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Bioactive agent release coating and controlled humidity method

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US20110054417A1
US20110054417A1 US12941132 US94113210A US2011054417A1 US 20110054417 A1 US20110054417 A1 US 20110054417A1 US 12941132 US12941132 US 12941132 US 94113210 A US94113210 A US 94113210A US 2011054417 A1 US2011054417 A1 US 2011054417A1
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Prior art keywords
coating
bioactive
composition
agent
release
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Abandoned
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US12941132
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Ralph A. Chappa
Robert W. Hergenrother
Aron B. Anderson
Linh V. Tran
Laurie R. Lawin
Ronald F. Ofstead
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SurModics Inc
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SurModics Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • 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
    • 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 in the form of a one or multi-part system, and method of applying such a composition under conditions of controlled humidity, for use in coating device surfaces to control and/or improve their ability to release bioactive agents in aqueous systems. The coating composition is particularly adapted for use with medical devices that undergo significant flexion and/or expansion in the course of their delivery and/or use, such as stents and catheters. The composition includes the bioactive agent in combination with a first polymer component such as polyalkyl(meth)acrylate, polyaryl(meth)acrylate, polyaralkyl(meth)acrylate, or polyaryloxyalkyl(meth)acrylate and a second polymer component such as poly(ethylene-co-vinyl acetate).

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • [0001]
    This application is a divisional of application Ser. No. of 11/207,380 filed Aug. 19, 2005, which will issue as U.S. Pat. No. 7,833,548 on Nov. 16, 2010, which is a continuation of application Ser. No. 10/175,210, filed Jun. 18, 2002, now U.S. Pat. No. 7,097,850, issued on Aug. 29, 2006, which applications are incorporated herein by reference.
  • TECHNICAL FIELD
  • [0002]
    In one aspect, the present invention relates to a process of treating implantable medical devices with coating compositions to provide the 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, and to devices or surfaces coated with such compositions. In yet another aspect, the invention relates to methods of coating compositions on devices.
  • BACKGROUND OF THE INVENTION
  • [0003]
    Many surgical interventions require the placement of a medical device into the body. While necessary and beneficial for treating a variety of medical conditions, the placement of metal or polymeric devices in the body gives rise to numerous 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 wound healing response resulting in hyperplasia and restenosis. These, and other complications must be dealt with when introducing a metal or polymeric device into the body.
  • [0004]
    One approach to reducing the potential harmful effects of such an introduction is to attempt to provide a more biocompatible implantable device. While there are several methods available to improve the biocompatibility of implantable devices, one method which has met with limited success is to provide the device with the ability to deliver bioactive compounds to the vicinity of the implant. By so doing, 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 anti-proliferative drugs can be released to inhibit hyperplasia. Another benefit to the local release of bioactive agents is the avoidance of toxic concentrations of drugs which are sometimes necessary, when given systemically, to achieve therapeutic concentrations at the site where they are needed.
  • [0005]
    Although the potential benefits expected from the use of medical devices capable of releasing pharmaceutical agents from their surfaces is great, the development of such medical devices has been slow. This development has been hampered by the many challenges that need to be successfully overcome when undertaking said development. Some of these challenges are: 1) the requirement, in some instances, for long term release of bioactive agents; 2) the need for a biocompatible, non-inflammatory device surface; 3) the need for significant durability, particularly with devices that undergo flexion and/or expansion when being implanted or used in the body; 4) concerns regarding processability, to enable the device to be manufactured in an economically viable and reproducible manner; and 5) the requirement that the finished device be sterilizable using conventional methods.
  • [0006]
    Several implantable medical devices capable of delivering medicinal agents have been described. Several patents are directed to devices utilizing biodegradable or bioresorbable polymers as drug containing and releasing coatings, including Tang et al, U.S. Pat. No. 4,916,193 and MacGregor, U.S. Pat. No. 4,994,071. Other patents are directed to the formation of a drug containing hydrogel on the surface of an implantable medical device, these include Amiden et al, U.S. Pat. No. 5,221,698 and Sahatjian, U.S. Pat. No. 5,304,121. Still other patents describe methods for preparing coated intravascular stents via application of polymer solutions containing dispersed therapeutic material to the stent surface followed by evaporation of the solvent. This method is described in Berg et al, U.S. Pat. No. 5,464,650.
  • [0007]
    However, there remain significant problems to be overcome in order to provide a therapeutically significant amount of a bioactive compound on the surface of the implantable medical device. This is particularly true when the coated composition must be kept on the device in the course of flexion and/or expansion of the device during implantation or use. It is also desirable to have a facile and easily processable method of controlling the rate of bioactive release from the surface of the device.
  • [0008]
    Although a variety of hydrophobic polymers have previously been described for use as drug release coatings, Applicant has found that only a small number possess the physical characteristics that would render them useful for implantable medical devices which undergo flexion and/or expansion upon implantation. Many polymers which demonstrate good drug release characteristics, when used alone as drug delivery vehicles, provide coatings that are too brittle to be used on devices which undergo flexion and/or expansion. Other polymers can provoke an inflammatory response when implanted. These or other polymers demonstrate good drug release characteristics for one drug but very poor characteristics for another.
  • [0009]
    Some polymers show good durability and flexibility characteristics when applied to devices without drug, but lose these favorable characteristics when drug is added. Furthermore, often times the higher the concentration of drugs or the thicker the application of polymer to the device surface, the poorer the physical characteristics of the polymer become. It has been very difficult to identify a polymer which provides the proper physical characteristics in the presence of drugs and one in which the drug delivery rate can be controlled by altering the concentration of the drug in the polymer or the thickness of the polymer layer.
  • [0010]
    Applicants have previously provided an implantable medical device that can undergo flexion and/or expansion upon implantation, and that is also capable of delivering a therapeutically significant amount of a pharmaceutical agent or agents from the surface of the device. Applicant's issued U.S. Pat. No. 6,214,901 and published PCT Application No. WO 00/55396 provide a coating composition that comprises at least one polyalkyl(meth)acrylate, as a first polymeric component and poly(ethylene-co-vinyl acetate) (“pEVA”) as a second polymeric component, and describe the use of such compositions for coating an implant surface using any suitable means, e.g., by dipping, spraying and the like.
  • [0011]
    While certainly suitable for their intended use, Applicants have found that devices coated with such compositions have the potential to exhibit properties with detectable, and undesirable, variability, for instance, when evaluated using an “accelerated bioactive release” test method, or a “bioactive agent elution” test method, as described herein. It would be helpful to find ways of affecting, and preferably controlling, the potential for such variability, in order to provide coated devices with uniform properties.
  • [0012]
    Various other references relate to the use of coatings to provide implantable medical devices with bioactive agents. See, for instance, US 20020007213, and published PCT Application Nos. WO 200187372, WO 200187373, WO 200187374, WO 200187375, WO 200187376, WO 200226139, WO 200226271, WO 200226281, WO 200187342, and WO 200187263
  • [0013]
    Finally, Applicant's corresponding US application, filed on a date even herewith and having Attorney Docket No. 9896.129.10, describes the use of one or more aromatic poly(meth)acrylate polymers selected from the group consisting of polyaryl(meth)acrylates, polyaralkyl(meth)acrylates, and polyaryloxyalkyl(meth)acrylates as the first polymeric component in such a composition.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0014]
    In the Drawings:
  • [0015]
    FIG. 1 provides a plot showing the experimental results described in Example 1.
  • [0016]
    FIG. 2 provides a plot showing the experimental results described in Example 2.
  • [0017]
    FIG. 3 provides a plot showing the experimental results described in Example 3.
  • SUMMARY OF THE INVENTION
  • [0018]
    The term “coating composition”, as used herein, will refer to one or more vehicles (e.g., a system of 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. In turn, the term “coated composition” will refer to the effective combination, upon a surface, 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. The present invention provides a coating composition, and related method for 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. In a preferred embodiment, the device is one that undergoes flexion and/or expansion in the course of implantation or use in vivo. In a further preferred embodiment, the method of coating a device comprises 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.
  • [0019]
    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. In turn, even ambient humidity can be considered “controlled” humidity for purposes of this invention, if indeed it has been correlated with and determined to provide a corresponding controlled bioactive release profile.
