying the concentration of bioactive agent in a coated composition.
  • [0028]
    Some embodiments of the invention include a method of coating a device comprising the step of applying the composition to the device surface under conditions of controlled relative humidity (at a given temperature), for instance, under conditions of increased or decreased relative humidity as compared to ambient humidity. Humidity can be “controlled” in any suitable manner, including at the time of preparing and/or using (as by applying) the composition, for instance, by coating the surface in a confined chamber or area adapted to provide a relative humidity different than ambient conditions, and/or by adjusting the water content of the coating or coated composition itself. Without intending to be bound by theory, it appears that the elution rate of a bioactive agent from a coating composition generally increases as relative humidity increases.
  • [0029]
    In some embodiments, the coating composition includes a mixture of two or more polymers having complementary physical characteristics, and a bioactive agent or agents applicable to the surface of an implantable medical device. The device can be of any suitable type or configuration, and in many embodiments is one that undergoes flexion and/or expansion upon implantation or use, as in the manner of a stent or catheter. The applied coating composition is cured (e.g., by solvent evaporation) to provide a tenacious and flexible bioactive-releasing composition on the surface of the medical device. Such coating compositions are particularly well suited for devices that are themselves sufficiently small, or have portions that are sufficiently small (as in the struts of an expandable stent or the twists of an ocular coil), to permit the coated composition to form a contiguous, e.g., circumferential, coating, thereby further improving the ability of the coating to remain intact (e.g., avoid delamination).
  • [0030]
    The complementary polymers are selected such that a broad range of relative polymer concentrations can be used without detrimentally affecting the desirable physical characteristics of the polymers. By use of the polymer combinations (including mixtures and blends) of the invention the bioactive release rate from a coated medical device can be manipulated by adjusting the relative concentrations of the polymers.
  • [0031]
    In various embodiments, the present invention relates to a coating composition and related method for coating an implantable medical device which undergoes flexion and/or expansion upon implantation. However it is noted that the coating composition may also be utilized with medical devices that have minimal or do not undergo flexion and/or expansion. The structure and composition of the underlying device can be of any suitable, and medically acceptable, design and can be made of any suitable material that is compatible with the coating itself. The natural or pretreated surface of the medical device is provided with a coating containing one or more bioactive agents.
  • [0032]
    A first polymer component of this invention provides an optimal combination of similar properties, and particularly when used in admixture with the second polymer component. Various first polymers include polybutenes. Examples of suitable polymers are commercially available from sources such as Sigma-Aldrich.
  • [0033]
    First polymers may include polybutenes. “Polybutenes” suitable for use in the present invention may include polymers derived by homopolymerizing or randomly interpolymerizing isobutylene, 1-butene and/or 2-butene. The polybutene can be a homopolymer of any of the isomers or it can be a copolymer or a terpolymer of any of the monomers in any ratio. In various embodiments, the polybutene contains at least about 90% (wt) of isobutylene or 1-butene, and in some embodiments, the polybutene contains at least about 90% (wt) of isobutylene. The polybutene may contain non-interfering amounts of other ingredients or additives, for instance it can contain up to 1000 ppm of an antioxidant (e.g., 2,6-di-tert-butyl-methylphenol).
  • [0034]
    In various embodiments, the polybutene has a molecular weight between about 100 kilodaltons and about 1,000 kilodaltons, in some embodiments, between about 150 kilodaltons and about 600 kilodaltons, and in some embodiments, between about 150 kilodaltons and about 250 kilodaltons. In other embodiments, the polybutene has a molecular weight between about 150 kilodaltons and about 1,000 kilodaltons, optionally, between about 200 kilodaltons and about 600 kilodaltons, and further optionally, between about 350 kilodaltons and about 500 kilodaltons. Polybutenes having a molecular weight greater than about 600 kilodaltons, including greater than 1,000 kilodaltons are available but are expected to be more difficult to work with. Other examples of suitable copolymers of this type are commercially available from sources such as Sigma-Aldrich.
  • [0035]
    Other examples of suitable copolymers of this type are commercially available from sources such as Sigma-Aldrich and include the following products. For example, suitable copolymers of this type and their related descriptions may be found in the 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory Equipment, the entire contents of which are incorporated by reference herein.
  • [0036]
    A second polymer component of this invention provides an optimal combination of various structural/functional properties, including hydrophobicity, durability, bioactive agent release characteristics, biocompatibility, molecular weight, and availability. In one such an embodiment, the composition comprises at least one second polymer component selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).
  • [0037]
    In some embodiments, the second polymer component is a poly(alkyl)methacrylate, that is, an ester of a methacrylic acid. Examples of suitable poly(alkyl(meth)acrylates) include those with alkyl chain lengths from 2 to 8 carbons, inclusive, and with molecular weights from 50 kilodaltons to 900 kilodaltons. In various embodiments, the polymer mixture includes a poly(alkyl(meth)acrylate) with a molecular weight of from about 100 kilodaltons to about 1000 kilodaltons, in some embodiments from about 150 kilodaltons to about 500 kilodaltons, and in some embodiments from about 200 kilodaltons to about 400 kilodaltons. An example of one embodiment of a second polymer is poly(n-butyl methacrylate). Examples of other polymers are poly(n-butyl methacrylate-co-methyl methacrylate, with a monomer ratio of 3:1, poly(n-butyl methacrylate-co-isobutyl methacrylate, with a monomer ratio of 1:1 and poly(t-butyl methacrylate). Such polymers are available commercially (e.g., from Sigma-Aldrich, Milwaukee, Wis.) with molecular weights ranging from about 150 kilodaltons to about 350 kilodaltons, and with varying inherent viscosities, solubilities and forms (e.g., as slabs, granules, beads, crystals or powder).
  • [0038]
    Examples of suitable poly(aromatic(meth)acrylates) include poly(aryl(meth)acrylates), poly(aralkyl(meth)acrylates), poly(alkaryl(meth)acrylates), poly(aryloxyalkyl(meth)acrylates), and poly(alkoxyaryl(meth)acrylates). Such terms are used to describe polymeric structures wherein at least one carbon chain and at least one aromatic ring are combined with (meth)acrylic groups, typically esters, to provide a composition of this invention. For instance, and more specifically, a poly(aralkyl(meth)acrylate) can be made from aromatic esters derived from alcohols also containing aromatic moieties, such as benzyl alcohol. Similarly, a poly(alkaryl(meth)acrylate) can be made from aromatic esters derived from aromatic alcohols such as p-anisole. Suitable poly(aromatic(meth)acrylates) include aryl groups having from 6 to 16 carbon atoms and with molecular weights from about 50 to about 900 kilodaltons. Examples of suitable poly(aryl(meth)acrylates) include poly(9-anthracenyl methacrylate), poly(chlorophenyl acrylate), poly(methacryloxy-2-hydroxybenzophenone), poly(methacryloxybenzotriazole), poly(naphthyl acrylate), poly(naphthylmethacrylate), poly-4-nitrophenylacrylate, poly(pentachloro(bromo, fluoro)acrylate) and methacrylate, poly(phenyl acrylate) and poly(phenyl methacrylate). Examples of suitable poly(aralkyl(meth)acrylates) include poly(benzyl acrylate), poly(benzyl methacrylate), poly(2-phenethyl acrylate), poly(2-phenethyl methacrylate) and poly(1-pyrenylmethyl methacrylate). Examples of suitable poly(alkaryl(meth)acrylates include poly(4-sec-butylphenyl methacrylate), poly(3-ethylphenyl acrylate), and poly(2-methyl-1-naphthyl methacrylate). Examples of suitable poly(aryloxyalkyl (meth)acrylates) include poly(phenoxyethyl acrylate), poly(phenoxyethyl methacrylate), and poly(polyethylene glycol phenyl ether acrylate) and poly(polyethylene glycol phenyl ether methacrylate) with varying polyethylene glycol molecular weights. Examples of suitable poly(alkoxyaryl(meth)acrylates) include poly(4-methoxyphenyl methacrylate), poly(2-ethoxyphenyl acrylate) and poly(2-methoxynaphthyl acrylate).
  • [0039]
    Acrylate or methacrylate monomers or polymers and/or their parent alcohols are commercially available from Sigma-Aldrich (Milwaukee, Wis.) or from Polysciences, Inc, (Warrington, Pa.).
  • [0040]
    Optionally, the coating composition may include one or more additional polymers in combination with the first and second polymer components, the additional polymers being, for example, selected from the group consisting of (i) poly(alkylene-co-alkyl(meth)acrylates), (ii) ethylene copolymers with other alkylenes, (iii) diolefin derived non-aromatic polymers and copolymers, (iv) aromatic group-containing copolymers, (v) epichlorohydrin-containing polymers and (vi) poly(ethylene-co-vinyl acetate). In some embodiments, the additional polymers may act as substitutes for a portion of the first polymer. For example, the additional polymers may substitute up to about 25% of the first polymer. In other embodiments, the additional polymers may substitute up to about 50% of the first polymer.
  • [0041]
    Suitable poly(alkylene-co-alkyl(meth)acrylates) include those copolymers in which the alkyl groups are either linear or branched, and substituted or unsubstituted with non-interfering groups or atoms. In some embodiments, such alkyl groups comprise from 1 to 8 carbon atoms, inclusive, and in some embodiments, from 1 to 4 carbon atoms, inclusive. In various embodiments, the alkyl group is methyl.
  • [0042]
    In turn, copolymers that include such alkyl groups may comprise from about 15% to about 80% (wt) of alkyl acrylate. In various embodiments, when the alkyl group is methyl, the polymer contains from about 20% to about 40% methyl acrylate, and in some embodiments, from about 25 to about 30% methyl acrylate. When the alkyl group is ethyl, the polymer, in some embodiments, contains from about 15% to about 40% ethyl acrylate, and when the alkyl group is butyl, the polymer, in some embodiments, contains from about 20% to about 40% butyl acrylate.
  • [0043]
    The alkylene groups are selected from ethylene and/or propylene, and in some embodiments, the alkylene group is ethylene. In various embodiments, the (meth)acrylate comprises an acrylate (i.e., no methyl substitution on the acrylate group). Various copolymers provide a molecular weight (Mw) of about 50 kilodaltons to about 500 kilodaltons, and in some embodiments, Mw is 50 kilodaltons to about 200 kilodaltons.
  • [0044]
    The glass transition temperature for these copolymers varies with ethylene content, alkyl length on the (meth)acrylate and whether the first copolymer is an acrylate or methacrylate. At higher ethylene content, the glass transition temperature tends to be lower, and closer to that of pure polyethylene (−120° C.). A longer alkyl chain also lowers the glass transition temperature. A methyl acrylate homopolymer has a glass transition temperature of about 10° C. while a butyl acrylate homopolymer has one of −54° C.
  • [0045]
    Copolymers such as poly(ethylene-co-methyl acrylate), poly(ethylene-co-butyl acrylate) and poly(ethylene-co-2-ethylhexyl acrylate) copolymers are available commercially from sources such as Atofina Chemicals, Inc., Philadelphia, Pa., and can be prepared using methods available to those skilled in the respective art.
  • [0046]
    Other examples of suitable additional polymers of this type are commercially available from sources such as Sigma-Aldrich and include, but are not limited to, poly(ethylene-co-methyl acrylate), poly(ethylene-co-ethyl acrylate), and poly(ethylene-co-butyl acrylate).
  • [0047]
    Suitable additional polymers also include ethylene copolymers with other alkylenes, which in turn, can include straight chain and branched alkylenes, as well as substituted or unsubstituted alkylenes. Examples include copolymers prepared from alkylenes that comprise from 3 to 8 branched or linear carbon atoms, inclusive, in some embodiments, alkylene groups that comprise from 3 to 4 branched or linear carbon atoms, inclusive, and in some embodiments, the alkylene group contains 3 carbon atoms (e.g., propylene). In various embodiments, the other alkylene is a straight chain alkylene (e.g., 1-alkylene).
  • [0048]
    Various copolymers of this type can comprise from about 20% to about 90% (based on moles) of ethylene, and in some embodiments, from about 35% to about 80% (mole) of ethylene. Such copolymers will have a molecular weight of between about 30 kilodaltons to about 500 kilodaltons. Examples of copolymers are selected from the group consisting of poly(ethylene-co-propylene), poly(ethylene-co-1-butene), polyethylene-co-1-butene-co-1-hexene) and/or poly(ethylene-co-1-octene).
  • [0049]
    Examples of copolymers include poly(ethylene-co-propylene) random copolymers in which the copolymer contains from about 35% to about 65% (mole) of ethylene; and in some embodiments, from about 55% to about 65% (mole) ethylene, and the molecular weight of the copolymer is from about 50 kilodaltons to about 250 kilodaltons, in some embodiments, from about 100 kilodaltons to about 200 kilodaltons.
  • [0050]
    Copolymers of this type can optionally be provided in the form of random terpolymers prepared by the polymerization of both ethylene and propylene with optionally one or more additional diene monomers, such as those selected from the group consisting of ethylidene norborane, dicyclopentadiene and/or hexadiene. Various terpolymers of this type can include up to about 5% (mole) of the third diene monomer.
  • [0051]
    Other examples of suitable additional polymers of this type are commercially available from sources such as Sigma-Aldrich and include, but are not limited to, poly(ethylene-co-propylene), poly(ethylene-co-1-butene), poly(ethylene-co-1-butene-co-1-hexene), poly(ethylene-co-1-octene) and poly(ethylene-co-propylene-co-5-methylene-2-norborene).
  • [0052]
    Alternative additional polymers include diolefin-derived, non-aromatic polymers and copolymers, including those in which the diolefin monomer used to prepare the polymer or copolymer is selected from butadiene (CH2═CH—CH═CH2) and/or isoprene (CH2═CH—C(CH3)═CH2). A butadiene polymer can include one or more butadiene monomer units which can be selected from the monomeric unit structures (a), (b), or (c):
    Figure US20050220841A1-20051006-C00001