  • [0020]
    Moreover, and particularly when coating a plurality of coating compositions (including components thereof) in the form of a corresponding plurality of layers, humidity can be controlled in different ways (e.g., using a controlled environment as compared to a hydrated or dehydrated coating composition) and/or at different levels to provide a desired release profile for the resulting coated composition. As described and exemplified below, 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 polymeric components), over which are coated one or more additional layers containing suitable combinations of bioactive agent, first and/or second polymeric component, the combined result of which is to provide a coated composition of the invention. In turn, and in a particularly preferred embodiment, 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, the method comprising the step of coating the device with a coating composition comprising the bioactive agent under conditions of controlled humidity. Applicants have discovered that coating compositions of this invention under conditions of increased humidity will typically accelerate release of the bioactive agent in vivo, while decreasing humidity levels will tend to decelerate release. The controlled humidity can be accomplished by any suitable means, e.g., by controlling humidity in the environment during the coating process and/or by hydrating the coating composition itself.
  • [0021]
    Moreover, a plurality of coating compositions and corresponding coating steps can be employed, each with its own controlled humidity, in order to provide a desired combination of layers, each with its corresponding release profile. 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.
  • [0022]
    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 or less after implantation, and a longer term release component, which can range from on the order of hours to days or even months of useful release. As used herein, the “acceleration” or “deceleration” of bioactive release can include either or both of these release kinetics components.
  • [0023]
    In yet another embodiment, the present invention comprises a method for selecting an optimal release rate from a coated composition, the method comprising the steps of coating sample surfaces at a plurality of different humidity levels and evaluating the corresponding release profiles to determine a controlled humidity level corresponding to a desired profile. In a related embodiment, the invention provides a chamber for use in coating a medical device with a coating composition of the present invention under conditions of controlled humidity.
  • [0024]
    In one such embodiment, for instance, the coating composition is coated onto the device under relative humidity controlled at a level of between about 0% and about 95% relative humidity (at a given temperature, between about 15° C. and 30° C.), and more preferably between about 0% and about 50% relative humidity. Without intending to be bound by theory, Applicants have found that potential differences in the ambient humidity, as between coating runs at the same location, and/or as between different coating locations, can vary significantly, and in a manner that might affect such properties as the release or elution of the bioactive agent. By using a controlled humidity, Applicants can provide a coating in a manner that is significantly more controllable and reproducible.
  • [0025]
    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 polyalkyl(meth)acrylate and/or aromatic poly(meth)acrylate to be used in the coating composition 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.
  • [0026]
    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. 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.
  • [0027]
    In a preferred embodiment the coated composition comprises at least one polyalkyl(meth)acrylate, as a first polymeric component and poly(ethylene-co-vinyl acetate) (“pEVA”) as a second polymeric component. A particularly preferred polymer mixture for use in this invention includes mixtures of poly(n-butyl methacrylate) (“pBMA”) and poly(ethylene-co-vinyl acetate) co-polymers (pEVA). This mixture of polymers has proven useful with absolute polymer concentrations (i.e., the total combined concentrations of both polymers in the coating composition), of between about 0.05 and about 70 percent (by weight of the coating composition). In one preferred embodiment the polymer mixture includes a polyalkyl(meth)acrylate (such as poly(n-butyl methacrylate)) with a weight average molecular weight of from about 100 kilodaltons to about 1000 kilodaltons and a pEVA copolymer with a vinyl acetate content of from about 20 to about 40 weight percent.
  • [0028]
    In a particularly preferred embodiment the polymer mixture includes a polyalkyl(meth)acrylate (e.g., poly(n-butyl methacrylate)) with a weight average molecular weight of from about 200 kilodaltons to about 500 kilodaltons and a pEVA copolymer with a vinyl acetate content of from about 30 to about 34 weight percent. 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.
  • [0029]
    As discussed in Applicant's co-pending application, coating compositions that include one or more aromatic poly(meth)acrylates as the first polymeric component, permit the use of a broad array of bioactive agents, particularly in view of the use of a corresponding broad array of solvents. For instance, such compositions of this invention permit the inclusion of polar bioactive agents, by the use of solvents and solvent systems that are themselves more polar than typically used. In such an embodiment, the composition preferably comprises at least one polymeric component selected from the group consisting of polyaryl(meth)acrylates, polyaralkyl(meth)acrylates, and polyaryloxyalkyl(meth)acrylates, and a second polymeric component comprising poly(ethylene-co-vinyl acetate). Such terms are used to describe polymeric structures wherein at least one carbon chain and at least one aromatic ring are combined with acrylic groups, specifically esters, to provide a coating composition of this invention. For instance, and more specifically, a polyaralkyl(meth)acrylate or polyarylalky(meth)acrylate is made from aromatic esters derived from alcohols also containing aromatic moieties.
  • [0030]
    Such compositions provide unexpected advantages in certain applications, even as compared to compositions that instead employ a polyalkyl(meth)acrylate. Such advantages relate, for instance, to the ability to provide coatings with different characteristics (e.g., different solubility characteristics) than other coated compositions (e.g., those that include a polyalkyl(meth)acrylate component), while maintaining an optimal combination of other desired properties. Without intending to be bound by theory, it would appear that the increased solubility (particularly in more polar solvents) that is provided by an aromatic, rather than alkyl poly(meth)acrylate of this invention, permits the use of poly(ethylene-co-vinyl acetate) components that are themselves more polar (e.g., having significantly greater vinyl acetate concentrations) than those typically preferred for use with the polyalkyl(meth)acrylates.
  • [0031]
    Suitable polymers, and bioactive agents, for use in preparing coating compositions of the present invention can be prepared using conventional organic synthetic procedures and/or are commercially available from a variety of sources, including for instance, from Sigma Aldrich (e.g., 1,3-dioxolane, vincristine sulfate, and poly(ethylene-co-vinylacetate), and Polysciences, Inc, Warrington, Pa. (e.g., polybenzylmethacryate and poly(methyl methacrylate-co-n-butyl methacrylate). Optionally, and preferably, such polymer components are either provided in a form suitable for in vivo use, or are purified for such use to a desired extent (e.g., by removing impurities) by conventional methods available to those skilled in the art.
  • [0032]
    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 a preferred embodiment, 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.
  • [0033]
    A preferred coating composition of this invention includes a mixture of two or more polymers having complementary physical characteristics, and a pharmaceutical agent or agents applied to the surface of an implantable medical device which undergoes flexion and/or expansion upon implantation or use. The applied coating composition is cured (e.g., solvent evaporated) to provide a tenacious and flexible bioactive-releasing coated composition on the surface of the medical device. 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 mixtures of the invention the bioactive release rate from a coated medical device can be manipulated by adjusting the relative concentrations of the polymers.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0034]
    In a particularly preferred embodiment, 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. 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 surface of the medical device is provided with a coating containing one or more bioactive agents.
  • [0035]
    In order to provide a preferred coating, a coating composition is prepared to include a solvent, a combination of complementary polymers dissolved in the solvent, and the bioactive agent or agents dispersed in the polymer/solvent mixture. The solvent is preferably 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. For instance, Applicant's previous U.S. Pat. No. 6,214,901 exemplifies the use of tetrahydrofuran as a solvent. While THF is certainly suitable, and at times is preferred, for certain coating compositions, Applicants have further discovered that other solvents can be used as well, in order to provide unexpected advantages. These 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 and cyclohexane), amides (e.g., dimethylformamide), ethers (e.g., THF and dioxolane), ketones (e.g., methylethylketone), aromatic compounds (e.g., toluene and xylene), nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate).
  • [0036]
    The resultant coating composition can be applied to the device in any suitable fashion, under conditions of controlled relative humidity, e.g., it 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, or any conventional technique. In one such embodiment, for instance, the coating comprises at least two layers, which are either coated under different conditions of relative humidity and/or which are themselves different. For instance, a base layer having either bioactive agent alone, or together with one or more of the polymeric components, after which one or more topcoat layers are coated, each with or without bioactive agent and/or each under different conditions of relative humidity. These different layers, in turn, can cooperate in the resultant composite coating to provide an overall release profile having certain desired characteristics, and is particularly preferred for use with bioactive agents of high molecular weight. Preferably, the composition is coated onto the device surface in one or more applications. 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 temperature, elevated temperature, or with the assistance of vacuum.
  • [0037]
    The polymer mixture for use in this invention is preferably biocompatible, e.g., such that it results in no induction of inflammation or irritation when implanted. In addition, the polymer combination must be useful under 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. Furthermore, the ability of the coating to control the release rates of a variety of pharmaceutical agents can preferably be manipulated by varying the absolute and relative concentrations of the polymers.
  • [0038]
    A first 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.
  • [0039]
    Further examples of suitable first polymers include polyaryl(meth)acrylates, polyaralkyl(meth)acrylates, and polyaryloxyalkyl(meth)acrylates, in particular those with aryl groups having from 6 to 16 carbon atoms and with weight average molecular weights from about 50 to about 900 kilodaltons. Examples of polyaryl(meth)acrylates include poly-9-anthracenylmethacrylate, polychlorophenylacrylate, polymethacryloxy-2-hydroxybenzophenone, polymethacryloxybenzotriazole, polynaphthylacrylate, polynaphthylmethacrylate, poly-4-nitrophenylacrylate, polypentachloro(bromo, fluoro)acrylate and methacrylate, polyphenylacrylate and methacrylate. Examples of polyaralkyl(meth)acrylates include polybenzylacrylate and methacrylate, poly-2-phenethylacrylate and methacrylate, poly-1-pyrenylmethylmethacrylate. Examples of polyaryloxyalkyl(meth)acrylates include polyphenoxyethylacrylate and methacrylate, polyethyleneglycolphenylether acrylates and methacrylates with varying polyethyleneglycol molecular weights.
  • [0040]
    A second polymer component of this invention provides an optimal combination of similar properties, and particularly when used in admixture with the first polymer component. Examples of suitable second polymers are available commercially and include poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations of between about 8% and about 90%, in the form of beads, pellets, granules, etc. pEVA co-polymers with lower percent vinyl acetate become increasingly insoluble in typical solvents.
  • [0041]
    A particularly preferred coating composition for use in this invention includes mixtures of polyalkyl(meth)acrylates (e.g., polybutyl(meth)acrylate) or aromatic poly(meth)acrylates (e.g., polybenzyl(meth)acrylate) and poly(ethylene-co-vinyl acetate) co-polymers (pEVA). This mixture of polymers has proven useful with absolute polymer concentrations (i.e., the total combined concentrations of both polymers in the coating composition), of between about 0.05 and about 70 percent (by weight), and more preferably between about 0.25 and about 10 percent (by weight). In one preferred embodiment the polymer mixture includes a first polymer component (e.g., pBMA) with a weight average molecular weight of from about 100 kilodaltons to about 500 kilodaltons and a pEVA copolymer with a vinyl acetate content of from about 8 to about 90 weight percent, and more preferably between about 20 to about 40 weight percent. In a particularly preferred embodiment the polymer mixture includes a first polymer component with a molecular weight of from about 200 kilodaltons to about 400 kilodaltons and a pEVA copolymer with a vinyl acetate content of from about 30 to about 34 weight percent. 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.
  • [0042]
    The bioactive (e.g., pharmaceutical) agents useful in the present invention include virtually any therapeutic substance which possesses desirable therapeutic characteristics for application to the implant site. These agents include: thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives (including antiangiogenesis agents), anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, ACE inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.
  • [0043]
    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 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.
  • [0044]
    A coating composition of this invention is preferably used to coat an implantable medical device that undergoes flexion or expansion in the course of its implantation or use in vivo. The words “flexion” and “expansion” as used herein with regard to implantable devices will refer to a device, or portion thereof, that is bent (e.g., by at least 45 degrees or more) and/or expanded (e.g., to more than twice its initial dimension), either in the course of its placement, or thereafter in the course of its use in vivo.
  • [0045]
    Examples of suitable catheters include urinary catheters, which would benefit from the incorporation of antimicrobial agents (e.g., antibiotics such as vancomycin or norfloxacin) into a surface coating, and intravenous catheters which would benefit from antimicrobial agents and or from antithrombotic agents (e.g., heparin, hirudin, coumadin). Such catheters are typically fabricated from such materials as silicone rubber, polyurethane, latex and polyvinylchloride.
  • [0046]
    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.
  • [0047]
    A coating composition of the present invention can be used to coat an implant surface using any suitable means, e.g., by dipping, spraying and the like. 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.
  • [0048]
    The overall weight of the coating upon the surface is typically not critical. The weight of the coating attributable to the bioactive agent is preferably in the range of about one microgram to about 10 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. More preferably, the weight of the coating attributable to the bioactive is between about 0.01 mg and about 0.5 mg of bioactive agent per cm2 of the gross surface area of the device. This quantity of drug is generally required to provide adequate activity under physiological conditions.
  • [0049]
    In turn, the final coating thickness of a presently preferred coated composition will typically be in the range of about 0.1 micrometers to about 100 micrometers, and preferably 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.
  • [0050]
    The coated composition provides a means to deliver bioactive agents from a variety of biomaterial surfaces. Preferred 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 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, polylauryl lactam, polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, and also polyurethanes, polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate), polylactic acid, polyglycolic acid, polydimethylsiloxanes, and polyetheretherketone.
  • [0051]
    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. The ceramics include, but are not limited to, silicon nitride, silicon carbide, zirconia, and alumina, as well as glass, silica, and sapphire. Combinations of ceramics and metals would be another class of biomaterials. Another class of biomaterials are fibrous or porous in nature. The surface of such biomaterials can be pretreated (e.g., with a Parylene coating composition) in order to alter the surface properties of the biomaterial.
  • [0052]
    Biomaterials can be used to fabricate a variety of implantable devices. General classes of suitable implantable devices include, but are not limited to, vascular devices such as grafts, stents, catheters, valves, artificial hearts, and heart assist devices; orthopedic devices such as joint implants, fracture repair devices, and artificial tendons; dental devices such as dental implants and fracture repair devices; drug delivery devices; ophthalmic devices and glaucoma drain shunts; urological devices such as penile, sphincter, urethral, bladder, and renal devices; and other catheters, synthetic prostheses such as breast prostheses and artificial organs. Other suitable biomedical devices include dialysis tubing and membranes, blood oxygenator tubing and membranes, blood bags, sutures, membranes, cell culture devices, chromatographic support materials, biosensors, and the like.
  • [0053]
    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 Methods
  • [0054]
    The potential suitability of particular coated compositions for in vivo use can be determined by a variety of methods, including the Durability, Flexibility and Release Tests, examples of each of which are described herein.
  • Sample Preparation
  • [0055]
    One millimeter diameter stainless steel wires (e.g. 304 grade) are cut into 5 centimeter lengths. The wire segments can be treated with a Parylene C coating composition (Parylene is a trademark of the Union Carbide Corporation) or evaluated with no treatment. The wire segments are weighed on a micro-balance.
  • [0056]
    Bioactive agent/polymer mixtures are prepared at a range of concentrations in an appropriate solvent, in the manner described herein. The coating mixtures are applied to respective wires, or portions thereof, by dipping or spraying, and the coated wires are allowed to cure by solvent evaporation. The coated wires are re-weighed. From this weight, the mass of the coating is calculated, which in turn permits the mass of the coated polymer(s) and bioactive agent to be determined. The coating thickness can be measured using any suitable means, e.g., by the use of a microprocessor coating thickness gauge (Minitest 4100).
  • [0057]
    The Durability and Flexibility of the coated composition can be determined in the following manner.
  • Durability Test
  • [0058]
    A suitable Durability Test, involves a method in which a coated specimen (e.g., wire) is subjected to repeated frictional forces intended to simulate the type of abrasion the sample would be exposed to in actual use.
  • [0059]
    The Test described below employs a repetitive 60 cycle treatment, and is used to determine whether there is any change in force measurements between the first 5 cycles and the last 5 cycles, or whether there is any observable flaking or scarring detectable by scanning electron microscopy (“SEM”) analysis. Regenerated cellulose membrane is hydrated and wrapped around a 200 gram stainless steel sled. The cellulose membrane is clipped tightly on the opposite side of the sled. The sled with rotatable arm is then attached to a 250 gram digital force gauge with computer interface. The testing surface is mounted on a rail table with micro-stepper motor control. The wires are clamped onto the test surface. The cellulose covered sled is placed on top of the wires. Initial force measurements are taken as the sled moves at 0.5 cm/sec over a 5 cm section for 5 push/pull cycles. The sled then continues cycling over the coated samples for 50 push/pull cycles at 5 cm/sec to simulate abrasion. The velocity is then reduced to 0.5 cm/sec and the final force measurements are taken over another 5 push/pull cycles.
  • [0060]
    SEM micrographs are taken of abraded and nonabraded coated wires to evaluate the effects of the abrasion on the coating.
  • Flexibility Test
  • [0061]
    A suitable Flexibility Test, in turn, can be used to detect imperfections (when examined by scanning electron microscopy) that develop in the course of flexing of a coated specimen, and in particular, signs of cracking at or near the area of a bend.