    An isoprene polymer can include one or more isoprene monomer units which can be selected from the monomeric unit structures (d), (e), (f) or (g):
    Figure US20050220841A1-20051006-C00002
  • [0053]
    In some embodiments, the additional polymer is a homopolymer derived from diolefin monomers or is a copolymer of diolefin monomer with non-aromatic mono-olefin monomer, and optionally, the homopolymer or copolymer can be partially hydrogenated. Such polymers can be selected from the group consisting of polybutadienes containing polymerized cis-, trans- and/or 1,2-monomer units, and in some embodiments, a mixture of all three co-polymerized monomer units, and polyisoprenes containing polymerized cis-1,4- and/or trans-1,4-monomer units, polymerized 1,2-vinyl monomer units, polymerized 3,4-vinyl monomer units and/or others as described in the Encyclopedia of Chemical Technology, Vol. 8, page 915 (1993), the entire contents of which is hereby incorporated by reference.
  • [0054]
    Alternatively, the additional polymer is a copolymer, including graft copolymers, and random copolymers based on a non-aromatic mono-olefin co-monomer such as acrylonitrile, an alkyl(meth)acrylate and/or isobutylene. In various embodiments, when the mono-olefin monomer is acrylonitrile, the interpolymerized acrylonitrile is present at up to about 50% by weight; and when the mono-olefin monomer is isobutylene, the diolefin monomer is isoprene (e.g., to form what is commercially known as a “butyl rubber”). In some embodiments, the polymers and copolymers have a Mw between about 50 kilodaltons and about 1,000 kilodaltons. In other embodiments, the polymers and copolymers have a Mw between about 100 kilodaltons and about 450 kilodaltons. In yet other embodiments the polymers and copolymers have a Mw between about 150 kilodaltons and about 1,000 kilodaltons, and optionally between about 200 kilodaltons and about 600 kilodaltons.
  • [0055]
    Other examples of suitable additional polymers of this type are commercially available from sources such as Sigma-Aldrich, such as the 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory Equipment. For example, suitable additional polymers include, but are not limited to, polybutadiene, poly(butadiene-co-acrylonitrile), polybutadiene-block-polyisoprene, polybutadiene-graft-poly(methyl acrylate-co-acrylonitrile), polyisoprene, and partially hydrogenated polyisoprene.
  • [0056]
    Suitable additional polymers may also include aromatic group-containing copolymers, including random copolymers, block copolymers and graft copolymers. In various embodiments, the aromatic group is incorporated into the copolymer via the polymerization of styrene, and in some embodiments, the random copolymer is a copolymer derived from copolymerization of styrene monomer and one or more monomers selected from butadiene, isoprene, acrylonitrile, a C1-C4 alkyl(meth)acrylate (e.g., methyl methacrylate) and/or butene (e.g., isobutylene). Useful block copolymers include copolymer containing (a) blocks of polystyrene, (b) blocks of a polyolefin selected from polybutadiene, polyisoprene and/or polybutene (e.g., isobutylene), and (c) optionally a third monomer (e.g., ethylene) copolymerized in the polyolefin block.
  • [0057]
    The aromatic group-containing copolymers may contain about 10% to about 50% (wt) of polymerized aromatic monomer and the molecular weight of the copolymer may be from about 50 kilodaltons to about 500 kilodaltons. In some embodiments, the molecular weight of the copolymer may be from about 300 kilodaltons to about 500 kilodaltons. In other embodiments, the molecular weight of the copolymer may be from about 100 kilodaltons to about 300 kilodaltons.
  • [0058]
    Other examples of suitable copolymers of this type are commercially available from sources such as Sigma-Aldrich and include, but are not limited to, poly(styrene-co-butadiene) (random), polystyrene-block-polybutadiene, polystyrene-block-polybutadiene-block-polystyrene, polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene, polystyrene-block-polyisoprene-block-polystyrene, polystyrene-block-polyisobutylene-block-polystyrene, poly(styrene-co-acrylonitrile), poly(styrene-co-butadiene-co-acrylonitrile) and poly(styrene-co-butadiene-co-methyl methacrylate).
  • [0059]
    Suitable additional polymers include epichlorohydrin homopolymers and poly(epichlorohydrin-co-alkylene oxide) copolymers. In some embodiments, in the case of the copolymer, the copolymerized alkylene oxide is ethylene oxide. In various embodiments, epichlorohydrin content of the epichlorohydrin-containing polymer is from about 30% to 100% (wt), and in some embodiments, from about 50% to 100% (wt). In some embodiments, the epichlorohydrin-containing polymers have an Mw from about 100 kilodaltons to about 300 kilodaltons.
  • [0060]
    Other examples of suitable copolymers of this type are commercially available from sources such as Sigma-Aldrich and include, but are not limited to, polyepichlorohydrin and poly(epichlorohydrin-co-ethylene oxide).
  • [0061]
    One additional polymer that may be utilized in the coating composition of the present invention includes poly(ethylene-co-vinyl acetate) (pEVA). Examples of suitable polymers of this type are available commercially and include poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations of from about 8% and about 90%, in some embodiments, from about 20 to about 40 weight percent and in some embodiments, from about 30 to about 34 weight percent. Such polymers are generally found in the form of beads, pellets, granules, etc. It has generally been found that pEVA co-polymers with lower percent vinyl acetate become increasingly insoluble in typical solvents.
  • [0062]
    In many embodiments, the coating compositions for use in this invention includes mixtures of first and second polymer components as described herein. Optionally, both first and second polymer components are purified for such use to a desired extent and/or provided in a form suitable for in vivo use. Moreover, biocompatible additives may be added, such as dyes and pigments (e.g., titanium dioxide, Solvent Red 24, iron oxide, and Ultramarine Blue); slip agents (e.g., amides such as oleyl palmitamide, N,N′-ethylene bisoleamide, erucamide, stearamide, and oleamide); antioxidants (e.g. butylated hydroxytoluene (BHT), vitamin E (tocopherol), BNX™, dilauryl thiodipropionate (DLTDP), Irganox™ series, phenolic and hindered phenolic antioxidants, organophosphites (e.g., trisnonylphenyl phosphite, Irgafos™ 168), lactones (e.g., substituted benzofuranone), hydroxylamine, and MEHQ (monomethyl ether of hydroquinone)); surfactants (e.g., anionic fatty acid surfactants (e.g., sodium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium stearate, and sodium palmitate), cationic fatty acid surfactants (e.g., quaternary ammonium salts and amine salts), and nonionic ethoxylated surfactants (e.g., ethoxylated p-octylphenol)); and leachable materials (i.e., permeation enhancers) (e.g., hydrophilic polymers (e.g., poly(ethylene glycol), polyvinylpyrrolidone, and poly(vinyl alcohol)) and hydrophilic small molecules (e.g., sodium chloride, glucose)). In addition, any impurities may be removed by conventional methods available to those skilled in the art.
  • [0063]
    In various embodiments of the present invention, the polymer mixture includes a first polymer component comprising one or more polymers selected from the group consisting of polybutenes, and a second polymer component selected from the group consisting of poly (alkyl(meth)acrylates) and poly(aromatic(meth)acrylates) and having a molecular weight of from about 150 kilodaltons to about 500 kilodaltons, and in some embodiments, from about 200 kilodaltons to about 400 kilodaltons.
  • [0064]
    These mixtures of polymers have proven useful with absolute polymer concentrations (i.e., the total combined concentrations of both polymers in the coating composition), of between about 0.1 and about 50 percent (by weight), and in some embodiments, between about 0.1 and about 35 percent (by weight). Various polymer mixtures contain at least about 10 percent by weight of either the first polymer or the second polymer.
  • [0065]
    In some embodiments, the polymer composition may comprise about 5% to about 95% of the first and/or second polymers based on the total weights of the first and second polymers. In various embodiments, the composition may comprise about 15% to about 85% of the first and/or second polymers. In some embodiments, the composition may include about 25% to about 75% of the first and/or second polymers.
  • [0066]
    In some embodiments, the bioactive agent may comprise about 1% to about 75% of the first polymer, second polymer, and bioactive agent mixture (i.e., excluding solvents and other additives). In various embodiments, the bioactive agent may comprise about 5% to about 60% of such a mixture. In some embodiments, the bioactive agent may comprise about 25% to about 45% of such a mixture. The concentration of the bioactive agent or agents dissolved or suspended in the coating mixture can range from about 0.01 to about 90 percent, by weight, based on the weight of the final coating composition, and in some embodiments, from about 0.1 to about 50 percent by weight.
  • [0067]
    The term “bioactive agent”, as used herein, will refer to a wide range of biologically active materials or drugs that can be incorporated into a coating composition of the present invention. In some embodiments, the bioactive agent(s) to be incorporated do not chemically interact with the coating composition during fabrication or during the bioactive agent release process.
  • [0068]
    Bioactive agent will, in turn, refer to a peptide, protein, carbohydrate, nucleic acid, lipid, polysaccharide or combinations thereof, or synthetic or natural inorganic or organic molecule, that causes a biological effect when administered in vivo to an animal, including but not limited to birds and mammals, including humans. Nonlimiting examples are antigens, enzymes, hormones, receptors, peptides, and gene therapy agents. Examples of suitable gene therapy agents include a) therapeutic nucleic acids, including antisense DNA and antisense RNA, and b) nucleic acids encoding therapeutic gene products, including plasmid DNA and viral fragments, along with associated promoters and excipients. Examples of other molecules that can be incorporated include nucleosides, nucleotides, antisense, vitamins, minerals, and steroids.
  • [0069]
    Controlled release of bioactive agent is vitally important in many medical areas, including cardiology, oncology, central nervous system disorders, neurology, immunology, diabetes control, musculoskeletal and joint diseases, ophthalmology, vaccination, respiratory, endocrinology, dermatology, and diagnostics/imaging.
  • [0070]
    Furthermore, it is recognized that thrombus formation on or around medical devices such as stents may create variations in biological agent uptake in target tissue sites and can act to either increase or decrease wall deposition according to the clot and device geometry. The embodiments of this invention further enable reliable and predictable delivery and update of bioactive agents through enhancement of the conformable, durable and stable coatings which result, regardless of flexion or other motion of the medical device substrate.
  • [0071]
    Coating compositions prepared according to this process can be used to deliver drugs such as nonsteroidal anti-inflammatory compounds, anesthetics, chemotherapeutic agents, immunotoxins, immunosuppressive agents, steroids, antibiotics, antivirals, antifungals, steroidal antiinflammatories, anticoagulants, antiproliferative agents, angiogenic agents, and anti-angiogenic agents. In various embodiments, the bioactive agent to be delivered is a hydrophobic drug having a relatively low molecular weight (i.e., a molecular weight no greater than about two kilodaltons, and in some embodiments, no greater than about 1.5 kilodaltons). For example, hydrophobic drugs such as rapamycin, paclitaxel, dexamethasone, lidocaine, triamcinolone acetonide, retinoic acid, estradiol, pimecrolimus, tacrolimus or tetracaine can be included in the coating and are released over several hours or longer.
  • [0072]
    Classes of medicaments which can be incorporated into coatings of this invention include, but are not limited to, anti-AIDS substances, anti-neoplastic substances, antibacterials, antifungals and antiviral agents, enzyme inhibitors, neurotoxins, opioids, hypnotics, antihistamines, immunomodulators (e.g., cyclosporine), tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinsonism substances, anti-spasmodics and muscle contractants, miotics and anti-cholinergics, immunosuppressants (e.g. cyclosporine), anti-glaucoma solutes, anti-parasite and/or anti-protozoal solutes, anti -hypertensives, analgesics, anti-pyretics and anti-inflammatory agents (such as NSAIDs), local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents, specific targeting agents, neurotransmitters, proteins, and cell response modifiers. A more complete listing of classes of medicaments may be found in the Pharmazeutische Wirkstoffe, ed. A. Von Kleemann and J. Engel, Georg Thieme Verlag, Stuttgart/New York, 1987, incorporated herein by reference.
  • [0073]
    Antibiotics are recognized as substances which inhibit the growth of or kill microorganisms. Antibiotics can be produced synthetically or by microorganisms. Examples of antibiotics include penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycin, geldanamycin, cephalosporins, and analogues thereof. Examples of cephalosporins include cephalothin, cephapirin, cefazolin, cephalexin, cephradine, cefadroxil, cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid, ceforanide, cefotaxime, moxalactam, ceftizoxime, ceftriaxone, and cefoperazone.
  • [0074]
    Antiseptics are recognized as substances that prevent or arrest the growth or action of microorganisms, generally in a nonspecific fashion, e.g., either by inhibiting their activity or destroying them. Examples of antiseptics include silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds.
  • [0075]
    Anti-viral agents are substances capable of destroying or suppressing the replication of viruses. Examples of anti-viral agents include methyl-P-adamantane methylamine, hydroxy-ethoxymethylguanine, adamantanamine, 5-iodo-2′-deoxyuridine, trifluorothymidine, interferon, and adenine arabinoside.
  • [0076]
    Enzyme inhibitors are substances which inhibit an enzymatic reaction. Examples of enzyme inhibitors include edrophonium chloride, N-methylphysostigmine, neostigmine bromide, physostigmine sulfate, tacrine HCl, tacrine, 1-hydroxymaleate, iodotubercidin, p-bromotetramisole, 10-(α-diethylaminopropionyl)-phenothiazine hydrochloride, calmidazolium chloride, hemicholinium-3,3,5-dinitrocatechol, diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor II, 3-phenylpropargylamine, N-monomethyl-L-arginine acetate, carbidopa, 3-hydroxybenzylhydrazine HCl, hydralazine HCl, clorgyline HCl, deprenyl HCl, L(−), deprenyl.HCl, D(+), hydroxylamine HCl, iproniazid phosphate, 6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCl, quinacrine HCl, semicarbazide HCl, tranylcypromine HCl, N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride, 3-isobutyl-1-methylxanthne, papaverine HCl, indomethacin, 2-cyclooctyl-2-hydroxyethylamine hydrochloride, 2,3-dichloro-α-methylbenzylamine (DCMB), 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride, p-aminoglutethimide, p-aminoglutethimide tartrate, R(+), p-aminoglutethimide tartrate, S(−), 3-iodotyrosine, alpha-methyltyrosine, L(−), alpha-methyltyrosine, D L(−), cetazolamide, dichlorphenamide, 6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.
  • [0077]
    Anti-pyretics are substances capable of relieving or reducing fever. Anti-inflammatory agents are substances capable of counteracting or suppressing inflammation. Examples of such agents include aspirin (acetylsalicylic acid), indomethacin, sodium indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodium salicylamide.
  • [0078]
    Local anesthetics are substances which inhibit pain signals in a localized region. Examples of such anesthetics include procaine, lidocaine, tetracaine and dibucaine.
  • [0079]
    Imaging agents are agents capable of imaging a desired site, e.g., tumor, in vivo. Examples of imaging agents include substances having a label which is detectable in vivo, e.g., antibodies attached to fluorescent labels. The term antibody includes whole antibodies or fragments thereof.
  • [0080]
    Cell response modifiers are chemotactic factors such as platelet-derived growth factor (pDGF). Other chemotactic factors include neutrophil-activating protein, monocyte chemoattractant protein, macrophage-inflammatory protein, SIS (small inducible secreted), platelet factor, platelet basic protein, melanoma growth stimulating activity, epidermal growth factor, transforming growth factor (alpha), fibroblast growth factor, platelet-derived endothelial cell growth factor, estradiols, insulin-like growth factor, nerve growth factor, bone growth/cartilage-inducing factor (alpha and beta), and matrix metallo proteinase inhibitors. Other cell response modifiers are the interleukins, interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 10; interferons, including alpha, beta and gamma; hematopoietic factors, including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor; tumor necrosis factors, including alpha and beta; transforming growth factors (beta), including beta-1, beta-2, beta-3, inhibin, activin, DNA that encodes for the production of any of these proteins, antisense molecules, androgenic receptor blockers and statin agents.
  • [0081]
    Examples of bioactive agents include sirolimus, including analogues and derivatives thereof (including rapamycin, ABT-578, everolimus). Sirolimus has been described as a macrocyclic lactone or triene macrolide antibiotic and is produced by Streptomyces hygroscopicus, having a molecular formula of C51H79O13 and a molecular weight of 914.2. Sirolimus has been shown to have antifungal, antitumor and immunosuppressive properties. Another suitable bioactive agent includes paclitaxel (Taxol) which is a lipophilic (i.e., hydrophobic) natural product obtained via a semi-synthetic process from Taxus baccata and having antitumor activity.
  • [0082]
    Other suitable bioactive agents include, but are not limited to, the following compounds, including analogues and derivatives thereof: dexamethasone, betamethasone, retinoic acid, vinblastine, vincristine, vinorelbine, etoposide, teniposide, dactinomycin (actinomycin D), daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, mechlorethamine, cyclophosphamide and its analogs, melphalan, chlorambucil, ethylenimines and methylmelamines, alkyl sulfonates-busulfan, nitrosoureas, carmustine (BCNU) and analogs, streptozocin, trazenes-dacarbazinine, methotrexate, fluorouracil, floxuridine, cytarabine, mercaptopurine, thioguanine, pentostatin, 2-chlorodeoxyadenosine, cisplatin, carboplatin, procarbazine, hydroxyurea, mitotane, aminoglutethimide, estrogen, heparin, synthetic heparin salts, tissue plasminogen activator, streptokinase, urokinase, dipyridamole, ticlopidine, clopidogrel, abciximab, breveldin, cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6U-methylprednisolone, triamcinolone, triamcinolone acetonide, acetaminophen, etodalac, tolmetin, ketorolac, ibuprofen and derivatives, mefenamic acid, meclofenamic acid, piroxicam, tenoxicam, phenylbutazone, oxyphenthatrazone, nabumetone, auranofin, aurothioglucose, gold sodium thiomalate, tacrolimus (FK-506), azathioprine, mycophenolate mofetil, vascular endothelial growth factor (VEGF), angiotensin receptor blocker, nitric oxide donors, anti-sense oligonucleotides and combinations thereof, cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors. Another suitable bioactive agent includes morpholino phosphorodiamidate oligmer.
  • [0083]
    A comprehensive listing of bioactive agents can be found in The Merck Index. Thirteenth Edition, Merck & Co. (2001), the entire contents of which is incorporated by reference herein. Bioactive agents are commercially available from Sigma Aldrich (e.g., vincristine sulfate). The concentration of the bioactive agent or agents dissolved or suspended in the coating mixture can range from about 0.01 to about 90 percent, by weight, based on the weight of the final coated composition. Additives such as inorganic salts, BSA (bovine serum albumin), and inert organic compounds can be used to alter the profile of bioactive agent release, as known to those skilled in the art.
  • [0084]
    In some embodiments, in order to provide a coating, a coating composition is prepared to include one or more solvents, a combination of complementary polymers dissolved in the solvent, and the bioactive agent or agents dispersed in the polymer/solvent mixture. The solvent may be one in which the polymers form a true solution. The pharmaceutical agent itself may either be soluble in the solvent or form a dispersion throughout the solvent. Suitable solvents include, but are not limited to, alcohols (e.g., methanol, butanol, propanol and isopropanol), alkanes (e.g., halogenated or unhalogenated alkanes such as hexane, cyclohexane, methylene chloride and chloroform), amides (e.g., dimethylformamide), ethers (e.g., tetrahydrofuran (THF), dioxolane, and dioxene), ketones (e.g., methyl ethyl ketone), aromatic compounds (e.g., toluene and xylene), nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate). THF and chloroform have been found to be effective solvents due to their excellent solvency for a variety of polymers and bioactive agents of the present invention.
  • [0085]
    A coating composition of this invention can be used to coat the surface of a variety of devices, and is particularly useful for those devices that will come in contact with aqueous systems. Such devices are coated with a coating composition adapted to release bioactive agent in a prolonged and controlled manner, generally beginning with the initial contact between the device surface and its aqueous environment.
  • [0086]
    The coated composition provides a means to deliver bioactive agents from a variety of biomaterial surfaces. Various biomaterials include those formed of synthetic polymers, including oligomers, homopolymers, and copolymers resulting from either addition or condensation polymerizations. Examples of suitable addition polymers include, but are not limited to, acrylics such as those polymerized from methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic acid, glyceryl acrylate, glyceryl methacrylate, methacrylamide, and acrylamide; vinyls, such as those polymerized from ethylene, propylene, styrene, vinyl chloride, vinyl acetate, vinyl pyrrolidone, and vinylidene difluoride. Examples of condensation polymers include, but are not limited to, nylons such as polycaprolactam, poly(lauryl lactam), poly(hexamethylene adipamide), and poly(hexamethylene dodecanediamide), and also polyurethanes, polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), polydimethylsiloxanes, polyetheretherketone, poly(butylene terephthalate), poly(butylene terephthalate-co-polyethylene glycol terephthalate), esters with phosphorus containing linkages, non-peptide polyamino acid polymers, polyiminocarbonates, amino acid-derived polycarbonates and polyarylates, and copolymers of polyethylene oxides with amino acids or peptide sequences.
  • [0087]
    Certain natural materials are also suitable biomaterials, including human tissue such as bone, cartilage, skin and teeth; and other organic materials such as wood, cellulose, compressed carbon, and rubber. Other suitable biomaterials include metals and ceramics. The metals include, but are not limited to, titanium, stainless steel, and cobalt chromium. A second class of metals include the noble metals such as gold, silver, copper, and platinum. Alloys of metals may be suitable for biomaterials as well, such as nitinol (e.g. MP35). The ceramics include, but are not limited to, silicon nitride, silicon carbide, zirconia, and alumina, as well as glass, silica, and sapphire. Yet other suitable biomaterials include combinations of ceramics and metals, as well as biomaterials that are fibrous or porous in nature.
  • [0088]
    Optionally, and in some embodiments, the surface of some biomaterials can be pretreated (e.g., with a silane and/or Parylene™ coating composition in one or more layers) in order to alter the surface properties of the biomaterial. For example, in various embodiments of the present invention a layer of silane may be applied to the surface of the biomaterial followed by a layer of Parlene™. Parylene™ C is the polymeric form of the low-molecular-weight dimer of para-chloro-xylylene. Silane and/or Parylene™ C (a material supplied by Specialty Coating Systems (Indianapolis)) can be deposited as a continuous coating on a variety of medical device parts to provide an evenly distributed, transparent layer. In one embodiment, the deposition of Parylene™ is accomplished by a process termed vapor deposition polymerization, in which dimeric Parylene™ C is vaporized under vacuum at 150° C., pyrolyzed at 680° C. to form a reactive monomer, then pumped into a chamber containing the component to be coated at 25° C. At the low chamber temperature, the monomeric xylylene is deposited on the part, where it immediately polymerizes via a free-radical process. The polymer coating reaches molecular weights of approximately 500 kilodaltons.
  • [0089]
    Deposition of the xylylene monomer takes place in only a moderate vacuum (0.1 torr) and is not line-of-sight. That is, the monomer has the opportunity to surround all sides of the part to be coated, penetrating into crevices or tubes and coating sharp points and edges, creating what is called a “conformal” coating. With proper process control, it is possible to deposit a pinhole-free, insulating coating that will provide very low moisture permeability and high part protection to corrosive biological fluids.
  • [0090]
    Adherence is a function of the chemical nature of the surface to be coated. It has been reported, for instance, that tantalum and silicon surfaces can be overcoated with silicon dioxide, then with plasma-polymerized methane, and finally with Parylene™ C to achieve satisfactory adherence.
  • [0091]
    Most applications of Parylene™ C coating in the medical device industry are for protecting sensitive components from corrosive body fluids or for providing lubricity to surfaces. Typical anticorrosion applications include blood pressure sensors, cardiac-assist devices, prosthetic components, bone pins, electronic circuits, ultrasonic transducers, bone-growth stimulators, and brain probes. Applications to promote lubricity include mandrels, injection needles, cannulae, and catheters.
  • [0092]
    Also, as previously described above, the surface to which the composition is applied can itself be pretreated in other manners sufficient to improve attachment of the composition to the underlying (e.g., metallic) surface. Additional examples of such pretreatments include photografted polymers, epoxy primers, polycarboxylate resins, and physical roughening of the surface. It is further noted that the pretreatment compositions and/or techniques may be used in combination with each other or may be applied in separate layers to form a pretreatment coating on the surface of the medical device.
  • [0093]
    In some embodiments, a tie-in layer may be utilized to facilitate one or more physical and/or covalent bonds between layers. For example, the pretreatment layer may include a multi-interface system to facilitate adhesion and cohesion interaction relative to the different materials positioned at the interface of each layer. For example, the application of Parylene pretreatments to metal surfaces may be aided by a first application of a reactive organosilane reagent. A reactive organosilane reagent containing an unsaturated pendant group is capable of participating with the Parylene radicals as they deposit on the surface from the vapor phase. After cleaning of the metal surface, an organosilane reagent with an unsaturated pendant group may be applied to the metal oxide surface on a metal substrate. Without intending to be bound by theory, it appears that the silicon in the organosilane reagent couples covalently to the metal oxide, linking the organosilane group to the surface. The substrate may then be placed in a Parylene reactor and exposed to the vapor-phase Parylene process. During this process, the unsaturated pendant groups on the organosilane-treated surface can react with the Parylene diradicals depositing from the vapor phase. This forms a covalent link between the Parylene and the organosilane layer. The Parylene also forms covalent bonds to itself as it deposits. Thus, this process yields a layered surface in which the layers are covalently bonded to each other. This forms a very strong bond between the Parylene and the metal surface, resulting in high durability to mechanical challenges. Further, in some embodiments, the Parylene may physically bond with the bioactive agent delivery coating or may include a reactive acrylate group that can be reacted with the bioactive agent delivery coating to improve durability to mechanical challenges.
  • [0094]
    The coating composition of the present invention can be used in combination with a variety of devices, including those used on a temporary, transient, or permanent basis upon and/or within the body.
  • [0095]
    Compositions of this invention can be used to coat the surface of a variety of implantable devices, for example: drug-delivering vascular stents (e.g., self-expanding stents typically made from nitinol, balloon-expanded stents typically prepared from stainless steel); other vascular devices (e.g., grafts, catheters, valves, artificial hearts, heart assist devices); implantable defibrillators; blood oxygenator devices (e.g., tubing, membranes); surgical devices (e.g., sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds); membranes; cell culture devices; chromatographic support materials; biosensors; shunts for hydrocephalus; wound management devices; endoscopic devices; infection control devices; orthopedic devices (e.g., for joint implants, fracture repairs); dental devices (e.g., dental implants, fracture repair devices), urological devices (e.g., penile, sphincter, urethral, bladder and renal devices, and catheters); colostomy bag attachment devices; ophthalmic devices (e.g. ocular coils); glaucoma drain shunts; synthetic prostheses (e.g., breast); intraocular lenses; respiratory, peripheral cardiovascular, spinal, neurological, dental, ear/nose/throat (e.g., ear drainage tubes); renal devices; and dialysis (e.g., tubing, membranes, grafts).
  • [0096]
    Examples of useful devices include urinary catheters (e.g., surface-coated with antimicrobial agents such as vancomycin or norfloxacin), intravenous catheters (e.g., treated with antithrombotic agents (e.g., heparin, hirudin, coumadin), small diameter grafts, vascular grafts, artificial lung catheters, atrial septal defect closures, electro-stimulation leads for cardiac rhythm management (e.g., pacer leads), glucose sensors (long-term and short-term), degradable coronary stents (e.g., degradable, non-degradable, peripheral), blood pressure and stent graft catheters, birth control devices, benign prostate and prostate cancer implants, bone repair/augmentation devices, breast implants, cartilage repair devices, dental implants, implanted drug infusion tubes, intravitreal drug delivery devices, nerve regeneration conduits, oncological implants, electrostimulation leads, pain management implants, spinal/orthopedic repair devices, wound dressings, embolic protection filters, abdominal aortic aneurysm grafts, heart valves (e.g., mechanical, polymeric, tissue, percutaneous, carbon, sewing cuff), valve annuloplasty devices, mitral valve repair devices, vascular intervention devices, left ventricle assist devices, neuro aneurysm treatment coils, neurological catheters, left atrial appendage filters, hemodialysis devices, catheter cuff, anastomotic closures, vascular access catheters, cardiac sensors, uterine bleeding patches, urological catheters/stents/implants, in vitro diagnostics, aneurysm exclusion devices, and neuropatches.
  • [0097]
    Examples of other suitable devices include, but are not limited to, vena cava filters, urinary dialators, endoscopic surgical tissue extractors, atherectomy catheters, clot extraction catheters, percutaneous transluminal angioplasty catheters, PTCA catheters, stylets (vascular and non-vascular), coronary guidewires, drug infusion catheters, esophageal stents, circulatory support systems, angiographic catheters, transition sheaths and dilators, coronary and peripheral guidewires, hemodialysis catheters, neurovascular balloon catheters, tympanostomy vent tubes, cerebro-spinal fluid shunts, defibrillator leads, percutaneous closure devices, drainage tubes, thoracic cavity suction drainage catheters, electrophysiology catheters, stroke therapy catheters, abscess drainage catheters, biliary drainage products, dialysis catheters, central venous access catheters, and parental feeding catheters.
  • [0098]
    Examples of medical devices suitable for the present invention include, but are not limited to catheters, implantable vascular access ports, blood storage bags, vascular stents, blood tubing, arterial catheters, vascular grafts, intraaortic balloon pumps, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such as pancreas or liver and artificial lungs, as well as filters adapted for deployment in a blood vessel in order to trap emboli (also known as “distal protection devices”).
  • [0099]
    The compositions are particularly useful for those devices that will come in contact with aqueous systems, such as bodily fluids. Such devices are coated with a coating composition adapted to release bioactive agent in a prolonged and controlled manner, generally beginning with the initial contact between the device surface and its aqueous environment. It is important to note that the local delivery of combinations of bioactive agents may be utilized to treat a wide variety of conditions utilizing any number of medical devices, or to enhance the function and/or life of the device. Essentially, any type of medical device may be coated in some fashion with one or more bioactive agents that enhances treatment over use of the individual use of the device or bioactive agent.
  • [0100]
    In one some embodiments, the coating composition can also be used to coat stents, e.g., either self-expanding stents, which are typically prepared from nitinol, or balloon-expandable stents, which are typically prepared from stainless steel. Other stent materials, such as cobalt chromium alloys, can be coated by the coating composition as well.
  • [0101]
    Devices which are particularly suitable include vascular stents such as self-expanding stents and balloon expandable stents. Examples of self-expanding stents useful in the present invention are illustrated in U.S. Pat. Nos. 4,655,771 and 4,954,126 issued to Wallsten and U.S. Pat. No. 5,061,275 issued to Wallsten et al. Examples of suitable balloon-expandable stents are shown in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco and U.S. Pat. No. 4,886,062 issued to Wiktor.
  • [0102]
    In other embodiments, the coating composition can also be used to coat ophthalmic devices, e.g. ocular coils. A therapeutic agent delivery device that is particularly suitable for delivery of a therapeutic agent to limited access regions, such as the vitreous chamber of the eye and inner ear is described in U.S. Pat. No. 6,719,750 and U.S. patent application Publication No. 2005/0019371 A1.
  • [0103]
    The resultant coating composition can be applied to the device in any suitable fashion (e.g., the coating composition can be applied directly to the surface of the medical device, or alternatively, to the surface of a surface-modified medical device, by dipping, spraying, ultrasonic deposition, or using any other conventional technique). The suitability of the coating composition for use on a particular material, and in turn, the suitability of the coated composition can be evaluated by those skilled in the art, given the present description. In one such embodiment, for instance, the coating comprises at least two layers which are themselves different. For instance, a base layer may be applied having bioactive agent(s) alone, or together with or without one or more of the polymer components, after which one or more topcoat layers are coated, each with either first and/or second polymers as described herein, and with or without bioactive agent. In various embodiments, these different layers, in turn, can cooperate in the resultant composite coating to provide an overall release profile having certain desired characteristics, and may be used with bioactive agents of high molecular weight. In some embodiments, the composition is coated onto the device surface in one or more applications of a single composition that includes first and second polymers, together with bioactive agent. However, as previously suggested a pretreatment layer or layers may be first applied to the surface of the device, wherein subsequent coating with the composition may be performed onto the pretreatment layer(s). The method of applying the coating composition to the device is typically governed by the geometry of the device and other process considerations. The coating is subsequently cured by evaporation of the solvent. The curing process can be performed at room or elevated temperature, and optionally with the assistance of vacuum and/or controlled humidity.
  • [0104]
    It is also noted that one or more additional layers may be applied to the coating layer(s) that include bioactive agent. Such layer(s) or topcoats can be utilized to provide a number of benefits, such as biocompatibility enhancement, delamination protection, durability enhancement, bioactive agent release control, to just mention a few. In one embodiment the topcoat may include one or more of the first, second, and/or additional polymers described herein without the inclusion of a bioactive agent. In various embodiments, the topcoat includes a second polymer that is a poly(alkyl(meth)acrylate). An example of a poly(alkyl(meth)acrylate) includes poly(n-butyl methacrylate). In another embodiment, the first or second polymers could further include functional groups (e.g. hydroxy, thiol, methylol, amino, and amine-reactive functional groups such as isocyanates, thioisocyanates, carboxylic acids, acyl halides, epoxides, aldehydes, alkyl halides, and sulfonate esters such as mesylate, tosylate, and tresylate) that could be utilized to bind the topcoat to the adjacent coating composition. In another embodiment of the present invention one or more of the pretreatment materials (e.g. Parylene™) may be applied as a topcoat. Additionally, biocompatible topcoats (e.g. heparin, collagen, extracellular matrices, cell receptors . . . ) may be applied to the coating composition of the present invention. Such biocompatible topcoats may be adjoined to the coating composition of the present invention by utilizing photochemical or thermochemical techniques known in the art. Additionally, release layers may be applied to the coating composition of the present invention as a friction barrier layer or a layer to protect against delamination. Examples of biocompatible topcoats that may be used include those disclosed in U.S. Pat. Nos. 4,979,959 and 5,744,515.
  • [0105]
    In some embodiments, the polymer composition for use in this invention is biocompatible, e.g., such that it results in no significant induction of inflammation or irritation when implanted. In addition, the polymer combination may be useful throughout a broad spectrum of both absolute concentrations and relative concentrations of the polymers. This means that the physical characteristics of the coating, such as tenacity, durability, flexibility and expandability, will typically be adequate over a broad range of polymer concentrations. In turn, and in some embodiments, the ability of the coating to control the release rates of a variety of bioactive agents can be manipulated by varying the absolute and relative concentrations of the polymers.
  • [0106]
    Additionally, the coatings of the present invention are generally hydrophobic and limit the intake of aqueous fluids. For example, many embodiments of the present invention are coating compositions including two or more hydrophobic polymers wherein the resulting coating shows <10% (wt) weight change when exposed to water, and in some embodiments <5% (wt) weight change when exposed to water.
  • [0107]
    A coating composition can be provided in any suitable form, e.g., in the form of a true solution, or fluid or paste-like emulsion, mixture, dispersion or blend. Various polymer combinations of this invention are capable of being provided in the form of a true solution, and in turn, can be used to provide a coating that is both optically clear (upon microscopic examination), while also containing a significant amount of bioactive agent. In turn, the coated composition will generally result from the removal of solvents or other volatile components and/or other physical-chemical actions (e.g., heating or illuminating) affecting the coated composition in situ upon the surface.
  • [0108]
    A further example of a coating composition embodiment may include a configuration of one or more bioactive agents within an inner matrix structure, for example, bioactive agents within or delivered from a degradable encapsulating matrix or a microparticle structure formed of semipermeable cells and/or degradable polymers. One or more inner matrices may be placed in one or more locations within the coating composition and at one or more locations in relation to the substrate. Examples of inner matrices, for example degradable encapsulating matrices formed of semipermeable cells and/or degradable polymers, are disclosed and/or suggested in U.S. Publication No. 20030129130, U.S. Patent Application Ser. No. 60/570,334 filed May 12, 2004, U.S. Patent Application Ser. No. 60/603,707, filed Aug. 23, 2004, U.S. Publication No. 20040203075, filed Apr. 10, 2003, U.S. Publication No. 20040202774 filed on Apr. 10, 2003, and U.S. patent application Ser. No. 10/723,505, filed Nov. 26, 2003, the entire contents of which are incorporated by reference herein.
  • [0109]
    The overall weight of the coating upon the surface may vary depending on the application. However, in some embodiments, the weight of the coating attributable to the bioactive agent is in the range of about one microgram to about 10 milligram (mg) of bioactive agent per cm2 of the effective surface area of the device. By “effective” surface area it is meant the surface amenable to being coated with the composition itself. For a flat, nonporous, surface, for instance, this will generally be the macroscopic surface area itself, while for considerably more porous or convoluted (e.g., corrugated, pleated, or fibrous) surfaces the effective surface area can be significantly greater than the corresponding macroscopic surface area. In various embodiments, the weight of the coating attributable to the bioactive agent is between about 0.005 mg and about 10 mg, and in some embodiments, between about 0.01 mg and about 1 mg of bioactive agent per cm2 of the gross surface area of the device. This quantity of bioactive agent is generally required to provide desired activity under physiological conditions.
  • [0110]
    In turn, and in some embodiments, the final coating thickness of a coated composition will typically be in the range of about 0.1 micrometers to about 100 micrometers, and in some embodiments, between about 0.5 micrometers and about 25 micrometers. This level of coating thickness is generally required to provide an adequate concentration of drug to provide adequate activity under physiological conditions.
  • [0111]
    The invention will be further described with reference to the following non-limiting Examples. It will be apparent to those skilled in the art that many changes can be made in the embodiments described without departing from the scope of the present invention. Thus the scope of the present invention should not be limited to the embodiments described in this application, but only by the embodiments described by the language of the claims and the equivalents of those embodiments. Unless otherwise indicated, all percentages are by weight.
  • EXAMPLES Test Procedures
  • [0112]
    The potential suitability of particular coated compositions for in vivo use can be determined by a variety of screening methods, examples of each of which are described herein. Not all of these test procedures were used in connection with the example included in this application, but they are described here to enable consistent comparison of coatings in accordance with the invention.
  • [0000]
    Sample Preparation Procedure
  • [0113]
    Stainless steel stents used in the following example were manufactured by Laserage Technology Corporation, Waukegan, Ill. In some cases, the metal surface of the stents may be coated without any pretreatment beyond washing. In other cases, a primer may be applied to the stents by first cleaning the stents with aqueous base, then pre-treating with a silane followed by vapor deposition of Parylene™ polymer. The silane used was [3-(methacroyloxy)propyl]trimethoxysilane, available from Sigma-Aldrich Fine Chemicals as Product No. 44,015-9. The silane may be applied as essentially a monolayer by mixing the silane at a low concentration in 50/50 (vol) isopropanol/water, soaking the stents in the aqueous silane solution for a suitable length of time to allow the water to hydrolyze the silane and produce some cross-linking, washing off residual silane, then baking the silane-treated stent at 100° C. for conventional periods of time. Following the silane treatment, Parylene™ C coating (available from Union Carbide Corporation, Danbury, Conn.) is vapor-deposited at a thickness of about 1 mm. Prior to coating, the stents should be weighed on a microbalance to determine a tare weight.
  • [0114]
    Bioactive agent/polymer solutions were prepared at a range of concentrations in an appropriate solvent (typically tetrahydrofuran or chloroform), in the manner described herein. In all cases the coating solutions were applied to respective stents by spraying, and the solvent was allowed to evaporate under ambient conditions. The coated stents were then re-weighed to determine the mass of coating and consequently the mass of polymer and bioactive agent.
  • [0000]
    Rapamycin Release Assay Procedure
  • [0115]
    The Rapamycin Release Assay Procedure, as described herein, was used to determine the extent and rate of release of an exemplary bioactive agent, rapamycin, under in vitro elution conditions. Spray-coated stents prepared using the Sample Preparation Procedure were placed in sample baskets into 10 milliliters of Sotax™ dissolution system (elution media containing 2% (wt) surfactant/water solution, available from Sotax Corporation, Horsham, Pa.). Amount of bioactive agent elution was monitored by UV spectrometry over the course of several days. The elution media was held at 37° C. After the elution measurements, the stents were removed, rinsed, dried, and weighed to compare measured bioactive agent elution to weighed mass loss.
  • [0000]
    Dexamethasone Release Assay Procedure
  • [0116]
    A Dexamethasone Release Assay Procedure can be used to determine the extent and rate of dexamethasone release under in vitro conditions. Spray-coated stents made using the Sample Preparation Procedure may be placed in 10 milliliters of pH 7 phosphate buffer solution (“PBS”) contained in an amber vial. A magnetic stirrer bar is added to the vial, and the vial with its contents are placed into a 37° C. water bath. After a sample interval, the stent is removed and placed into a new buffer solution contained in a new vial. Dexamethasone concentration in the buffer is measured using ultraviolet spectroscopy and the concentration converted to mass of bioactive agent released from the coating. After the experiment, the stent should be dried and weighed to correlate actual mass loss to the loss measured by the elution experiment.
  • [0000]
    Durability Test Procedure
  • [0117]
    The durability of the coated composition can be determined by the following manner. To simulate use of the coated devices, the coated stents are placed over sample angioplasty balloons. The stent is then crimped onto the balloon using a laboratory test crimper (available from Machine Solutions, Brooklyn, N.Y.). The stent and balloon are then placed in a phosphate buffer bath having a pH of 7.4 and temperature of 37° C. After 5 minutes of soaking, the balloon is expanded using air at 5 atmospheres (3800 torr) of pressure. The balloon is then deflated, and the stent is removed.
  • [0118]
    The stent is then examined by optical and scanning electron microscopy to determine the amount of coating damage caused by cracking and/or delamination. Coatings with extensive damage are considered unacceptable for a commercial medical device. A “Rating” coresponding to a qualitatitive scale used to describe the amount of damage to the coating from the stent crimping and expansion procedure can be assigned based on optical microscopy examination by an experienced coating engineer. A low rating indicates a large percentage of the coating cracked, smeared, and/or delaminated from the surface. For example, a coating with a rating of ten shows no damage while one with a rating of I will show a majority of the coating damaged to the point where clinical efficacy maybe diminished. Commercially attractive coatings typically have a rating of nine or higher.
  • [0000]
    Stress-Strain Measurement Test Procedure
  • [0119]
    Polymer films are prepared by hot pressing polymer beads at 100° C. in a constant film maker kit to a thickness of approximately 0.5 mm. The resulting films can be cut into strips using a razor blade. A Q800 Dynamic Mechanical Analyzer (available from Texas Instruments, Dallas, Tex.) is fitted with a film tension clamp. Each sample is equilibrated at 35° C. for five minutes prior to straining the sample. Then the sample is loaded into the clamp such that the sample length was between 5 and 7 mm in length. A static force of 0.01N is applied to each sample throughout the measurements. Simultaneously, a 0.5 N/min force is applied to the sample until the movable clamp reaches its maximum position. Films are elongated at constant stress and the average tensile modulus (i.e., the initial slope of the stress-strain curve, in MPa) is determined.
  • Example 1 Release of Rapamycin from Poly(isobutylene) and Poly(butyl methacrylate)
  • [0120]
    Three solutions were prepared for coating the stents. The solutions included mixtures of poly(isobutylene) (“PIB”, available from Scientific Polymer Products as Catalog #681, CAS #9003-27-4, Mw approx. 85 kilodaltons), (“PBMA”, available from Sigma-Aldrich Fine Chemicals as Product No. 18,152-8, having a weight average molecular weight (Mw) of about 337 kilodaltons), and rapamycin (“RAPA”, available from LC Laboratories, Woburn, Mass.) dissolved in THF to form a homogeneous solution. The stents were not given a primer pre-treatment.
  • [0121]
    The solutions were prepared to include the following ingredients at the stated weights per milliliter of THF:
      • 1) 16 mg/ml PIB/4 mg/ml PBMA/10 mg/ml RAPA
      • 2) 10 mg/ml PIB/10 mg/ml PBMA/10 mg/ml RAPA
      • 3) 4 mg/ml PEB/16 mg/ml PBMA/10 mg/ml RAPA
  • [0125]
    Using the Sample Preparation Procedure, two stents were spray coated using each solution. After solvent removal via ambient evaporation, the drug elution for each coated stent was monitored using the Rapamycin Release Assay Procedure.
  • [0126]
    Results, provided in FIG. 1, demonstrate the ability to control the elution rate of rapamycin, a pharmaceutical agent, from a coated stent surface by varying the relative concentrations of PIB and PBMA in the polymer mixture as described herein.
  • [0127]
    Other embodiments of this invention will be apparent to those skilled in the art upon consideration of this specification or from practice of the invention disclosed herein. Various omissions, modifications, and changes to the principles and embodiments described herein may be made by one skilled in the art without departing from the true scope and spirit of the invention which is indicated by the following claims. All patents, patent documents, and publications cited herein are hereby incorporated by reference as if individually incorporated.