  • [0062]
    A wire specimen is obtained and coated in the manner described above. One end of the coated wire (1.0 cm) is clamped in a bench vice. The free end of the wire (1.0 cm) is held with a pliers. The wire is bent until the angle it forms with itself is less than 90 degrees. The wire is removed from the vice and examined by SEM to determine the effect of the bending on the coating.
  • Bioactive Agent Release Assay
  • [0063]
    A suitable Bioactive Agent Release Assay, as described herein, can be used to determine the extent and rate of drug release under physiological conditions. In general it is desirable that less than 50% of the total quantity of the drug released, be released in the first 24 hours. It is frequently desirable for quantities of drug to be released for a duration of at least 30 days. After all the drug has been released, SEM evaluation should reveal an intact coating.
  • [0064]
    Except as otherwise provided herein, each coated wire is placed in a test tube with 5 ml of buffer, which unless stated otherwise herein, was provided in the form of Phosphate Buffered Saline (“PBS”, 10 mM phosphate, 150 mM NaC1, pH 7.4, aqueous solution).
  • [0065]
    The tubes are placed on a rack in an environmental orbital shaker and agitated at 37° C. At timed intervals, the PBS is removed from the tube and replaced with fresh PBS. The drug concentration in each PBS sample is determined using the appropriate method.
  • [0066]
    After all measurable drug has been released from the coated wire, the wire is washed with water, dried, re-weighed, the coating thickness re-measured, and the coating quality examined by SEM analysis.
  • Comparative Example 1 Release of Hexachlorophene from Coated Stainless Steel Wires
  • [0067]
    A one millimeter diameter stainless steel wire (304 grade) was cut into two centimeter segments. The segments were treated with a Parylene C coating composition in order to deposit a thin, conformal, polymeric coating on the wires.
  • [0068]
    Four solutions were prepared for use in coating the wires. The solutions included mixtures of: pEVA (33 weight percent vinyl acetate, from Aldrich Chemical Company, Inc.); poly(n-butyl methacrylate “pBMA”) (337,000 average molecular weight, from Aldrich Chemical Company, Inc.); and hexachlorophene (“HCP”) from Sigma Chemical Co., dissolved in tetrahydrofuran. The solutions were prepared as follows:
  • [0000]
    1) 10 mg/ml pEVA//60 mg/ml pBMA//100 mg/ml HCP
    2) 35 mg/ml pEVA//35 mg/ml pBMA//100 mg/ml HCP
    3) 60 mg/ml pEVA//10 mg/ml pBMA//100 mg/ml HCP
    4) 0 mg/ml pEVA//0 mg/ml pBMA//100 mg/ml HCP
  • [0069]
    Nine wire segments were coated with each coating solution. The following protocol was followed for coating the wire segments. The Parylene-treated wire segments were wiped with an isopropyl alcohol dampened tissue prior to coating. The wire segments were dipped into the coating solution using a 2 cm/second dip speed. The wire segments were immediately withdrawn from the coating solution at a rate of 1 cm/second, after which the coated segments were air-dried at room temperature.
  • [0070]
    Individual wire segments were placed in tubes containing 2 ml of phosphate buffered saline (“PBS”, pH 7.4). The tubes were incubated at 37 degrees centigrade on an environmental, orbital shaker at 100 rotations/minute. The PBS was changed at 1 hour, 3 hours, and 5 hours on the first day, and daily thereafter. The PBS samples were analyzed for HCP concentration by measuring the absorbance of the samples at 298 nms on a UV/visible light spectrophotometer and comparing to an HCP standard curve.
  • [0071]
    Results are provided in FIG. 1 of U.S. Pat. No. 6,214,901, which demonstrates the ability to control the release rate of a pharmaceutical agent from a coated surface by varying the relative concentrations of a polymer mixture.
  • Comparative Example 2
  • [0072]
    The polymers described in this disclosure have been evaluated using an Assay protocol as outlined above. The polymer mixtures evaluated have ranged from 100% pBMA to 100% pEVA. Representative results of those evaluations are summarized below.
  • [0073]
    Control coatings that are made up entirely of pBMA are very durable showing no signs of wear in the Durability Test. When subjected to the Flexibility Test, however, these coatings develop cracks, particularly in the presence of significant concentrations of drug. These coatings also release drug very slowly.
  • [0074]
    Control coatings that are made up entirely of pEVA, in contrast, are less durable and show no signs of cracking in the Flexibility Test, but develop significant scarring in the Durability Test. These coatings release drugs relatively rapidly, usually releasing more than 50% of the total within 24 hours.
  • [0075]
    The coatings, which contain a mixture of both polymers, are very durable, with no signs of wear in the Durability Test and no cracking in the Flexibility Test. Drug release from these coatings can be manipulated by varying the relative concentrations of the polymers. For instance, the rate of drug release can be controllably increased by increasing the relative concentration of pEVA.
  • [0076]
    Bioactive agent containing coatings which show no signs of scarring in the Durability Test and no cracking in the Flexibility Test possess the characteristics necessary for application to implantable medical devices that undergo flexion and/or expansion in the course of implantation and/or use.
  • Example 1
  • [0077]
    Three different polymer solutions, each at a concentration of 35 mg/ml, were prepared in 1,3-dioxolane in the manner provided below in order to provide coating compositions in the form of one part systems. The first solution contained poly(n-butyl methacrylate), with approximate weight average molecular weight of 337 kilodaltons; the second solution contained poly(ethylene-co-vinylacetate), with a vinyl acetate content of 60% (w/w) and poly(benzyl methacrylate) (“PEVA60/P[benzyl]MA”), in a polymer ratio of (50/50% w/w), respectively. The poly(n-butyl methacrylate) and poly(ethylene-co-vinylacetate) were purified by extraction with organic solvents to remove impurities, e.g., monomer residues. The third solution contained poly(ethylene-co-vinylacetate) with a vinyl acetate content of 60% (w/w) and poly(methyl methacrylate-co-n-butyl methacrylate) (“PEVA60/P[Methyl-co-n-Butyl]MA”), commercially available and known as poly(methyl methacrylate/n-butyl methacrylate), in a polymer ratio of (50/50% w/w), respectively. Vincristine sulfate and some additional 1,3-dioxolane were added to each of the three solutions in order to provide coating compositions in the form of one part systems (at final concentrations of 17.5 mg/ml). The vincristine/polymer ratio was 30/70% (w/w).
  • Sample Preparation
  • [0078]
    Sixteen-millimeter diameter stainless steel discs with an overall thickness of two millimeters were fabricated with a fourteen-millimeter diameter flat pedestal. The pedestal had a surface area of 1.54 cm2. A surface treatment such as Parylene could be applied to the disc or the surface could be left untreated. The discs were weighed on a microbalance.
  • [0079]
    Polymer solutions containing vincristine sulfate were applied to the pedestal surface of the discs with a pipette. Two coats were applied with drying of the coat between applications. The solvent was evaporated from the discs and the discs were re-weighed on a microbalance to obtain the amount of vincristine sulfate per disc.
  • Bioactive Agent Release Assay
  • [0080]
    A suitable Bioactive Agent Release Assay, as described herein, can be used to determine the extent and rate of bioactive agent release. In general it is desirable that less than 50% of the total quantity of the bioactive agent be released in the first 24 hours. It is frequently desirable for quantities of bioactive agent to be released for a duration of at least 30 days.
  • [0081]
    Except as otherwise provided herein, each coated disc was placed in an amber vial with 4 mls of elution solvent. The elution solvent was composed of 50% methanol and 50% PBS. The vials were placed in a water bath and stirred at 37° C. At time intervals, the disc was removed from the vial, placed into a new vial containing fresh elution solvent and the new vial was placed into the water bath to continue the experiment. The bioactive agent concentration in each elution solvent sample was determined using UV spectroscopy.
  • [0082]
    After all measurable bioactive agent was released from the coated disc; the disc was washed with water, dried and re-weighed to determine the weight loss of the disc.
  • Conclusions
  • [0083]
    Results are provided in FIG. 1, where it can be seen that approximately 80% or more of the vincristine sulfate was released within 1 day for coatings that contained either poly(n-butyl methacrylate) or a blend of poly(methyl methacrylate-co-n-butyl methacrylate) and poly(ethylene-co-vinylacetate). The blend containing poly(benzyl methacrylate) and poly(ethylene-co-vinylacetate) showed sustained controlled release of vincristine sulfate for more than a one-month period.