Claims (51)

  1. 1. A composition for coating the surface of a medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one polybutene and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).
  2. 2. A composition according to claim 1 wherein the first polymer component includes a polybutene prepared by the homopolymerization of isobutylene, 1-butene or 2-butene.
  3. 3. A composition according to claim 1 wherein the first polymer component includes a polybutene prepared by the random interpolymerization of isobutylene, 1-butene and 2-butene.
  4. 4. A composition according to claim 1 wherein the first polymer component includes a polybutene prepared by the copolymerization of any two of isobutylene, 1-butene and 2-butene.
  5. 5. A composition according to claim 1, the first polymer component having a molecular weight from about 100 kilodaltons to about 1,000 kilodaltons.
  6. 6. A composition according to claim 1, the first polymer component having a molecular weight from about 150 kilodaltons to about 600 kilodaltons.
  7. 7. A composition according to claim 1, the first polymer component having a molecular weight from about 150 kilodaltons to about 250 kilodaltons.
  8. 8. A composition according to claim 1 wherein the composition includes at least one additional polymer selected from the group consisting of poly(alkylene-co-alkyl(meth)acrylates), ethylene copolymer with other alkylenes, aromatic group-containing copolymers, diolefin-derived non-aromatic polymers or copolymers, epichlorohydrin-containing polymers and poly(ethylene-co-vinyl acetate).
  9. 9. A composition according to claim 8 wherein the poly(alkylene-co-alkyl(meth)acrylates are selected from the group consisting of poly(ethylene-co-methyl acrylate), poly(ethylene-co-ethyl acrylate), poly(ethylene-co-2-ethylhexyl acrylate) and poly(ethylene-co-butyl acrylate), the ethylene copolymers with other alkylenes are selected from the group consisting of poly(ethylene-co-propylene), poly(ethylene-co-1-butene), poly(ethylene-co-1-butene-co-1-hexene), poly(ethylene-co-1-octene) and poly(ethylene-co-propylene-co-5-methylene-2-norborene), the diolefin-derived non-aromatic polymer or copolymer is selected from the group consisting of polybutadienes prepared by the polymerization of cis-, trans- and/or 1,2-monomer units, and polyisoprenes prepared by the polymerization of cis-1,4- and/or trans-1,4-monomer units, the aromatic group-containing copolymers include a copolymer derived from copolymerization of styrene monomer and one or more monomers selected from the group consisting of butadiene, isoprene, acrylonitrile, a C1-C4 alkyl(meth)acrylate and butene, the epichlorohydrin-containing polymers are selected from the group consisting of epichlorohydrin homopolymers and poly(epichlorohydrin-co-alkylene oxide) copolymers and the poly(ethylene-co-vinyl acetate) polymers have a vinyl acetate concentration from about 8% to about 90%.
  10. 10. A composition according to claim 1 wherein the poly(alkyl(meth)acrylate) includes an alkyl chain length from two to eight carbons.
  11. 11. A composition according to claim 1, the poly(alkyl(meth)acrylate) having a molecular weight from about 50 kilodaltons to about 900 kilodaltons.
  12. 12. A composition according to claim 1 wherein the poly(alkyl(meth)acrylate) is selected from the group consisting of poly(n-butyl methacrylate), poly(n-butyl methacrylate-co-isobutyl methacrylate), and poly(t-butyl methacrylate).
  13. 13. A composition according to claim 1 wherein the poly(aromatic(meth)acrylate) includes aryl groups having from six to sixteen carbon atoms.
  14. 14. A composition according to claim 1, the poly(aromatic(meth)acrylate) having a molecular weight from about 50 kilodaltons to about 900 kilodaltons.
  15. 15. A composition according to claim 1 wherein the poly(aromatic(meth)acrylate) is selected from the group consisting of poly(aryl(meth)acrylates), poly(aralkyl(meth)acrylates), poly(alkaryl(meth)acrylates), poly(aryloxyalkyl(meth)acrylates), and poly(alkoxyaryl(meth)acrylates).
  16. 16. A composition according to claim 15, wherein the poly(aryl(meth)acrylates) are selected from the group consisting of poly(9-anthracenyl methacrylate), poly(chlorophenyl acrylate), poly(methacryloxy-2-hydroxybenzophenone), poly(methacryloxybenzotriazole), poly(naphthyl acrylate), poly(naphthylmethacrylate), poly-4-nitrophenylacrylate, poly(pentachloro(bromo, fluoro)acrylate) and methacrylate, poly(phenyl acrylate) and poly(phenyl methacrylate); the poly(aralkyl(meth)acrylates) are selected from the group consisting of poly(benzyl acrylate), poly(benzyl methacrylate), poly(2-phenethyl acrylate), poly(2-phenethyl methacrylate) and poly(1-pyrenylmethyl methacrylate); the poly(alkaryl(meth)acrylates are selected from the group consisting of poly(4-sec-butylphenyl methacrylate), poly(3-ethylphenyl acrylate), and poly(2-methyl-1-naphthyl methacrylate); the poly(aryloxyalkyl(meth)acrylates) are selected from the group consisting of poly(phenoxyethyl acrylate), poly(phenoxyethyl methacrylate), and poly(polyethylene glycol phenyl ether acrylate) and poly(polyethylene glycol phenyl ether methacrylate) with varying polyethylene glycol molecular weights; and the poly(alkoxyaryl(meth)acrylates) are selected from the group consisting of poly(4-methoxyphenyl methacrylate), poly(2-ethoxyphenyl acrylate) and poly(2-methoxynaphthyl acrylate).
  17. 17. A composition according to claim 1 wherein the composition further comprises a solvent in which the first and second polymer components form a true solution.
  18. 18. A composition according to claim 1 wherein the bioactive agent is dissolved or suspended in the coating mixture at a concentration of 0.01% to 90% by weight.
  19. 19. A composition according to claim 1 wherein the device is one that undergoes flexion and expansion in the course of implantation or use in vivo.
  20. 20. A composition according to claim 1 wherein the composition permits the amount and rate of release of agent(s) from the medical device to be controlled by adjusting the relative types and concentrations of the first and second polymer components in the mixture.
  21. 21. A combination comprising a medical device and a composition for coating the surface of the medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one polybutene and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).
  22. 22. The combination of claim 21 wherein a pretreatment coating, adapted to alter the surface properties of the medical device, is applied to the surface of the medical device.
  23. 23. The combination of claim 21 wherein the first polymer component includes a polybutene prepared by the homopolymerization of isobutylene, 1-butene or 2-butene.
  24. 24. The combination of claim 21 wherein the first polymer component includes a polybutene prepared by the random interpolymerization of isobutylene, 1-butene and 2-butene.
  25. 25. The combination of claim 21 wherein the first polymer component includes a polybutene prepared by the copolymerization of any two of isobutylene, 1-butene and 2-butene.
  26. 26. The combination of claim 21 wherein the composition includes at least one additional polymer selected from the group consisting of poly(alkylene-co-alkyl(meth)acrylates, ethylene copolymers with other alkylenes, diolefin-derived non-aromatic polymers or copolymers, aromatic group-containing copolymers, epichlorohydrin-containing polymers, and poly(ethylene-co-vinyl acetate).
  27. 27. The combination of claim 22 wherein the pretreatment coating is selected from the group consisting of Parylene™, silane, photografted polymers, epoxy primers, polycarboxylate resins and combinations thereof.
  28. 28. The combination of claim 21 wherein the composition permits the amount and rate of release of agent(s) from the medical device to be controlled by adjusting the relative types and concentrations of the first and second polymer components in the mixture.
  29. 29. A composition for coating the surface of a medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one polybutene and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates), wherein the composition includes at least one additional polymer selected from the group consisting of poly(alkylene-co-alkyl(meth)acrylates), ethylene copolymers with other alkylenes, diolefin-derived non-aromatic polymers or copolymers, aromatic group-containing copolymers, epichlorohydrin-containing polymers, and poly(ethylene-co-vinyl acetate).
  30. 30. A composition according to claim 29 wherein the first polymer component is selected from the group consisting of polybutene prepared by the homopolymerization of isobutylene, 1-butene or 2-butene, polybutene prepared by the random interpolymerization of isobutylene, 1-butene and 2-butene, and polybutene prepared by the copolymerization of any two of isobutylene, 1-butene and 2-butene.
  31. 31. A method of coating the surface of a medical device, the method comprising the steps of providing a composition including at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one polybutene and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates), and applying the composition to the surface of the device.
  32. 32. A combination comprising a stent and a composition for coating the surface of a stent with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising poly(isobutylene), a second polymer component comprising poly(n-butyl methacrylate), a solvent in which the first and second polymer components form a true solution, and at least one biocompatible additive, and further comprising a pretreatment layer including a multi-interface system to facilitate adhesion and cohesion interaction relative to the stent and coating composition.
  33. 33. A combination according to claim 32, wherein the bioactive agent is selected from the group consisting of rapamycin, paclitaxel, dexamethasone, and estradiol.
  34. 34. A combination according to claim 32, wherein the stent includes a material selected from the group consisting of polymers, tissue, metals, ceramics, and combinations thereof.
  35. 35. A combination according to claim 34, wherein the polymers include polycarbonates and the metals are selected from the group consisting of titanium, stainless steel, gold, silver, and nitinol.
  36. 36. A combination according to claim 32, wherein the solvent is selected from the group consisting of tetrahydrofuran, chloroform, methylene chloride, and cyclohexane.
  37. 37. A combination according to claim 32, wherein the biocompatible additive includes one or more antioxidants selected from the group consisting of butylated hydroxytoluene, vitamin E, BNX, and dilauryl thiodipropionate.
  38. 38. A combination according to claim 32, wherein the pretreatment layer includes organosilane and Parylene.
  39. 39. A composition according to claim 1, further comprising a pretreatment layer including a multi-interface system to facilitate adhesion and cohesion interaction relative to the medical device and composition.
  40. 40. A composition according to claim 39, wherein the pretreatment layer includes organosilane and Parylene.
  41. 41. A combination comprising a medical device and a composition for coating the surface of a medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising poly(isobutylene), a second polymer component comprising poly(n-butyl methacrylate), a solvent in which the first and second polymer components form a true solution selected from the group consisting of tetrahydrofuran, chloroform, methylene chloride, and cyclohexane, and at least one biocompatible additive including one or more antioxidants selected from the group consisting of butylated hydroxytoluene, vitamin E, BNX, and dilauryl thiodipropionate, and further comprising a pretreatment layer including a multi-interface system to facilitate adhesion and cohesion interaction relative to the medical device and coating composition.
  42. 42. A combination according to claim 41, wherein the bioactive agent is selected from the group consisting of rapamycin, paclitaxel, dexamethasone, and estradiol.
  43. 43. The combination of claim 41 further comprising a topcoat including poly(butyl methacrylate).
  44. 44. The combination of claim 41, wherein the medical device comprises a stent.
  45. 45. A method of manufacturing a medical device for delivering one or more bioactive agents to a subject comprising: providing a medical device comprising a substrate surface; applying a pretreatment coating including a plurality of bonding layer-sites to enhance the cohesion and adhesion of the pretreatment coating and a bioactive agent coating to at least a portion of the medical device substrate surface; and bonding the bioactive agent coating comprising a bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one polybutene and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).
  46. 46. The method of claim 45 further comprising the step of applying a topcoat layer to the bioactive agent coating for the purpose of biocompatibility enhancement.
  47. 47. The method of claim 45 further comprising the step of applying a topcoat layer to the bioactive agent coating for the purpose of delamination protection.
  48. 48. The method of claim 45 further comprising the step of applying a topcoat layer to the bioactive agent coating for the purpose of durability enhancement.
  49. 49. The method of claim 45 further comprising the step of applying a topcoat layer to the bioactive agent coating for the purpose of bioactive agent release control.
  50. 50. The method of claim 45 further comprising the step of applying a topcoat layer to the bioactive agent coating, the topcoat layer configured to function as a medical device deployment protective release layer.
  51. 51. The method of claim 45, wherein the medical device comprises a stent.
US11099911 2004-04-06 2005-04-06 Coating compositions for bioactive agents Abandoned US20050220841A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US55982104 true 2004-04-06 2004-04-06
US11099911 US20050220841A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US11099911 US20050220841A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
EP20050812405 EP1868666A1 (en) 2005-04-06 2005-10-06 Bioactive coating compositions for medical devices
US11244823 US20060083772A1 (en) 2004-04-06 2005-10-06 Coating compositions for bioactive agents
PCT/US2005/035957 WO2006107336A1 (en) 2005-04-06 2005-10-06 Bioactive coating compositions for medical devices
JP2008505283A JP2008535563A (en) 2005-04-06 2005-10-06 The coating composition for the bioactive agent
CA 2563253 CA2563253A1 (en) 2005-04-06 2005-10-06 Bioactive coating compositions for medical devices

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11244823 Continuation-In-Part US20060083772A1 (en) 2004-04-06 2005-10-06 Coating compositions for bioactive agents

Publications (1)

Publication Number Publication Date
US20050220841A1 true true US20050220841A1 (en) 2005-10-06

Family

ID=34965640

Family Applications (6)

Application Number Title Priority Date Filing Date
US11099939 Abandoned US20050220843A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099997 Abandoned US20050244459A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099935 Abandoned US20050220842A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099910 Expired - Fee Related US7541048B2 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099911 Abandoned US20050220841A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099796 Expired - Fee Related US7544673B2 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents

Family Applications Before (4)

Application Number Title Priority Date Filing Date
US11099939 Abandoned US20050220843A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099997 Abandoned US20050244459A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099935 Abandoned US20050220842A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11099910 Expired - Fee Related US7541048B2 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11099796 Expired - Fee Related US7544673B2 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents

Country Status (7)

Country Link
US (6) US20050220843A1 (en)
EP (2) EP1740235B1 (en)
JP (2) JP2007532187A (en)
CN (2) CN1964749A (en)
CA (2) CA2563069A1 (en)
DE (1) DE602005015564D1 (en)
WO (3) WO2005099787A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060110428A1 (en) * 2004-07-02 2006-05-25 Eugene Dejuan Methods and devices for the treatment of ocular conditions
US20060257451A1 (en) * 2005-04-08 2006-11-16 Varner Signe E Sustained release implants and methods for subretinal delivery of bioactive agents to treat or prevent retinal disease
WO2009030620A1 (en) * 2007-09-06 2009-03-12 Basf Se Blends from branched polyaryl ethers and hydrophilic polymers
US20100114107A1 (en) * 2000-08-30 2010-05-06 Warsaw Orthopedic, Inc. Intervertebral Disc Nucleus Implants and Methods
US7862605B2 (en) 1995-06-07 2011-01-04 Med Institute, Inc. Coated implantable medical device
US8133553B2 (en) 2007-06-18 2012-03-13 Zimmer, Inc. Process for forming a ceramic layer
US8309521B2 (en) 2007-06-19 2012-11-13 Zimmer, Inc. Spacer with a coating thereon for use with an implant device
US8313760B2 (en) 2002-05-24 2012-11-20 Angiotech International Ag Compositions and methods for coating medical implants
US8372420B2 (en) 2002-05-24 2013-02-12 Angiotech International Ag Compositions and methods for coating medical implants
US8602290B2 (en) 2007-10-10 2013-12-10 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate

Families Citing this family (131)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7713297B2 (en) 1998-04-11 2010-05-11 Boston Scientific Scimed, Inc. Drug-releasing stent with ceramic-containing layer
US6569194B1 (en) 2000-12-28 2003-05-27 Advanced Cardiovascular Systems, Inc. Thermoelastic and superelastic Ni-Ti-W alloy
US7151139B2 (en) * 2001-04-23 2006-12-19 Massachusetts Institute Of Technology Antimicrobial polymeric surfaces
US9089407B2 (en) 2001-04-23 2015-07-28 Massachusetts Institute Of Technology Antibacterial coatings that inhibit biofilm formation on implants
WO2003002243A3 (en) 2001-06-27 2004-03-04 Remon Medical Technologies Ltd Method and device for electrochemical formation of therapeutic species in vivo
US20050064011A1 (en) * 2003-08-11 2005-03-24 Young-Ho Song Implantable or insertable medical devices containing phenolic compound for inhibition of restenosis
EP1868666A1 (en) * 2005-04-06 2007-12-26 SurModics, Inc. Bioactive coating compositions for medical devices
US8236338B2 (en) 2004-07-13 2012-08-07 The University Of Tennessee Research Foundation Adhesive composition for carrying therapeutic agents as delivery vehicle on coatings applied to vascular grafts
KR100511618B1 (en) * 2005-01-17 2005-08-24 이경범 Multi-layer coating of drug release controllable coronary stent and method for manufacturing the same
US20070054127A1 (en) * 2005-08-26 2007-03-08 Hergenrother Robert W Silane coating compositions, coating systems, and methods
US20070134288A1 (en) * 2005-12-13 2007-06-14 Edward Parsonage Anti-adhesion agents for drug coatings
US8840660B2 (en) 2006-01-05 2014-09-23 Boston Scientific Scimed, Inc. Bioerodible endoprostheses and methods of making the same
US8089029B2 (en) 2006-02-01 2012-01-03 Boston Scientific Scimed, Inc. Bioabsorbable metal medical device and method of manufacture
US20070200268A1 (en) * 2006-02-24 2007-08-30 Vipul Dave Implantable device prepared from solution processing
US20070200271A1 (en) * 2006-02-24 2007-08-30 Vipul Dave Implantable device prepared from melt processing
US20070224235A1 (en) 2006-03-24 2007-09-27 Barron Tenney Medical devices having nanoporous coatings for controlled therapeutic agent delivery
US8187620B2 (en) 2006-03-27 2012-05-29 Boston Scientific Scimed, Inc. Medical devices comprising a porous metal oxide or metal material and a polymer coating for delivering therapeutic agents
US8048150B2 (en) 2006-04-12 2011-11-01 Boston Scientific Scimed, Inc. Endoprosthesis having a fiber meshwork disposed thereon
US8986713B2 (en) * 2006-05-12 2015-03-24 W. L. Gore & Associates, Inc. Medical device capable of being compacted and expanded having anti-thrombin III binding activity
US8496953B2 (en) * 2006-05-12 2013-07-30 W. L. Gore & Associates, Inc. Immobilized biologically active entities having a high degree of biological activity following sterilization
US8021677B2 (en) 2006-05-12 2011-09-20 Gore Enterprise Holdings, Inc. Immobilized biologically active entities having a high degree of biological activity
US20080279909A1 (en) * 2006-05-12 2008-11-13 Cleek Robert L Immobilized Biologically Active Entities Having A High Degree of Biological Activity Following Sterilization
US9114194B2 (en) * 2006-05-12 2015-08-25 W. L. Gore & Associates, Inc. Immobilized biologically active entities having high biological activity following mechanical manipulation
US20080124372A1 (en) 2006-06-06 2008-05-29 Hossainy Syed F A Morphology profiles for control of agent release rates from polymer matrices
US8815275B2 (en) 2006-06-28 2014-08-26 Boston Scientific Scimed, Inc. Coatings for medical devices comprising a therapeutic agent and a metallic material
JP2009542671A (en) * 2006-06-28 2009-12-03 サーモディクス,インコーポレイティド Active agent elution matrix containing fine particles
US8771343B2 (en) 2006-06-29 2014-07-08 Boston Scientific Scimed, Inc. Medical devices with selective titanium oxide coatings
US9192697B2 (en) 2007-07-03 2015-11-24 Hemoteq Ag Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis
CA2659761A1 (en) 2006-08-02 2008-02-07 Boston Scientific Scimed, Inc. Endoprosthesis with three-dimensional disintegration control
WO2008022258A3 (en) * 2006-08-16 2008-07-24 Surmodics Inc Methods and materials for increasing the adhesion of elution control matrices to substrates
JP2010503469A (en) 2006-09-14 2010-02-04 ボストン サイエンティフィック リミテッド Medical device having a drug eluting coating
CA2663271A1 (en) 2006-09-15 2008-03-20 Boston Scientific Limited Bioerodible endoprostheses and methods of making the same
US8808726B2 (en) 2006-09-15 2014-08-19 Boston Scientific Scimed. Inc. Bioerodible endoprostheses and methods of making the same
EP2959925A1 (en) 2006-09-15 2015-12-30 Boston Scientific Limited Medical devices and methods of making the same
ES2368125T3 (en) 2006-09-15 2011-11-14 Boston Scientific Scimed, Inc. bioerodible endoprostheses biostable inorganic layers.
CA2663762A1 (en) 2006-09-18 2008-03-27 Boston Scientific Limited Endoprostheses
JP5161452B2 (en) 2006-10-03 2013-03-13 日本コヴィディエン株式会社 The method of manufacturing medical devices, a method to confer antibiotic on the surface of the medical device and medical device
EP2076211A4 (en) 2006-10-20 2015-07-22 Elixir Medical Corp Luminal prostheses and methods for coating thereof
CA2668130A1 (en) * 2006-11-03 2008-06-05 Boston Scientific Limited Stents with drug eluting coatings
CN101627092A (en) * 2006-11-08 2010-01-13 麻省理工学院 Polymeric coatings that inactivate viruses and bacteria
US7981150B2 (en) 2006-11-09 2011-07-19 Boston Scientific Scimed, Inc. Endoprosthesis with coatings
EP2091481A2 (en) * 2006-12-18 2009-08-26 Alcon Research, Ltd. Devices and methods for ophthalmic drug delivery
DE602007010669D1 (en) 2006-12-28 2010-12-30 Boston Scient Ltd hear it
DE112008000881A5 (en) 2007-01-21 2010-01-21 Hemoteq Ag Medical device for treating obstructions of body passages and prevent the threat of re-closures
US8221496B2 (en) 2007-02-01 2012-07-17 Cordis Corporation Antithrombotic and anti-restenotic drug eluting stent
EP2124815A1 (en) * 2007-02-02 2009-12-02 University of Miami Therapeutic hybrid implantable devices
US20080208315A1 (en) * 2007-02-27 2008-08-28 National Taiwan University Of Science & Technology Coronary stent having a surface of multi-layer immobilized structures
US8431149B2 (en) 2007-03-01 2013-04-30 Boston Scientific Scimed, Inc. Coated medical devices for abluminal drug delivery
US8070797B2 (en) 2007-03-01 2011-12-06 Boston Scientific Scimed, Inc. Medical device with a porous surface for delivery of a therapeutic agent
US8911765B2 (en) * 2007-03-29 2014-12-16 Tyrx, Inc. Biodegradable, polymer coverings for breast implants
US8067054B2 (en) 2007-04-05 2011-11-29 Boston Scientific Scimed, Inc. Stents with ceramic drug reservoir layer and methods of making and using the same
WO2008134416A1 (en) * 2007-04-24 2008-11-06 Ramon Sanchez Morillo Use of silanes as adhesion promoters between two organic surfaces
US8147769B1 (en) * 2007-05-16 2012-04-03 Abbott Cardiovascular Systems Inc. Stent and delivery system with reduced chemical degradation
US7976915B2 (en) 2007-05-23 2011-07-12 Boston Scientific Scimed, Inc. Endoprosthesis with select ceramic morphology
US7942926B2 (en) 2007-07-11 2011-05-17 Boston Scientific Scimed, Inc. Endoprosthesis coating
US8002823B2 (en) 2007-07-11 2011-08-23 Boston Scientific Scimed, Inc. Endoprosthesis coating
EP2182798A4 (en) * 2007-07-16 2012-07-04 Allvivo Vascular Inc Antimicrobial constructs
US20090024197A1 (en) * 2007-07-18 2009-01-22 Cardiac Pacemakers, Inc. Elution control via geometric features of an implantable substance matrix
US9284409B2 (en) 2007-07-19 2016-03-15 Boston Scientific Scimed, Inc. Endoprosthesis having a non-fouling surface
DE102007034041A1 (en) 2007-07-20 2009-01-22 Biotronik Vi Patent Ag Drug depots for medical implants
US7931683B2 (en) 2007-07-27 2011-04-26 Boston Scientific Scimed, Inc. Articles having ceramic coated surfaces
US8815273B2 (en) 2007-07-27 2014-08-26 Boston Scientific Scimed, Inc. Drug eluting medical devices having porous layers
US8221822B2 (en) 2007-07-31 2012-07-17 Boston Scientific Scimed, Inc. Medical device coating by laser cladding
WO2009020520A1 (en) 2007-08-03 2009-02-12 Boston Scientific Scimed, Inc. Coating for medical device having increased surface area
US8052745B2 (en) 2007-09-13 2011-11-08 Boston Scientific Scimed, Inc. Endoprosthesis
US7938855B2 (en) 2007-11-02 2011-05-10 Boston Scientific Scimed, Inc. Deformable underlayer for stent
US8216632B2 (en) 2007-11-02 2012-07-10 Boston Scientific Scimed, Inc. Endoprosthesis coating
US8029554B2 (en) 2007-11-02 2011-10-04 Boston Scientific Scimed, Inc. Stent with embedded material
US20090130293A1 (en) * 2007-11-16 2009-05-21 David Shykind Biocompatible coatings for medical devices
GB0725018D0 (en) * 2007-12-21 2008-01-30 Univ Cardiff Monitoring system for microneedle delivery
US8551555B2 (en) * 2007-12-26 2013-10-08 Intel Corporation Biocompatible coatings for medical devices
US8951545B2 (en) * 2008-03-28 2015-02-10 Surmodics, Inc. Insertable medical devices having microparticulate-associated elastic substrates and methods for drug delivery
US8496954B2 (en) * 2008-04-18 2013-07-30 Surmodics, Inc. Coating systems for the controlled delivery of hydrophilic bioactive agents
US8920491B2 (en) 2008-04-22 2014-12-30 Boston Scientific Scimed, Inc. Medical devices having a coating of inorganic material
WO2009132176A3 (en) 2008-04-24 2010-09-02 Boston Scientific Scimed, Inc. Medical devices having inorganic particle layers
US7998192B2 (en) 2008-05-09 2011-08-16 Boston Scientific Scimed, Inc. Endoprostheses
US8236046B2 (en) 2008-06-10 2012-08-07 Boston Scientific Scimed, Inc. Bioerodible endoprosthesis
WO2009155328A3 (en) 2008-06-18 2010-09-16 Boston Scientific Scimed, Inc. Endoprosthesis coating
DE102008034826A1 (en) * 2008-07-22 2010-01-28 Alexander Rübben A method for producing a bioactive surface on the balloon of a balloon catheter
US8147898B2 (en) * 2008-07-25 2012-04-03 Medtronic Vascular, Inc. Low temperature drug deposition
US7985252B2 (en) 2008-07-30 2011-07-26 Boston Scientific Scimed, Inc. Bioerodible endoprosthesis
US9295820B2 (en) 2008-08-14 2016-03-29 Surmodics, Inc. Method and apparatus for coating balloon catheters
EP2331157B1 (en) * 2008-08-27 2016-02-24 Boston Scientific Scimed, Inc. Medical devices having fluorine-containing polymer coatings with improved adhesion
US8382824B2 (en) 2008-10-03 2013-02-26 Boston Scientific Scimed, Inc. Medical implant having NANO-crystal grains with barrier layers of metal nitrides or fluorides
US8329206B2 (en) * 2008-11-25 2012-12-11 Bomac Research Limited Bolus devices for the delivery of active agents to animals
US8231980B2 (en) 2008-12-03 2012-07-31 Boston Scientific Scimed, Inc. Medical implants including iridium oxide
US8725529B2 (en) 2008-12-30 2014-05-13 The Invention Science Fund I, Llc Methods and systems for presenting an inhalation experience
US20100166613A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100168525A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100163027A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US8738395B2 (en) * 2008-12-30 2014-05-27 The Invention Science Fund I, Llc Methods and systems for presenting an inhalation experience
US20100169260A1 (en) * 2008-12-30 2010-07-01 Searete Llc Methods and systems for presenting an inhalation experience
US8712794B2 (en) * 2008-12-30 2014-04-29 The Invention Science Fund I, Llc Methods and systems for presenting an inhalation experience
US20100163024A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Methods and systems for presenting an inhalation experience
US20100163036A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100163029A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Method for administering an inhalable compound
US20100163034A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100168529A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100168602A1 (en) * 2008-12-30 2010-07-01 Searete Llc Methods and systems for presenting an inhalation experience
US20100163033A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100163038A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100169259A1 (en) * 2008-12-30 2010-07-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting an inhalation experience
US20100163025A1 (en) * 2008-12-30 2010-07-01 Searete Llc Methods and systems for presenting an inhalation experience
US8694330B2 (en) * 2008-12-30 2014-04-08 The Invention Science Fund I, Llc Methods and systems for presenting an inhalation experience
US8706518B2 (en) * 2008-12-30 2014-04-22 The Invention Science Fund I, Llc Methods and systems for presenting an inhalation experience
DE102009007667B4 (en) * 2009-02-05 2012-04-19 Raumedic Ag Medical working medium and method and apparatus for producing such a medical working medium
US8267992B2 (en) 2009-03-02 2012-09-18 Boston Scientific Scimed, Inc. Self-buffering medical implants
US8071156B2 (en) 2009-03-04 2011-12-06 Boston Scientific Scimed, Inc. Endoprostheses
US9414864B2 (en) 2009-04-15 2016-08-16 Warsaw Orthopedic, Inc. Anterior spinal plate with preformed drug-eluting device affixed thereto
US9078712B2 (en) 2009-04-15 2015-07-14 Warsaw Orthopedic, Inc. Preformed drug-eluting device to be affixed to an anterior spinal plate
US8287937B2 (en) 2009-04-24 2012-10-16 Boston Scientific Scimed, Inc. Endoprosthese
US9289540B2 (en) * 2009-05-08 2016-03-22 Greatbatch Ltd. Surface modification for coating
US8591932B2 (en) * 2009-09-17 2013-11-26 W. L. Gore & Associates, Inc. Heparin entities and methods of use
US8529492B2 (en) 2009-12-23 2013-09-10 Trascend Medical, Inc. Drug delivery devices and methods
US9993441B2 (en) 2009-12-30 2018-06-12 Surmodics, Inc. Controlled release matrix barrier structure for subcutaneous medical devices
US8668732B2 (en) 2010-03-23 2014-03-11 Boston Scientific Scimed, Inc. Surface treated bioerodible metal endoprostheses
WO2012003293A1 (en) 2010-06-30 2012-01-05 Surmodics, Inc. Lipid coating for medical devices delivering bioactive agent
JP5703609B2 (en) * 2010-07-02 2015-04-22 ソニー株式会社 Microscope and area determination method
WO2012031236A1 (en) 2010-09-02 2012-03-08 Boston Scientific Scimed, Inc. Coating process for drug delivery balloons using heat-induced rewrap memory
US20120100187A1 (en) * 2010-10-26 2012-04-26 Surmodics, Inc. Coatings and methods for controlled elution of hydrophilic active agents
RU2625756C2 (en) 2011-03-11 2017-07-18 В.Л. Гор Энд Ассошиейтс, Инк. Advanced immobilized biological objects
US9528009B2 (en) 2011-04-15 2016-12-27 Craig Grossman Composition and method to form a self decontaminating surface
CN103635626A (en) * 2011-04-15 2014-03-12 联合生物科学服务股份有限公司 Composition and method to form self-decontaminating surface
US8669360B2 (en) 2011-08-05 2014-03-11 Boston Scientific Scimed, Inc. Methods of converting amorphous drug substance into crystalline form
US9056152B2 (en) 2011-08-25 2015-06-16 Boston Scientific Scimed, Inc. Medical device with crystalline drug coating
US9526603B2 (en) * 2011-09-30 2016-12-27 Covidien Lp Reversible stiffening of light weight mesh
US9487735B2 (en) 2012-05-14 2016-11-08 Ecolab Usa Inc. Label removal solution for low temperature and low alkaline conditions
EP2931328B1 (en) * 2012-12-13 2018-02-21 Istem Medikal Tibbi Cihaz ve Sanayi Limited Sirketi A ready for use hydrophilic catheter set that does not lose its lubricious efficiency when left in water for a extended period of time, with increased lubricious characteristics, and a production method for this catheter set
CN105377319A (en) * 2013-03-15 2016-03-02 界面生物公司 Compounds and compositions for drug release
EP2988730A4 (en) * 2013-04-25 2017-03-29 Innovative Surface Tech Inc Coatings for controlled release of highly water soluble drugs
CN104153186B (en) * 2014-07-14 2016-04-20 桐乡大和纺织服饰有限公司 Efficient self-cleaning antibacterial finishing agent and its preparation and use