  • Humidity Examples
  • [0084]
    Two examples are provided using two different bioactive agents, namely, β-estradiol, as an example of a low molecular weight bioactive agent that weighs 272 daltons, and tetramethylrhodamine isothiocyanate—Dextran (dextran-TRITC) as an example of a water soluble, high molecular weight bioactive agent that weighs 4400 daltons.
  • Example 2 Solution Preparation—Dextran
  • [0085]
    Two solutions were prepared in order to provide a coating composition of the presently claimed invention in the form of a two part system. The first solution was an aqueous solution containing the bioactive agent, dextran-TRITC, at a concentration of 15 mg/ml. The second solution contained poly(ethylene-co-vinylacetate) with a vinyl acetate concentration of 33% (w/w) and poly(n-butyl methacrylate), with approximate weight average molecular weight of 337 kilodaltons. The poly(n-butyl methacrylate) and poly(ethylene-co-vinylacetate) were purified by extraction with organic solvents to remove impurities, e.g., monomer residues. The polymers of the second solution were dissolved in tetrahydrofuran at a concentration of 10 mg/ml.
  • Sample Preparation
  • [0086]
    Fifteen-millimeter diameter stainless steel discs with an overall thickness of two millimeters were fabricated with a nine-millimeter diameter flat pedestal. The pedestal had a surface area of 0.64 cm2. A surface treatment such as Parylene could be applied to the disc or the surface could be left untreated. The discs were weighed on a microbalance. The aqueous bioactive agent solution was applied to the pedestal surface of the discs with a pipette. The water evaporated from the discs and the discs were re-weighed on a microbalance to obtain the amount of the bioactive agent on the disc. The polymer coating solution containing poly(ethylene-co-vinylacetate) and poly(n-butyl methacrylate) was applied to the entire surface of the disc, covering the dextran. The polymer coating solution was coated under a range of humidity conditions. The tetrahydrofuran evaporated from the discs and the coatings were dried under vacuum. The discs were weighed a third time to obtain the amount of the polymer coating per disc.
  • Bioactive Agent Release Assay
  • [0087]
    A suitable Bioactive Agent Release Assay, as describe herein, can be used to determine the extent and rate of bioactive agent release under physiological conditions. In general it is desirable that less than 50% of the total quantity of the bioactive agent be released in the first 24 hours. It is frequently desirable for quantities of bioactive agent to be released for a duration of at least 30 days.
  • [0088]
    Except as otherwise provided herein, each coated disc was placed in an amber vial with 4 mls of PBS. The vials were placed in a water bath and stirred at 37° C. At time intervals, the disc was removed from the vial, placed into a new vial containing fresh PBS and the new vial was placed into the water bath to continue the experiment. The concentration of bioactive agent in each PBS sample was determined using UV spectroscopy.
  • [0089]
    After all measurable bioactive agent was released from the coated disc; the disc was washed with water, dried, and re-weighed to determine the weight loss of the disc.
  • Conclusion
  • [0090]
    The results are provided in FIG. 2 below, where it can be seen that the relative humidity at which the polymeric topcoat composition was coated can be used to control the release rate of the bioactive agent coated in an underlying layer. The bioactive agent was released at a faster rate from the composite coating where the topcoat was coated at 48% relative humidity than from the polymer topcoat coating that was coated at 10% relative humidity.
  • Example 3 Solution Preparation β-estradiol
  • [0091]
    A polymer coating solution containing poly(ethylene-co-vinylacetate) with a vinyl acetate concentration of 33% (w/w) and poly(n-butyl methacrylate) was prepared in tetrahydrofuran at a polymer ratio of 14/86% (w/w), respectively. β-estradiol was added to the polymer coating solution after dissolution of the polymer in order to provide a coating composition of the presently claimed invention in the form of a one part system. The bioactive agent/polymer ratio of the β-estradiol containing polymer solution was 30/70% (w/w) at a concentration of 10 mg/ml.
  • Sample Preparation
  • [0092]
    Eighteen-millimeter long, electropolished stainless steel stents with a 2 mm outer diameter were fabricated (Laserage Technology Corporation, Waukegan Ill.). A surface treatment such as Parylene could be applied to the stent or the surface could be left untreated. The stents were weighed on a microbalance. The β-estradiol containing polymer solution was coated (e.g., sprayed) onto stainless steel stents in an environment maintained at 0, 20, 30 or 40 relative humidity at 22° C. The stents were re-weighed after drying on a microbalance to obtain the amount of the β-estradiol per stent.
  • Bioactive Agent Release Assay
  • [0093]
    A suitable Bioactive Agent Release Assay, as described herein, can be used to determine the extent and rate of bioactive agent release under physiological conditions. In general it is desirable that less that 50% of the total quantity of the bioactive agent be released in the first 24 hours. It is frequently desirable for quantities of bioactive agent to be released for a duration of at least 30 days.
  • [0094]
    Except as otherwise provided herein, each coated stent was placed in an amber vial with 1.6 mls of PBS. The vials were placed in a water bath and stirred at 37° C. At time intervals, the stent was removed from the vial, placed into a new vial containing fresh PBS and the new vial was placed into the water bath to continue the experiment. The concentration of β-estradiol in each PBS sample was determined using UV spectroscopy.
  • Conclusion
  • [0095]
    The results are provided in FIG. 3 below, where it can be seen that the coating of the stents under different humidity level conditions can be used to control the β-estradiol rate of release from coatings containing poly(ethylene-co-vinylacetate) and poly(n-butyl methacrylate).

Claims (13)

1. A method for selecting a bioactive release rate from a coated composition to be positioned in vivo, the method comprising the steps of:
(a) providing a composition comprising a bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one polymer selected from the group consisting of polyalkyl(meth)acrylates, polyaryl(meth)acrylates, polyaralkyl(meth)acrylates, and polyaryloxyalkyl(meth)acrylates, and a second polymer component comprising poly(ethylene-co-vinyl acetate);
(b) coating the composition on a plurality of surfaces, wherein the coating is applied to the surfaces at differing humidity levels;
(c) determining the release profiles of the bioactive agent from the plurality of surfaces; and
(d) correlating the release profiles to the humidity level at which the coating is applied.
2. A method according to claim 1, wherein increasing the humidity level accelerates the release of the bioactive agent and decreasing the humidity level decreases the release of the bioactive agent.
3. A method according to claim 1, wherein the humidity level is altered by a method selected from controlling the humidity at which the device is coated with the coating composition, controlling the water content of the coating composition, or a combination thereof.
4. A method according to claim 1 wherein the aromatic poly(meth)acrylates are selected from the group consisting of polyaryl(meth)acrylates, polyaralkyl(meth)acrylates, and polyaryloxyalkyl(meth)acrylates.
5. A method according to claim 1 wherein the first polymer component is selected from:
polyaryl(meth)acrylates, polyaralkyl(meth)acrylates, and polyaryloxyalkyl(meth)acrylates with aryl groups having from 6 to 16 carbon atoms, the first polymer component having a weight average molecular weight of about 50 to about 900 kilodaltons, and wherein the vinyl acetate content is between about 20% and about 40% by weight.
6. A method according to claim 1 wherein the total combined concentrations of both polymers in the composition is between about 0.05% and about 70% by weight.
7. A method according to claim 1, wherein the composition further comprises a solvent in which the polymers form a true solution.
8. A method according to claim 1 wherein the bioactive agent is selected from the group consisting of thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, ACE inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.
9. A method according to claim 1, wherein the concentration of bioactive agent is about 0.01 to about 90 percent, by weight, based on the weight of the coating composition.
10. A method according to claim 1, wherein the coating composition thickness is about 0.1 micrometers to about 100 micrometers.
11. A method according to claim 1 wherein the composition is provided in a form selected from a solution, emulsion, mixture, dispersion or blend.