Citations (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4069307A (en) * 1970-10-01 1978-01-17 Alza Corporation Drug-delivery device comprising certain polymeric materials for controlled release of drug
US4722906A (en) * 1982-09-29 1988-02-02 Bio-Metric Systems, Inc. Binding reagents and methods
US4826759A (en) * 1984-10-04 1989-05-02 Bio-Metric Systems, Inc. Field assay for ligands
US4916193A (en) * 1987-12-17 1990-04-10 Allied-Signal Inc. Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides
US4994071A (en) * 1989-05-22 1991-02-19 Cordis Corporation Bifurcating stent apparatus and method
US5002582A (en) * 1982-09-29 1991-03-26 Bio-Metric Systems, Inc. Preparation of polymeric surfaces via covalently attaching polymers
US5019096A (en) * 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
US5114719A (en) * 1987-04-29 1992-05-19 Sabel Bernhard A Extended drug delivery of small, water-soluble molecules
US5180366A (en) * 1990-10-10 1993-01-19 Woods W T Apparatus and method for angioplasty and for preventing re-stenosis
US5217492A (en) * 1982-09-29 1993-06-08 Bio-Metric Systems, Inc. Biomolecule attachment to hydrophobic surfaces
US5221698A (en) * 1991-06-27 1993-06-22 The Regents Of The University Of Michigan Bioactive composition
US5304121A (en) * 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5310559A (en) * 1982-09-01 1994-05-10 Hercon Laboratories Corporation Device for controlled release and delivery to mammalian tissue of pharmacologically active agents incorporating a rate controlling member which comprises an alkylene-alkyl acrylate copolymer
US5380299A (en) * 1993-08-30 1995-01-10 Med Institute, Inc. Thrombolytic treated intravascular medical device
US5414075A (en) * 1992-11-06 1995-05-09 Bsi Corporation Restrained multifunctional reagent for surface modification
US5419760A (en) * 1993-01-08 1995-05-30 Pdt Systems, Inc. Medicament dispensing stent for prevention of restenosis of a blood vessel
US5512055A (en) * 1991-02-27 1996-04-30 Leonard Bloom Anti-infective and anti-inflammatory releasing systems for medical devices
US5512329A (en) * 1982-09-29 1996-04-30 Bsi Corporation Substrate surface preparation
US5525348A (en) * 1989-11-02 1996-06-11 Sts Biopolymers, Inc. Coating compositions comprising pharmaceutical agents
US5591227A (en) * 1992-03-19 1997-01-07 Medtronic, Inc. Drug eluting stent
US5605696A (en) * 1995-03-30 1997-02-25 Advanced Cardiovascular Systems, Inc. Drug loaded polymeric material and method of manufacture
US5607687A (en) * 1995-03-06 1997-03-04 Ethicon, Inc. Polymer blends containing absorbable polyoxaesters
US5607475A (en) * 1995-08-22 1997-03-04 Medtronic, Inc. Biocompatible medical article and method
US5609629A (en) * 1995-06-07 1997-03-11 Med Institute, Inc. Coated implantable medical device
US5618552A (en) * 1995-03-06 1997-04-08 Ethicon, Inc. Absorbable polyoxaesters
US5620698A (en) * 1995-03-06 1997-04-15 Ethicon, Inc. Blends of absorbable polyoxaesters containing amines and/or amido groups
US5624975A (en) * 1985-11-04 1997-04-29 Biocompatibles Limited Plastics
US5624411A (en) * 1993-04-26 1997-04-29 Medtronic, Inc. Intravascular stent and method
US5633343A (en) * 1995-06-30 1997-05-27 Ethicon, Inc. High strength, fast absorbing, melt processable, gycolide-rich, poly(glycolide-co-p-dioxanone) copolymers
US5637113A (en) * 1994-12-13 1997-06-10 Advanced Cardiovascular Systems, Inc. Polymer film for wrapping a stent structure
US5705181A (en) * 1994-10-11 1998-01-06 Ethicon, Inc. Method of making absorbable polymer blends of polylactides, polycaprolactone and polydioxanone
US5714360A (en) * 1995-11-03 1998-02-03 Bsi Corporation Photoactivatable water soluble cross-linking agents containing an onium group
US5714551A (en) * 1995-10-02 1998-02-03 Ethicon, Inc. High strength, melt processable, lactide-rich, poly (lactide-co-p-dioxanone) copolymers
US5731087A (en) * 1995-06-07 1998-03-24 Union Carbide Chemicals & Plastics Technology Corporation Lubricious coatings containing polymers with vinyl and carboxylic acid moieties
US5744515A (en) * 1995-05-26 1998-04-28 Bsi Corporation Method and implantable article for promoting endothelialization
US5858653A (en) * 1997-09-30 1999-01-12 Surmodics, Inc. Reagent and method for attaching target molecules to a surface
US5877224A (en) * 1995-07-28 1999-03-02 Rutgers, The State University Of New Jersey Polymeric drug formulations
US5879697A (en) * 1997-04-30 1999-03-09 Schneider Usa Inc Drug-releasing coatings for medical devices
US5886026A (en) * 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US5895407A (en) * 1996-08-06 1999-04-20 Jayaraman; Swaminathan Microporous covered stents and method of coating
US5897911A (en) * 1997-08-11 1999-04-27 Advanced Cardiovascular Systems, Inc. Polymer-coated stent structure
US5899935A (en) * 1997-08-04 1999-05-04 Schneider (Usa) Inc. Balloon expandable braided stent with restraint
US5902475A (en) * 1997-04-08 1999-05-11 Interventional Technologies, Inc. Method for manufacturing a stent
US6013099A (en) * 1998-04-29 2000-01-11 Medtronic, Inc. Medical device for delivering a water-insoluble therapeutic salt or substance
US6214901B1 (en) * 1998-04-27 2001-04-10 Surmodics, Inc. Bioactive agent release coating
US6217895B1 (en) * 1999-03-22 2001-04-17 Control Delivery Systems Method for treating and/or preventing retinal diseases with sustained release corticosteroids
US6235306B1 (en) * 1991-06-27 2001-05-22 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US20020007215A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020005206A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Antiproliferative drug and delivery device
US20020007213A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020007214A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020013298A1 (en) * 1996-12-02 2002-01-31 William L. Hunter Compositions and methods for treating or preventing inflammatory diseases
US20020018795A1 (en) * 2000-04-13 2002-02-14 Whitbourne Richard J. Targeted therapeutic agent release devices and methods of making and using the same
US20020026176A1 (en) * 2000-08-30 2002-02-28 Varner Signe Erickson Devices for intraocular drug delivery
US6358556B1 (en) * 1995-04-19 2002-03-19 Boston Scientific Corporation Drug release stent coating
US6368586B1 (en) * 1996-01-26 2002-04-09 Brown University Research Foundation Methods and compositions for enhancing the bioadhesive properties of polymers
US20020051731A1 (en) * 1997-12-25 2002-05-02 Teruaki Fukami Silicon wafer storage water and silicon wafer storage method
US20020051730A1 (en) * 2000-09-29 2002-05-02 Stanko Bodnar Coated medical devices and sterilization thereof
US6506408B1 (en) * 2000-07-13 2003-01-14 Scimed Life Systems, Inc. Implantable or insertable therapeutic agent delivery device
US6506411B2 (en) * 1993-07-19 2003-01-14 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
US6511749B1 (en) * 1987-05-01 2003-01-28 Brown University Research Foundation Preparation of multiwall polymeric microcapsules from hydrophilic polymers
US20030039689A1 (en) * 2001-04-26 2003-02-27 Jianbing Chen Polymer-based, sustained release drug delivery system
US20030045924A1 (en) * 1999-12-22 2003-03-06 Arindam Datta Biodegradable stent
US6545097B2 (en) * 2000-12-12 2003-04-08 Scimed Life Systems, Inc. Drug delivery compositions and medical devices containing block copolymer
US6548569B1 (en) * 1999-03-25 2003-04-15 Metabolix, Inc. Medical devices and applications of polyhydroxyalkanoate polymers
US20030083646A1 (en) * 2000-12-22 2003-05-01 Avantec Vascular Corporation Apparatus and methods for variably controlled substance delivery from implanted prostheses
US6565872B2 (en) * 1999-02-16 2003-05-20 Xiao Yu Wu Polymeric system for drug delivery and solute separation
US20030094736A1 (en) * 1996-05-03 2003-05-22 Chuan Qin Method of surface modifying a medical tubing
US6569441B2 (en) * 1993-01-28 2003-05-27 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US6673453B2 (en) * 2001-06-12 2004-01-06 Biocoat Incorporated Coatings appropriate for medical devices
US6682553B1 (en) * 2000-12-28 2004-01-27 Advanced Cardiovascular Systems, Inc. System and method for stent retention
US20040022853A1 (en) * 2001-04-26 2004-02-05 Control Delivery Systems, Inc. Polymer-based, sustained release drug delivery system
US20040033251A1 (en) * 2002-08-13 2004-02-19 Medtronic, Inc. Active agent delivery system including a polyurethane, medical device, and method
US20040034405A1 (en) * 2002-07-26 2004-02-19 Dickson Andrew M. Axially expanding polymer stent
US20040039437A1 (en) * 2002-08-13 2004-02-26 Medtronic, Inc. Medical device exhibiting improved adhesion between polymeric coating and substrate
US20040047911A1 (en) * 2002-08-13 2004-03-11 Medtronic, Inc. Active agent delivery system including a poly(ethylene-co-(meth)Acrylate), medical device, and method
US6713081B2 (en) * 2001-03-15 2004-03-30 The United States Of America As Represented By The Department Of Health And Human Services Ocular therapeutic agent delivery devices and methods for making and using such devices
US20040072799A1 (en) * 2002-07-19 2004-04-15 Omeros Corporation Biodegradable triblock copolymers, synthesis methods therefore, and hydrogels and biomaterials made there from
US6730313B2 (en) * 2000-01-25 2004-05-04 Edwards Lifesciences Corporation Delivery systems for periadventitial delivery for treatment of restenosis and anastomotic intimal hyperplasia
US20040086569A1 (en) * 2002-08-13 2004-05-06 Medtronic, Inc. Active agent delivery systems, medical devices, and methods
US20040098118A1 (en) * 2002-09-26 2004-05-20 Endovascular Devices, Inc. Apparatus and method for delivery of mitomycin through an eluting biocompatible implantable medical device
US20050004663A1 (en) * 2001-05-07 2005-01-06 Llanos Gerard H. Heparin barrier coating for controlled drug release
US6846841B2 (en) * 1993-07-19 2005-01-25 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
US20050019371A1 (en) * 2003-05-02 2005-01-27 Anderson Aron B. Controlled release bioactive agent delivery device
US20050033417A1 (en) * 2003-07-31 2005-02-10 John Borges Coating for controlled release of a therapeutic agent
US6872438B1 (en) * 2000-07-17 2005-03-29 Advanced Design Concept Gmbh Profile or molding having a fringed surface structure
US7008979B2 (en) * 2002-04-30 2006-03-07 Hydromer, Inc. Coating composition for multiple hydrophilic applications
USRE39617E1 (en) * 1992-08-31 2007-05-08 Kraton Polymers Us Llc Butadiene polymers having terminal functional groups