12. A method according to claim 1, wherein the surface is provided by a device that comprises a catheter or stent.
13. A combination according to claim 12, wherein the catheter is selected from urinary catheters and intravenous catheters.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013123206A1 (en) * 2012-02-14 2013-08-22 Allegiance Corporation Antimicrobial elastomeric articles

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7097850B2 (en) * 2002-06-18 2006-08-29 Surmodics, Inc. Bioactive agent release coating and controlled humidity method
US8685427B2 (en) * 2002-07-31 2014-04-01 Boston Scientific Scimed, Inc. Controlled drug delivery
US7169178B1 (en) * 2002-11-12 2007-01-30 Advanced Cardiovascular Systems, Inc. Stent with drug coating
CA2518872A1 (en) * 2003-03-28 2004-10-14 Kosan Biosciences, Inc. Devices, methods, and compositions to prevent restenosis
WO2004098565A3 (en) 2003-05-02 2005-03-03 Aron B Anderson Implantable controlled release bioactive agent delivery device
US8246974B2 (en) 2003-05-02 2012-08-21 Surmodics, Inc. Medical devices and methods for producing the same
US20050129731A1 (en) * 2003-11-03 2005-06-16 Roland Horres Biocompatible, biostable coating of medical surfaces
US8137397B2 (en) * 2004-02-26 2012-03-20 Boston Scientific Scimed, Inc. Medical devices
EP1868666A1 (en) * 2005-04-06 2007-12-26 SurModics, Inc. Bioactive coating compositions for medical devices
US20050281857A1 (en) * 2004-05-25 2005-12-22 Heyer Toni M Methods and reagents for preparing biomolecule-containing coatings
US20050266043A1 (en) * 2004-05-27 2005-12-01 Medtronic Vascular, Inc. Methods and compounds for treatment of aneurysmal tissue
EP1781264B1 (en) 2004-08-04 2013-07-24 Evonik Corporation Methods for manufacturing delivery devices and devices thereof
US8246569B1 (en) 2004-08-17 2012-08-21 California Institute Of Technology Implantable intraocular pressure drain
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)
EP1888001B1 (en) * 2005-06-10 2014-08-06 Syneron Medical Ltd. Patch for transdermal drug delivery
US20080009500A1 (en) * 2005-11-08 2008-01-10 Michael Kahn Alpha-helix mimetics and methods relating to the treatment of fibrotic disorders
JP2009526096A (en) * 2006-02-07 2009-07-16 エフ エム シー コーポレーションFmc Corporation Coating method for making a sustained-release coating
US8685421B2 (en) 2006-07-07 2014-04-01 Surmodics, Inc. Beaded wound spacer device
CA2667000A1 (en) 2006-09-25 2008-04-03 James P. Murphy Bioactive load-bearing composites comprising peek and bioglass particles
JP5612474B2 (en) * 2007-10-17 2014-10-22 トランスファーマ メディカル リミテッド Verification of the dissolution rate
CA2704164A1 (en) * 2007-10-29 2009-05-07 Transpharma Medical Ltd. Vertical patch drying
CA2709712C (en) 2007-12-20 2016-05-10 Surmodics Pharmaceuticals, Inc. Process for preparing microparticles having a low residual solvent volume
DE102008034826A1 (en) * 2008-07-22 2010-01-28 Alexander Rübben A method for producing a bioactive surface on the balloon of a balloon catheter
US8622995B2 (en) 2009-10-26 2014-01-07 Pursuit Vascular, Inc. Method for delivery of antimicrobial to proximal end of catheter
US8622996B2 (en) 2008-10-27 2014-01-07 Pursuit Vascular, Inc. Method for applying antimicrobial to proximal end of catheter
US9022984B2 (en) 2008-10-27 2015-05-05 Pursuit Vascular, Inc. Apparatus for delivery of device and antimicrobial agent into trans-dermal catheter
US9078992B2 (en) 2008-10-27 2015-07-14 Pursuit Vascular, Inc. Medical device for applying antimicrobial to proximal end of catheter
US20100168798A1 (en) * 2008-12-30 2010-07-01 Clineff Theodore D Bioactive composites of polymer and glass and method for making same
US8529492B2 (en) 2009-12-23 2013-09-10 Trascend Medical, Inc. Drug delivery devices and methods
EP2678341A1 (en) 2011-02-25 2014-01-01 PRISM Pharma Co., Ltd. Alpha helix mimetics and methods relating thereto
EP2731658A4 (en) 2011-07-12 2016-01-06 Pursuit Vascular Inc Device for delivery of antimicrobial agent into trans-dermal catheter
US9827401B2 (en) 2012-06-01 2017-11-28 Surmodics, Inc. Apparatus and methods for coating medical devices
WO2013181498A1 (en) 2012-06-01 2013-12-05 Surmodics, Inc. Apparatus and method for coating balloon catheters
CA2888241A1 (en) 2012-10-16 2014-04-24 Surmodics, Inc. Wound packing device and methods
DE102013215912B3 (en) * 2013-08-12 2015-02-26 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Color Neutral copper-coated object, method for its production and use of an appropriate color-neutral coating
DE102013215919B3 (en) * 2013-08-12 2015-02-05 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Color Neutral metal-coated article comprising metal-containing or metal surface, a process for its preparation and use an appropriate color-neutral coating

Citations (86)

* 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
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
US5180366A (en) * 1990-10-10 1993-01-19 Woods W T Apparatus and method for angioplasty and for preventing re-stenosis
US5301559A (en) * 1991-09-26 1994-04-12 Mazda Motor Corporation Torque detecting system
US5304121A (en) * 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5380299A (en) * 1993-08-30 1995-01-10 Med Institute, Inc. Thrombolytic treated intravascular medical device
US5512329A (en) * 1982-09-29 1996-04-30 Bsi Corporation Substrate surface preparation
US5512055A (en) * 1991-02-27 1996-04-30 Leonard Bloom Anti-infective and anti-inflammatory releasing systems for medical devices
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
US5705181A (en) * 1994-10-11 1998-01-06 Ethicon, Inc. Method of making absorbable polymer blends of polylactides, polycaprolactone and polydioxanone
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
US5722424A (en) * 1995-09-29 1998-03-03 Target Therapeutics, Inc. Multi-coating stainless steel guidewire
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
US5859150A (en) * 1995-03-06 1999-01-12 Ethicon, Inc. Prepolymers of absorbable polyoxaesters
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
US6013099A (en) * 1998-04-29 2000-01-11 Medtronic, Inc. Medical device for delivering a water-insoluble therapeutic salt or substance
US6214370B1 (en) * 1995-02-10 2001-04-10 Medtronic, Inc. Method and device for administering analgesics
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
US20020004101A1 (en) * 1995-04-19 2002-01-10 Schneider (Usa) Inc. Drug coating with topcoat
US20020007214A1 (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
US20020007213A1 (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
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
US6348152B1 (en) * 1997-10-09 2002-02-19 Teijin Limited Medical material containing fluorinated polysulfone having excellent antithrombotic activity
US20020026236A1 (en) * 2000-01-25 2002-02-28 Helmus Michael N. Delivery systems for periadventitial delivery for treatment of restenosis and anastomotic intimal hyperplasia
US20020032477A1 (en) * 1995-04-19 2002-03-14 Michael N. Helmus Drug release coated stent
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
US20030004209A1 (en) * 1993-07-19 2003-01-02 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
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
US6517520B2 (en) * 2000-12-21 2003-02-11 Ethicon Endo Surgery, Inc. Peripherally inserted catheter with flushable guide-tube
US20030039689A1 (en) * 2001-04-26 2003-02-27 Jianbing Chen Polymer-based, sustained release drug delivery system
US20030039675A1 (en) * 1993-01-28 2003-02-27 Angiotech Pharmaceuticals, Inc. Therapeutic inhibitor of vascular smooth muscle cells
US20030045924A1 (en) * 1999-12-22 2003-03-06 Arindam Datta Biodegradable stent
US20030065377A1 (en) * 2001-09-28 2003-04-03 Davila Luis A. Coated medical devices
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
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
US20040030380A1 (en) * 2002-04-24 2004-02-12 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US20040033251A1 (en) * 2002-08-13 2004-02-19 Medtronic, Inc. Active agent delivery system including a polyurethane, medical device, and method
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
US20040054104A1 (en) * 2002-09-05 2004-03-18 Pacetti Stephen D. Coatings for drug delivery devices comprising modified poly(ethylene-co-vinyl alcohol)
US20040059408A1 (en) * 1999-01-12 2004-03-25 Quanam Medical Corporation Polymer compositions for intraluminal stent
US20040058056A1 (en) * 2001-07-06 2004-03-25 Shigemasa Osaki Drug diffusion coatings, applications and methods
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
US20050004663A1 (en) * 2001-05-07 2005-01-06 Llanos Gerard H. Heparin barrier coating for controlled drug release
US20050019371A1 (en) * 2003-05-02 2005-01-27 Anderson Aron B. Controlled release bioactive agent delivery device
US20050025802A1 (en) * 2003-07-31 2005-02-03 Richard Robert E. Implantable or insertable medical devices containing acrylic copolymer for controlled delivery of therapeutic agent
US20050025830A1 (en) * 2003-06-23 2005-02-03 Technische Universiteit Eindhoven Drug delivery device comprising an active compound and method for releasing an active compound from a drug delivery device
US20050033417A1 (en) * 2003-07-31 2005-02-10 John Borges Coating for controlled release of a therapeutic agent
US20050037048A1 (en) * 2003-08-11 2005-02-17 Young-Ho Song Medical devices containing antioxidant and therapeutic agent
US20050037052A1 (en) * 2003-08-13 2005-02-17 Medtronic Vascular, Inc. Stent coating with gradient porosity
US20050037047A1 (en) * 2003-08-11 2005-02-17 Young-Ho Song Medical devices comprising spray dried microparticles
US20050042293A1 (en) * 1997-10-29 2005-02-24 The University Of British Columbia Polymeric systems for drug delivery and uses thereof
US20050064038A1 (en) * 2003-08-13 2005-03-24 Dinh Thomas Q. Active agent delivery systems including a single layer of a miscible polymer blend, medical devices, and methods
US20050064005A1 (en) * 2003-08-13 2005-03-24 Dinh Thomas Q. Active agent delivery systems including a miscible polymer blend, medical devices, and methods
US20050064011A1 (en) * 2003-08-11 2005-03-24 Young-Ho Song Implantable or insertable medical devices containing phenolic compound for inhibition of restenosis
US20060057277A1 (en) * 2004-09-10 2006-03-16 Chappa Ralph A Methods, devices, and coatings for controlled active agent release
US7097850B2 (en) * 2002-06-18 2006-08-29 Surmodics, Inc. Bioactive agent release coating and controlled humidity method
US20070053835A1 (en) * 2002-08-19 2007-03-08 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
US7833584B2 (en) * 2005-04-13 2010-11-16 Dsm Ip Assets B.V. Aqueous vinyl coating compositions

Family Cites Families (161)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7213A (en) * 1850-03-26 Improvement in seed-planters
US32434A (en) * 1861-05-28 Improvement in animal-traps
CA1045977A (en) 1973-05-17 1979-01-09 Arthur D. Little Biodegradable, implantable drug delivery device, and process for preparing and using the same
US4391797A (en) 1977-01-05 1983-07-05 The Children's Hospital Medical Center Systems for the controlled release of macromolecules
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
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
US4973493A (en) * 1982-09-29 1990-11-27 Bio-Metric Systems, Inc. Method of improving the biocompatibility of solid surfaces
US5258041A (en) * 1982-09-29 1993-11-02 Bio-Metric Systems, Inc. Method of biomolecule attachment to hydrophobic surfaces
US5217492A (en) * 1982-09-29 1993-06-08 Bio-Metric Systems, Inc. Biomolecule attachment to hydrophobic 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
US6309669B1 (en) 1984-03-16 2001-10-30 The United States Of America As Represented By The Secretary Of The Army Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix
US6447796B1 (en) 1994-05-16 2002-09-10 The United States Of America As Represented By The Secretary Of The Army Sustained release hydrophobic bioactive PLGA microspheres
US4826759A (en) * 1984-10-04 1989-05-02 Bio-Metric Systems, Inc. Field assay for ligands
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
US4893623A (en) 1986-12-09 1990-01-16 Advanced Surgical Intervention, Inc. Method and apparatus for treating hypertrophy of the prostate gland
EP0281482A1 (en) 1987-03-06 1988-09-07 Research Triangle Institute Polymer blends for selective biodegradability
US5114719A (en) * 1987-04-29 1992-05-19 Sabel Bernhard A Extended drug delivery of small, water-soluble molecules
NL8701337A (en) 1987-06-09 1989-01-02 Sentron V O F A substrate provided with a blood-compatible surface produced by coupling to the surface of a physiologically active substance with inhibiting effect on the formation of blood clots, and / or capable of breaking down blood clots formed, as well as method for the production of the substrate.
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
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
US5024742A (en) 1988-02-24 1991-06-18 Cedars-Sinai Medical Center Method of crosslinking amino acid containing polymers using photoactivatable chemical crosslinkers
US5660692A (en) 1988-02-24 1997-08-26 Cedars-Sinai Medical Center Method of crosslinking amino acid-containing polymers using photoactivatable chemical crosslinkers
US5474783A (en) 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
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
DE69029735T2 (en) * 1989-09-15 1997-07-31 Chiron Vision Corp Synthetic material, which promotes the addition, the growth and attachment of epithelial cells, prosthetic device for subepithelial implantation and treated lens
US5525348A (en) * 1989-11-02 1996-06-11 Sts Biopolymers, Inc. Coating compositions comprising pharmaceutical agents
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
US5202352A (en) 1990-08-08 1993-04-13 Takeda Chemical Industries, Ltd. Intravascular embolizing agent containing angiogenesis-inhibiting substance
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
US5221698A (en) 1991-06-27 1993-06-22 The Regents Of The University Of Michigan Bioactive composition
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
US5270047A (en) 1991-11-21 1993-12-14 Kauffman Raymond F Local delivery of dipyridamole for the treatment of proliferative diseases
US5273760A (en) * 1991-12-24 1993-12-28 Euroceltigue, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5681585A (en) * 1991-12-24 1997-10-28 Euro-Celtique, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
CA2086642C (en) 1992-01-09 2004-06-15 Randall E. Morris Method of treating hyperproliferative vascular disease
DE69328523T2 (en) * 1992-02-13 2000-09-21 Surmodics Inc Immobilization of a chemical species in a networked matrix
CA2094858C (en) 1992-04-28 2004-06-15 Robert D. Mitchell Method of treating hyperproliferative vascular disease
US5248732A (en) 1992-06-01 1993-09-28 Enichem S.P.A. Blends of polyetherimides, aromatic alkyl methacrylates and polycarbonates
US5578075B1 (en) 1992-11-04 2000-02-08 Daynke Res Inc Minimally invasive bioactivated endoprosthesis for vessel repair
US5449382A (en) * 1992-11-04 1995-09-12 Dayton; Michael P. Minimally invasive bioactivated endoprosthesis for vessel repair
US5414075A (en) * 1992-11-06 1995-05-09 Bsi Corporation Restrained multifunctional reagent for surface modification
US5342348A (en) * 1992-12-04 1994-08-30 Kaplan Aaron V Method and device for treating and enlarging body lumens
EP0604022A1 (en) 1992-12-22 1994-06-29 Advanced Cardiovascular Systems, Inc. Multilayered biodegradable stent and method for its manufacture
US5419760A (en) * 1993-01-08 1995-05-30 Pdt Systems, Inc. Medicament dispensing stent for prevention of restenosis of a blood vessel
EP2263673A1 (en) 1993-07-01 2010-12-22 Euro-Celtique S.A. Opioid formulations having extended controlled release
JPH0717851A (en) * 1993-07-02 1995-01-20 Teijin Ltd Drug-containing salve using (meth)acrylic ester-based sticking agent
JPH0753835A (en) * 1993-08-10 1995-02-28 Takeda Chem Ind Ltd Core polymer and core-shell polymer containing active component and production thereof
US5443505A (en) * 1993-11-15 1995-08-22 Oculex Pharmaceuticals, Inc. Biocompatible ocular implants
US5849843A (en) 1993-11-16 1998-12-15 Baxter International Inc. Polymeric compositions for medical packaging and devices
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
US5981298A (en) * 1995-12-13 1999-11-09 Surmodics, Inc. Immunoassay device and method
US5637113A (en) * 1994-12-13 1997-06-10 Advanced Cardiovascular Systems, Inc. Polymer film for wrapping a stent structure
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