Family Cites Families (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5425530B2 (en) 1974-03-28 1979-08-29
US4391797A (en) 1977-01-05 1983-07-05 The Children's Hospital Medical Center Systems for the controlled release of macromolecules
JPS5930108B2 (en) * 1977-01-21 1984-07-25 Nippon Zeon Co
US4292965A (en) 1978-12-29 1981-10-06 The Population Council, Inc. Intravaginal ring
DE2920500A1 (en) * 1979-05-21 1980-11-27 Boehringer Sohn Ingelheim A pharmaceutical preparation in the form of a polyacrylatfilmes
US5258041A (en) 1982-09-29 1993-11-02 Bio-Metric Systems, Inc. Method of biomolecule attachment to hydrophobic surfaces
US4973493A (en) 1982-09-29 1990-11-27 Bio-Metric Systems, Inc. Method of improving the biocompatibility of solid surfaces
US4603152A (en) 1982-11-05 1986-07-29 Baxter Travenol Laboratories, Inc. Antimicrobial compositions
US4693887A (en) 1983-09-15 1987-09-15 The Kendall Company Microphase separated hydrogels for controlled release of bioactive materials
DE3344691A1 (en) 1983-12-10 1985-06-20 Bayer Ag Drug exhaust systems
DE3347278A1 (en) 1983-12-28 1985-07-11 Bayer Ag Drug delivery systems
EP0556940A1 (en) 1986-02-24 1993-08-25 Robert E. Fischell Intravascular stent
US4959217A (en) 1986-05-22 1990-09-25 Syntex (U.S.A.) Inc. Delayed/sustained release of macromolecules
US4979959A (en) 1986-10-17 1990-12-25 Bio-Metric Systems, Inc. Biocompatible coating for solid surfaces
US5263992A (en) 1986-10-17 1993-11-23 Bio-Metric Systems, Inc. Biocompatible device with covalently bonded biocompatible agent
US4968539A (en) 1987-12-01 1990-11-06 Lion Corporation Liquid crystal membrane
US4867968A (en) 1987-12-29 1989-09-19 Florida-Kansas Health Care, Inc. Elastomeric composition containing therapeutic agents and articles manufactured therefrom
US5660692A (en) 1988-02-24 1997-08-26 Cedars-Sinai Medical Center Method of crosslinking amino acid-containing polymers using photoactivatable chemical crosslinkers
US5024742A (en) 1988-02-24 1991-06-18 Cedars-Sinai Medical Center Method of crosslinking amino acid containing polymers using photoactivatable chemical crosslinkers
US5656286A (en) 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5165952A (en) 1989-01-18 1992-11-24 Becton, Dickinson And Company Anti-infective and antithrombogenic medical articles and method for their preparation
US5545208A (en) 1990-02-28 1996-08-13 Medtronic, Inc. Intralumenal drug eluting prosthesis
WO1991017724A1 (en) 1990-05-17 1991-11-28 Harbor Medical Devices, Inc. Medical device polymer
US5437656A (en) 1991-02-27 1995-08-01 Leonard Bloom Method and device for inhibiting H.I.V. hepatitis B and other viruses and germs when using a needle, scalpel and other sharp instrument in a medical environment
US5356433A (en) 1991-08-13 1994-10-18 Cordis Corporation Biocompatible metal surfaces
US5651968A (en) 1991-08-23 1997-07-29 Alberta Research Council Methods and compositions for attenuating antibody-mediated xenograft rejection in human recipients
DE69328523T2 (en) 1992-02-13 2000-09-21 Surmodics Inc Immobilization of a chemical species in a networked matrix
US5248732A (en) 1992-06-01 1993-09-28 Enichem S.P.A. Blends of polyetherimides, aromatic alkyl methacrylates and polycarbonates
US5449382A (en) 1992-11-04 1995-09-12 Dayton; Michael P. Minimally invasive bioactivated endoprosthesis for vessel repair
US5578075B1 (en) 1992-11-04 2000-02-08 Daynke Res Inc Minimally invasive bioactivated endoprosthesis for vessel repair
US5342348A (en) 1992-12-04 1994-08-30 Kaplan Aaron V Method and device for treating and enlarging body lumens
US5443505A (en) 1993-11-15 1995-08-22 Oculex Pharmaceuticals, Inc. Biocompatible ocular implants
JPH09508892A (en) 1993-11-17 1997-09-09 チルドレンズ メディカル センター コーポレイション Method for inhibiting angiogenesis using heparinase
US5466233A (en) 1994-04-25 1995-11-14 Escalon Ophthalmics, Inc. Tack for intraocular drug delivery and method for inserting and removing same
US5626862A (en) 1994-08-02 1997-05-06 Massachusetts Institute Of Technology Controlled local delivery of chemotherapeutic agents for treating solid tumors
FR2728463B1 (en) 1994-12-21 1997-02-21
US5688900A (en) 1995-01-19 1997-11-18 Ethicon, Inc. Absorbable polyalkylene diglycolates
US5676972A (en) 1995-02-16 1997-10-14 The University Of Akron Time-release delivery matrix composition and corresponding controlled-release compositions
WO1996025897A3 (en) 1995-02-22 1996-11-21 Menlo Care Inc Covered expanding mesh stent
US5859150A (en) * 1995-03-06 1999-01-12 Ethicon, Inc. Prepolymers of absorbable polyoxaesters
JPH10506560A (en) * 1995-04-19 1998-06-30 シュナイダー(ユーエスエー)インク Coated stent releases the drug
US6774278B1 (en) * 1995-06-07 2004-08-10 Cook Incorporated Coated implantable medical device
US5783502A (en) 1995-06-07 1998-07-21 Bsi Corporation Virus inactivating coatings
CA2178541C (en) 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
US5840059A (en) 1995-06-07 1998-11-24 Cardiogenesis Corporation Therapeutic and diagnostic agent delivery
US5773019A (en) 1995-09-27 1998-06-30 The University Of Kentucky Research Foundation Implantable controlled release device to deliver drugs directly to an internal portion of the body
US5722424A (en) * 1995-09-29 1998-03-03 Target Therapeutics, Inc. Multi-coating stainless steel guidewire
US5703200A (en) 1996-03-15 1997-12-30 Ethicon, Inc. Absorbable copolymers and blends of 6,6-dialkyl-1,4-dioxepan-2-one and its cyclic dimer
CA2306538C (en) * 1997-10-09 2006-09-19 Teijin Limited Medical material containing fluorinated polysulfone having excellent antithrombotic activity
US20020164374A1 (en) * 1997-10-29 2002-11-07 John Jackson Polymeric systems for drug delivery and uses thereof
US20020188037A1 (en) * 1999-04-15 2002-12-12 Chudzik Stephen J. Method and system for providing bioactive agent release coating
US6254634B1 (en) * 1998-06-10 2001-07-03 Surmodics, Inc. Coating compositions
US6530950B1 (en) * 1999-01-12 2003-03-11 Quanam Medical Corporation Intraluminal stent having coaxial polymer member
WO2000041732A1 (en) * 1999-01-19 2000-07-20 The Children's Hospital Of Philadelphia Hydrogel compositions for controlled delivery of virus vectors and methods of use thereof
US6395029B1 (en) * 1999-01-19 2002-05-28 The Children's Hospital Of Philadelphia Sustained delivery of polyionic bioactive agents
US6325807B1 (en) * 1999-06-11 2001-12-04 Scimed Life Systems, Inc. Variable strength sheath
US6908624B2 (en) * 1999-12-23 2005-06-21 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US8029561B1 (en) * 2000-05-12 2011-10-04 Cordis Corporation Drug combination useful for prevention of restenosis
US20040058056A1 (en) * 2001-07-06 2004-03-25 Shigemasa Osaki Drug diffusion coatings, applications and methods
DE10039383A1 (en) * 2000-08-11 2002-02-28 Perkinelmer Optoelectronics Flash lamp and flash lamp assembly
US20030065377A1 (en) * 2001-09-28 2003-04-03 Davila Luis A. Coated medical devices
US6517520B2 (en) * 2000-12-21 2003-02-11 Ethicon Endo Surgery, Inc. Peripherally inserted catheter with flushable guide-tube
US6913617B1 (en) * 2000-12-27 2005-07-05 Advanced Cardiovascular Systems, Inc. Method for creating a textured surface on an implantable medical device
GB0100761D0 (en) * 2001-01-11 2001-02-21 Biocompatibles Ltd Drug delivery from stents
US7771468B2 (en) * 2001-03-16 2010-08-10 Angiotech Biocoatings Corp. Medicated stent having multi-layer polymer coating
CA2747159A1 (en) * 2001-05-07 2002-11-07 Queen's University At Kingston Biodegradable elastomer and method of preparing same
US6753071B1 (en) * 2001-09-27 2004-06-22 Advanced Cardiovascular Systems, Inc. Rate-reducing membrane for release of an agent
US20030204168A1 (en) * 2002-04-30 2003-10-30 Gjalt Bosma Coated vascular devices
US7682387B2 (en) * 2002-04-24 2010-03-23 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7585516B2 (en) * 2001-11-12 2009-09-08 Advanced Cardiovascular Systems, Inc. Coatings for drug delivery devices
US8211455B2 (en) * 2002-06-19 2012-07-03 Boston Scientific Scimed, Inc. Implantable or insertable medical devices for controlled delivery of a therapeutic agent
US7491233B1 (en) * 2002-07-19 2009-02-17 Advanced Cardiovascular Systems Inc. Purified polymers for coatings of implantable medical devices
US20040054104A1 (en) * 2002-09-05 2004-03-18 Pacetti Stephen D. Coatings for drug delivery devices comprising modified poly(ethylene-co-vinyl alcohol)
US7125577B2 (en) * 2002-09-27 2006-10-24 Surmodics, Inc Method and apparatus for coating of substrates
US6800663B2 (en) * 2002-10-18 2004-10-05 Alkermes Controlled Therapeutics Inc. Ii, Crosslinked hydrogel copolymers
US20040111144A1 (en) * 2002-12-06 2004-06-10 Lawin Laurie R. Barriers for polymeric coatings
US20040147999A1 (en) * 2003-01-24 2004-07-29 Kishore Udipi Stent with epoxy primer coating
WO2004075943A1 (en) * 2003-02-28 2004-09-10 Biointeractions Ltd. Polymeric network system for medical devices and methods of use
US7241455B2 (en) * 2003-04-08 2007-07-10 Boston Scientific Scimed, Inc. Implantable or insertable medical devices containing radiation-crosslinked polymer for controlled delivery of a therapeutic agent
US7279174B2 (en) * 2003-05-08 2007-10-09 Advanced Cardiovascular Systems, Inc. Stent coatings comprising hydrophilic additives
NL1023720C2 (en) * 2003-06-23 2004-12-28 Univ Eindhoven Tech A method for modifying the transport properties of a material, method for releasing a drug from an implant, as well as implant with drug.
US7285304B1 (en) * 2003-06-25 2007-10-23 Advanced Cardiovascular Systems, Inc. Fluid treatment of a polymeric coating on an implantable medical device
US9114199B2 (en) * 2003-07-31 2015-08-25 Boston Scientific Scimed, Inc. Implantable or insertable medical devices containing acrylic copolymer for controlled delivery of therapeutic agent
US20050064011A1 (en) * 2003-08-11 2005-03-24 Young-Ho Song Implantable or insertable medical devices containing phenolic compound for inhibition of restenosis
US20050037048A1 (en) * 2003-08-11 2005-02-17 Young-Ho Song Medical devices containing antioxidant and therapeutic agent
US20050037047A1 (en) * 2003-08-11 2005-02-17 Young-Ho Song Medical devices comprising spray dried microparticles
US20050037052A1 (en) * 2003-08-13 2005-02-17 Medtronic Vascular, Inc. Stent coating with gradient porosity
WO2005018697A3 (en) * 2003-08-13 2005-12-15 Kiem Dang Active agent delivery systems, including a single layer of a miscible polymer blend, medical devices, and methods
EP1684820A2 (en) * 2003-08-13 2006-08-02 Medtronic, Inc. Active agent delivery systems including a miscible polymer blend, medical devices, and methods
WO2006031532A3 (en) * 2004-09-10 2006-06-08 Ralph A Chappa Methods, devices, and coatings for controlled active agent release
WO2006063021A3 (en) * 2004-12-07 2006-10-12 Ralph A Chappa Coatngs with crystallized active agents (s)

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4069307A (en) * 1970-10-01 1978-01-17 Alza Corporation Drug-delivery device comprising certain polymeric materials for controlled release of drug
US5310559A (en) * 1982-09-01 1994-05-10 Hercon Laboratories Corporation Device for controlled release and delivery to mammalian tissue of pharmacologically active agents incorporating a rate controlling member which comprises an alkylene-alkyl acrylate copolymer
US4722906A (en) * 1982-09-29 1988-02-02 Bio-Metric Systems, Inc. Binding reagents and methods
US5741551A (en) * 1982-09-29 1998-04-21 Bsi Corporation Preparation of polymeric surfaces
US5217492A (en) * 1982-09-29 1993-06-08 Bio-Metric Systems, Inc. Biomolecule attachment to hydrophobic surfaces
US5002582A (en) * 1982-09-29 1991-03-26 Bio-Metric Systems, Inc. Preparation of polymeric surfaces via covalently attaching polymers
US5512329A (en) * 1982-09-29 1996-04-30 Bsi Corporation Substrate surface preparation
US4826759A (en) * 1984-10-04 1989-05-02 Bio-Metric Systems, Inc. Field assay for ligands
US5624975A (en) * 1985-11-04 1997-04-29 Biocompatibles Limited Plastics
US5114719A (en) * 1987-04-29 1992-05-19 Sabel Bernhard A Extended drug delivery of small, water-soluble molecules
US6511749B1 (en) * 1987-05-01 2003-01-28 Brown University Research Foundation Preparation of multiwall polymeric microcapsules from hydrophilic polymers
US4916193A (en) * 1987-12-17 1990-04-10 Allied-Signal Inc. Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides
US5019096A (en) * 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
US4994071A (en) * 1989-05-22 1991-02-19 Cordis Corporation Bifurcating stent apparatus and method
US5525348A (en) * 1989-11-02 1996-06-11 Sts Biopolymers, Inc. Coating compositions comprising pharmaceutical agents
US5180366A (en) * 1990-10-10 1993-01-19 Woods W T Apparatus and method for angioplasty and for preventing re-stenosis
US5304121A (en) * 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5512055A (en) * 1991-02-27 1996-04-30 Leonard Bloom Anti-infective and anti-inflammatory releasing systems for medical devices
US5221698A (en) * 1991-06-27 1993-06-22 The Regents Of The University Of Michigan Bioactive composition
US6235306B1 (en) * 1991-06-27 2001-05-22 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5591227A (en) * 1992-03-19 1997-01-07 Medtronic, Inc. Drug eluting stent
USRE39617E1 (en) * 1992-08-31 2007-05-08 Kraton Polymers Us Llc Butadiene polymers having terminal functional groups
US5414075A (en) * 1992-11-06 1995-05-09 Bsi Corporation Restrained multifunctional reagent for surface modification
US5419760A (en) * 1993-01-08 1995-05-30 Pdt Systems, Inc. Medicament dispensing stent for prevention of restenosis of a blood vessel
US6569441B2 (en) * 1993-01-28 2003-05-27 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5624411A (en) * 1993-04-26 1997-04-29 Medtronic, Inc. Intravascular stent and method
US6506411B2 (en) * 1993-07-19 2003-01-14 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
US5886026A (en) * 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6544544B2 (en) * 1993-07-19 2003-04-08 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
US6846841B2 (en) * 1993-07-19 2005-01-25 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
US5380299A (en) * 1993-08-30 1995-01-10 Med Institute, Inc. Thrombolytic treated intravascular medical device
US5705181A (en) * 1994-10-11 1998-01-06 Ethicon, Inc. Method of making absorbable polymer blends of polylactides, polycaprolactone and polydioxanone
US5637113A (en) * 1994-12-13 1997-06-10 Advanced Cardiovascular Systems, Inc. Polymer film for wrapping a stent structure
US5607687A (en) * 1995-03-06 1997-03-04 Ethicon, Inc. Polymer blends containing absorbable polyoxaesters
US5618552A (en) * 1995-03-06 1997-04-08 Ethicon, Inc. Absorbable polyoxaesters
US5620698A (en) * 1995-03-06 1997-04-15 Ethicon, Inc. Blends of absorbable polyoxaesters containing amines and/or amido groups
US5605696A (en) * 1995-03-30 1997-02-25 Advanced Cardiovascular Systems, Inc. Drug loaded polymeric material and method of manufacture
US6358556B1 (en) * 1995-04-19 2002-03-19 Boston Scientific Corporation Drug release stent coating
US5744515A (en) * 1995-05-26 1998-04-28 Bsi Corporation Method and implantable article for promoting endothelialization
US5731087A (en) * 1995-06-07 1998-03-24 Union Carbide Chemicals & Plastics Technology Corporation Lubricious coatings containing polymers with vinyl and carboxylic acid moieties
US5609629A (en) * 1995-06-07 1997-03-11 Med Institute, Inc. Coated implantable medical device
US5633343A (en) * 1995-06-30 1997-05-27 Ethicon, Inc. High strength, fast absorbing, melt processable, gycolide-rich, poly(glycolide-co-p-dioxanone) copolymers
US5877224A (en) * 1995-07-28 1999-03-02 Rutgers, The State University Of New Jersey Polymeric drug formulations
US5607475A (en) * 1995-08-22 1997-03-04 Medtronic, Inc. Biocompatible medical article and method
US5714551A (en) * 1995-10-02 1998-02-03 Ethicon, Inc. High strength, melt processable, lactide-rich, poly (lactide-co-p-dioxanone) copolymers
US5714360A (en) * 1995-11-03 1998-02-03 Bsi Corporation Photoactivatable water soluble cross-linking agents containing an onium group
US6368586B1 (en) * 1996-01-26 2002-04-09 Brown University Research Foundation Methods and compositions for enhancing the bioadhesive properties of polymers
US20030094736A1 (en) * 1996-05-03 2003-05-22 Chuan Qin Method of surface modifying a medical tubing
US5895407A (en) * 1996-08-06 1999-04-20 Jayaraman; Swaminathan Microporous covered stents and method of coating
US20020013298A1 (en) * 1996-12-02 2002-01-31 William L. Hunter Compositions and methods for treating or preventing inflammatory diseases
US6689803B2 (en) * 1996-12-02 2004-02-10 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating surgical adhesions
US5902475A (en) * 1997-04-08 1999-05-11 Interventional Technologies, Inc. Method for manufacturing a stent
US5879697A (en) * 1997-04-30 1999-03-09 Schneider Usa Inc Drug-releasing coatings for medical devices
US6042875A (en) * 1997-04-30 2000-03-28 Schneider (Usa) Inc. Drug-releasing coatings for medical devices
US5899935A (en) * 1997-08-04 1999-05-04 Schneider (Usa) Inc. Balloon expandable braided stent with restraint
US5897911A (en) * 1997-08-11 1999-04-27 Advanced Cardiovascular Systems, Inc. Polymer-coated stent structure
US5858653A (en) * 1997-09-30 1999-01-12 Surmodics, Inc. Reagent and method for attaching target molecules to a surface
US20020051731A1 (en) * 1997-12-25 2002-05-02 Teruaki Fukami Silicon wafer storage water and silicon wafer storage method
US6344035B1 (en) * 1998-04-27 2002-02-05 Surmodics, Inc. Bioactive agent release coating
US20020032434A1 (en) * 1998-04-27 2002-03-14 Chudzik Stephen J. Bioactive agent release coating
US20030031780A1 (en) * 1998-04-27 2003-02-13 Chudzik Stephen J. Bioactive agent release coating
US6214901B1 (en) * 1998-04-27 2001-04-10 Surmodics, Inc. Bioactive agent release coating
US6013099A (en) * 1998-04-29 2000-01-11 Medtronic, Inc. Medical device for delivering a water-insoluble therapeutic salt or substance
US6565872B2 (en) * 1999-02-16 2003-05-20 Xiao Yu Wu Polymeric system for drug delivery and solute separation
US6548078B2 (en) * 1999-03-22 2003-04-15 Control Delivery Systems Method for treating and/or preventing retinal diseases with sustained release corticosteroids
US6217895B1 (en) * 1999-03-22 2001-04-17 Control Delivery Systems Method for treating and/or preventing retinal diseases with sustained release corticosteroids
US6838493B2 (en) * 1999-03-25 2005-01-04 Metabolix, Inc. Medical devices and applications of polyhydroxyalkanoate polymers
US6867247B2 (en) * 1999-03-25 2005-03-15 Metabolix, Inc. Medical devices and applications of polyhydroxyalkanoate polymers
US6548569B1 (en) * 1999-03-25 2003-04-15 Metabolix, Inc. Medical devices and applications of polyhydroxyalkanoate polymers
US20030045924A1 (en) * 1999-12-22 2003-03-06 Arindam Datta Biodegradable stent
US6537312B2 (en) * 1999-12-22 2003-03-25 Ethicon, Inc. Biodegradable stent
US6730313B2 (en) * 2000-01-25 2004-05-04 Edwards Lifesciences Corporation Delivery systems for periadventitial delivery for treatment of restenosis and anastomotic intimal hyperplasia
US20020018795A1 (en) * 2000-04-13 2002-02-14 Whitbourne Richard J. Targeted therapeutic agent release devices and methods of making and using the same
US20020007213A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020007215A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020005206A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Antiproliferative drug and delivery device
US20020007214A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US6506408B1 (en) * 2000-07-13 2003-01-14 Scimed Life Systems, Inc. Implantable or insertable therapeutic agent delivery device
US6872438B1 (en) * 2000-07-17 2005-03-29 Advanced Design Concept Gmbh Profile or molding having a fringed surface structure
US20020026176A1 (en) * 2000-08-30 2002-02-28 Varner Signe Erickson Devices for intraocular drug delivery
US20020051730A1 (en) * 2000-09-29 2002-05-02 Stanko Bodnar Coated medical devices and sterilization thereof
US6545097B2 (en) * 2000-12-12 2003-04-08 Scimed Life Systems, Inc. Drug delivery compositions and medical devices containing block copolymer
US20030083646A1 (en) * 2000-12-22 2003-05-01 Avantec Vascular Corporation Apparatus and methods for variably controlled substance delivery from implanted prostheses
US6682553B1 (en) * 2000-12-28 2004-01-27 Advanced Cardiovascular Systems, Inc. System and method for stent retention
US6713081B2 (en) * 2001-03-15 2004-03-30 The United States Of America As Represented By The Department Of Health And Human Services Ocular therapeutic agent delivery devices and methods for making and using such devices
US20040022853A1 (en) * 2001-04-26 2004-02-05 Control Delivery Systems, Inc. Polymer-based, sustained release drug delivery system
US20030039689A1 (en) * 2001-04-26 2003-02-27 Jianbing Chen Polymer-based, sustained release drug delivery system
US20050004663A1 (en) * 2001-05-07 2005-01-06 Llanos Gerard H. Heparin barrier coating for controlled drug release
US6673453B2 (en) * 2001-06-12 2004-01-06 Biocoat Incorporated Coatings appropriate for medical devices
US7008979B2 (en) * 2002-04-30 2006-03-07 Hydromer, Inc. Coating composition for multiple hydrophilic applications
US20040072799A1 (en) * 2002-07-19 2004-04-15 Omeros Corporation Biodegradable triblock copolymers, synthesis methods therefore, and hydrogels and biomaterials made there from
US20040034405A1 (en) * 2002-07-26 2004-02-19 Dickson Andrew M. Axially expanding polymer stent
US20040086569A1 (en) * 2002-08-13 2004-05-06 Medtronic, Inc. Active agent delivery systems, medical devices, and methods
US20040047911A1 (en) * 2002-08-13 2004-03-11 Medtronic, Inc. Active agent delivery system including a poly(ethylene-co-(meth)Acrylate), medical device, and method
US20040039437A1 (en) * 2002-08-13 2004-02-26 Medtronic, Inc. Medical device exhibiting improved adhesion between polymeric coating and substrate
US20040033251A1 (en) * 2002-08-13 2004-02-19 Medtronic, Inc. Active agent delivery system including a polyurethane, medical device, and method
US20040098118A1 (en) * 2002-09-26 2004-05-20 Endovascular Devices, Inc. Apparatus and method for delivery of mitomycin through an eluting biocompatible implantable medical device
US20050019371A1 (en) * 2003-05-02 2005-01-27 Anderson Aron B. Controlled release bioactive agent delivery device
US20050033417A1 (en) * 2003-07-31 2005-02-10 John Borges Coating for controlled release of a therapeutic agent

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7862605B2 (en) 1995-06-07 2011-01-04 Med Institute, Inc. Coated implantable medical device
US20100114107A1 (en) * 2000-08-30 2010-05-06 Warsaw Orthopedic, Inc. Intervertebral Disc Nucleus Implants and Methods
US8313760B2 (en) 2002-05-24 2012-11-20 Angiotech International Ag Compositions and methods for coating medical implants
US8425927B2 (en) 2002-05-24 2013-04-23 Angiotech International Ag Compositions and methods for coating medical implants
US8372420B2 (en) 2002-05-24 2013-02-12 Angiotech International Ag Compositions and methods for coating medical implants
US8454582B2 (en) 2004-07-02 2013-06-04 Surmodics, Inc. Methods and devices for the treatment of ocular conditions
US20060110428A1 (en) * 2004-07-02 2006-05-25 Eugene Dejuan Methods and devices for the treatment of ocular conditions
US20060257451A1 (en) * 2005-04-08 2006-11-16 Varner Signe E Sustained release implants and methods for subretinal delivery of bioactive agents to treat or prevent retinal disease
US8003124B2 (en) 2005-04-08 2011-08-23 Surmodics, Inc. Sustained release implants and methods for subretinal delivery of bioactive agents to treat or prevent retinal disease
US8133553B2 (en) 2007-06-18 2012-03-13 Zimmer, Inc. Process for forming a ceramic layer
US8663337B2 (en) 2007-06-18 2014-03-04 Zimmer, Inc. Process for forming a ceramic layer
US8309521B2 (en) 2007-06-19 2012-11-13 Zimmer, Inc. Spacer with a coating thereon for use with an implant device
US20100197859A1 (en) * 2007-09-06 2010-08-05 Basf Se Blends from branched polyaryl ethers and hydrophilic polymers
WO2009030620A1 (en) * 2007-09-06 2009-03-12 Basf Se Blends from branched polyaryl ethers and hydrophilic polymers
US8222342B2 (en) 2007-09-06 2012-07-17 Basf Se Blends from branched polyaryl ethers and hydrophilic polymers
US8602290B2 (en) 2007-10-10 2013-12-10 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate
US8608049B2 (en) 2007-10-10 2013-12-17 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate

Also Published As

Publication number Publication date Type
US20050220840A1 (en) 2005-10-06 application
WO2005097228A3 (en) 2005-12-15 application
WO2005099787A1 (en) 2005-10-27 application
US7541048B2 (en) 2009-06-02 grant
US20050220839A1 (en) 2005-10-06 application
CN1964748A (en) 2007-05-16 application
EP1740236A2 (en) 2007-01-10 application
WO2005099786A1 (en) 2005-10-27 application
JP2007532187A (en) 2007-11-15 application
JP2007532197A (en) 2007-11-15 application
DE602005015564D1 (en) 2009-09-03 grant
CA2563150A1 (en) 2005-10-20 application
EP1740235A1 (en) 2007-01-10 application
EP1740235B1 (en) 2009-07-22 grant
US20050220843A1 (en) 2005-10-06 application
CA2563069A1 (en) 2005-10-27 application
US20050244459A1 (en) 2005-11-03 application
US7544673B2 (en) 2009-06-09 grant
WO2005097228A2 (en) 2005-10-20 application
CN1964749A (en) 2007-05-16 application
US20050220842A1 (en) 2005-10-06 application

Similar Documents

Publication Publication Date Title
US6663662B2 (en) Diffusion barrier layer for implantable devices
US7247313B2 (en) Polyacrylates coatings for implantable medical devices
US7094256B1 (en) Coatings for implantable medical device containing polycationic peptides
US6713119B2 (en) Biocompatible coating for a prosthesis and a method of forming the same
US20030088307A1 (en) Potent coatings for stents
US20080021008A1 (en) Stent coatings comprising hydrophilic additives
US20050025799A1 (en) Biologically absorbable coatings for implantable devices and methods for fabricating the same
US20060204533A1 (en) Drug Delivery Compositions and Related Methods
US20050084515A1 (en) Biocompatible controlled release coatings for medical devices and related methods
US7713541B1 (en) Zwitterionic terpolymers, method of making and use on medical devices
US20090035350A1 (en) Polymers for implantable devices exhibiting shape-memory effects
US6908622B2 (en) Optimized dosing for drug coated stents
US20090098176A1 (en) Medical devices with triggerable bioadhesive material
US20080147178A1 (en) Zwitterionic copolymers, method of making and use on medical devices
US20030060783A1 (en) Wire, tube or catheter with hydrophilic coating
US20050064005A1 (en) Active agent delivery systems including a miscible polymer blend, medical devices, and methods
US20050106204A1 (en) Biologically beneficial coatings for implantable devices containing fluorinated polymers and methods for fabricating the same
US20070190104A1 (en) Coating comprising an adhesive polymeric material for a medical device and method of preparing the same
US20030158598A1 (en) System for sustained-release delivery of anti-inflammatory agents from a coated medical device
US20070065481A1 (en) Coatings including natural biodegradable polysaccharides and uses thereof
US20070078513A1 (en) Controllable drug releasing gradient coatings for medical devices
US20040208985A1 (en) Local drug delivery
US20030229390A1 (en) On-stent delivery of pyrimidines and purine analogs
US20100063570A1 (en) Coating on a balloon comprising a polymer and a drug
US20060088571A1 (en) Biocompatible and hemocompatible polymer compositions

Legal Events

Date Code Title Description
AS Assignment

Owner name: SURMODICS, INC., MINNESOTA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DEWITT, DAVID M.;FINLEY, MICHAEL J.;LAWIN, LAURIE R.;ANDOTHERS;REEL/FRAME:016516/0880;SIGNING DATES FROM 20050425 TO 20050426

Owner name: SURMODICS, INC., MINNESOTA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DEWITT, DAVID M.;FINLEY, MICHAEL J.;LAWIN, LAURIE R.;ANDOTHERS;REEL/FRAME:016511/0133;SIGNING DATES FROM 20050425 TO 20050426