US20020091433A1 (en) 1995-04-19 2002-07-11 Ni Ding Drug release coated stent
US6120536A (en) * 1995-04-19 2000-09-19 Schneider (Usa) Inc. Medical devices with long term non-thrombogenic coatings
CA2178541C (en) * 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
US5783502A (en) * 1995-06-07 1998-07-21 Bsi Corporation Virus inactivating coatings
US5840059A (en) 1995-06-07 1998-11-24 Cardiogenesis Corporation Therapeutic and diagnostic agent delivery
US6774278B1 (en) 1995-06-07 2004-08-10 Cook Incorporated 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
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
JP3985907B2 (en) * 1996-01-18 2007-10-03 旭化成ケミカルズ株式会社 Method for producing a film-coated granules
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
US5942555A (en) * 1996-03-21 1999-08-24 Surmodics, Inc. Photoactivatable chain transfer agents and semi-telechelic photoactivatable polymers prepared therefrom
US20030094736A1 (en) 1996-05-03 2003-05-22 Chuan Qin Method of surface modifying a medical tubing
US5951586A (en) * 1996-05-15 1999-09-14 Medtronic, Inc. Intraluminal stent
US6143037A (en) * 1996-06-12 2000-11-07 The Regents Of The University Of Michigan Compositions and methods for coating medical devices
EP0842657A1 (en) 1996-11-19 1998-05-20 OctoPlus B.V. Microspheres for controlled release and processes to prepare these microspheres
US20030157187A1 (en) 1996-12-02 2003-08-21 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating or preventing inflammatory diseases
US5980972A (en) * 1996-12-20 1999-11-09 Schneider (Usa) Inc Method of applying drug-release coatings
FR2757528A1 (en) 1996-12-20 1998-06-26 Dow Corning Interpenetrating polymer network used e.g. for reinforcing agents in silicone rubbers
US5997517A (en) 1997-01-27 1999-12-07 Sts Biopolymers, Inc. Bonding layers for medical device surface coatings
US5902475A (en) * 1997-04-08 1999-05-11 Interventional Technologies, Inc. Method for manufacturing a stent
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
US20010029351A1 (en) * 1998-04-16 2001-10-11 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
US6344055B1 (en) * 1997-05-14 2002-02-05 Novo Rps Ulc Method for production of an expandable stent
US6077916A (en) 1997-06-04 2000-06-20 The Penn State Research Foundation Biodegradable mixtures of polyphoshazene and other polymers
US6110483A (en) * 1997-06-23 2000-08-29 Sts Biopolymers, Inc. Adherent, flexible hydrogel and medicated coatings
US5899935A (en) * 1997-08-04 1999-05-04 Schneider (Usa) Inc. Balloon expandable braided stent with restraint
US6121027A (en) * 1997-08-15 2000-09-19 Surmodics, Inc. Polybifunctional reagent having a polymeric backbone and photoreactive moieties and bioactive groups
US6884721B2 (en) 1997-12-25 2005-04-26 Shin-Etsu Handotai Co., Ltd. Silicon wafer storage water and silicon wafer storage method
US6221425B1 (en) * 1998-01-30 2001-04-24 Advanced Cardiovascular Systems, Inc. Lubricious hydrophilic coating for an intracorporeal medical device
US6007833A (en) * 1998-03-19 1999-12-28 Surmodics, Inc. Crosslinkable macromers bearing initiator groups
ES2212821T3 (en) 1998-03-26 2004-08-01 Biomat B.V. Endovascular stents with polymeric coating.
US8303609B2 (en) 2000-09-29 2012-11-06 Cordis Corporation Coated medical devices
US20020111590A1 (en) 2000-09-29 2002-08-15 Davila Luis A. Medical devices, drug coatings and methods for maintaining the drug coatings thereon
US7261735B2 (en) 2001-05-07 2007-08-28 Cordis Corporation Local drug delivery devices and methods for maintaining the drug coatings thereon
US20020051730A1 (en) * 2000-09-29 2002-05-02 Stanko Bodnar Coated medical devices and sterilization thereof
US6074660A (en) 1998-04-20 2000-06-13 Ethicon, Inc. Absorbable polyoxaesters containing amines and/ or amido groups
US20020188037A1 (en) * 1999-04-15 2002-12-12 Chudzik Stephen J. Method and system for providing bioactive agent release coating
US20020055710A1 (en) 1998-04-30 2002-05-09 Ronald J. Tuch Medical device for delivering a therapeutic agent and method of preparation
US6254634B1 (en) 1998-06-10 2001-07-03 Surmodics, Inc. Coating compositions
US6153252A (en) * 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
US6335029B1 (en) 1998-08-28 2002-01-01 Scimed Life Systems, Inc. Polymeric coatings for controlled delivery of active agents
US6120847A (en) * 1999-01-08 2000-09-19 Scimed Life Systems, Inc. Surface treatment method for stent coating
US6395029B1 (en) 1999-01-19 2002-05-28 The Children's Hospital Of Philadelphia Sustained delivery of polyionic bioactive agents
US6565872B2 (en) 1999-02-16 2003-05-20 Xiao Yu Wu Polymeric system for drug delivery and solute separation
US6156373A (en) * 1999-05-03 2000-12-05 Scimed Life Systems, Inc. Medical device coating methods and devices
US6325807B1 (en) 1999-06-11 2001-12-04 Scimed Life Systems, Inc. Variable strength sheath
US6258121B1 (en) 1999-07-02 2001-07-10 Scimed Life Systems, Inc. Stent coating
US6596296B1 (en) 1999-08-06 2003-07-22 Board Of Regents, The University Of Texas System Drug releasing biodegradable fiber implant
US6790228B2 (en) * 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US6908624B2 (en) 1999-12-23 2005-06-21 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US6331313B1 (en) * 1999-10-22 2001-12-18 Oculex Pharmaceticals, Inc. Controlled-release biocompatible ocular drug delivery implant devices and methods
US6800073B2 (en) 1999-10-28 2004-10-05 Scimed Life Systems, Inc. Biocompatible pharmaceutical articles
US6251136B1 (en) * 1999-12-08 2001-06-26 Advanced Cardiovascular Systems, Inc. Method of layering a three-coated stent using pharmacological and polymeric agents
US6776796B2 (en) 2000-05-12 2004-08-17 Cordis Corportation Antiinflammatory drug and delivery device
JP4268741B2 (en) * 2000-07-03 2009-05-27 株式会社ニデック Soft intraocular lens
US6451373B1 (en) 2000-08-04 2002-09-17 Advanced Cardiovascular Systems, Inc. Method of forming a therapeutic coating onto a surface of an implantable prosthesis
US6746773B2 (en) * 2000-09-29 2004-06-08 Ethicon, Inc. Coatings for medical devices
US6824559B2 (en) 2000-12-22 2004-11-30 Advanced Cardiovascular Systems, Inc. Ethylene-carboxyl copolymers as drug delivery matrices
US7077859B2 (en) 2000-12-22 2006-07-18 Avantec Vascular Corporation Apparatus and methods for variably controlled substance delivery from implanted prostheses
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
US6780424B2 (en) 2001-03-30 2004-08-24 Charles David Claude Controlled morphologies in polymer drug for release of drugs from polymer films
CA2747159A1 (en) 2001-05-07 2002-11-07 Queen's University At Kingston Biodegradable elastomer and method of preparing same
US6787179B2 (en) 2001-06-29 2004-09-07 Ethicon, Inc. Sterilization of bioactive coatings
US6497691B1 (en) 2001-08-24 2002-12-24 Polymer Group, Inc. Structurally durable, drapeable breathable barrier film compositions and articles
US20030158598A1 (en) 2001-09-17 2003-08-21 Control Delivery Systems, Inc. System for sustained-release delivery of anti-inflammatory agents from a coated medical device
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
US7585516B2 (en) 2001-11-12 2009-09-08 Advanced Cardiovascular Systems, Inc. Coatings for drug delivery devices
WO2003079936A9 (en) 2002-03-18 2004-02-26 Medtronic Ave Inc Medical devices for delivering anti-proliferative compositions to anatomical sites at risk for restenosis
US6773888B2 (en) 2002-04-08 2004-08-10 Affymetrix, Inc. Photoactivatable silane compounds and methods for their synthesis and use
US20030203000A1 (en) 2002-04-24 2003-10-30 Schwarz Marlene C. Modulation of therapeutic agent release from a polymeric carrier using solvent-based techniques
US20030232087A1 (en) 2002-06-18 2003-12-18 Lawin Laurie R. Bioactive agent release coating with aromatic poly(meth)acrylates
US20030236513A1 (en) 2002-06-19 2003-12-25 Scimed Life Systems, Inc. Implantable or insertable medical devices for controlled delivery of a therapeutic agent
US7939094B2 (en) 2002-06-19 2011-05-10 Boston Scientific Scimed, Inc. Multiphase polymeric drug release region
US8211455B2 (en) 2002-06-19 2012-07-03 Boston Scientific Scimed, Inc. Implantable or insertable medical devices for controlled delivery of a therapeutic agent
JP4723244B2 (en) * 2002-07-19 2011-07-13 インスティチュート オブ マテリアルズ リサーチ アンド エンジニアリング Biodegradable triblock copolymer, a method of synthesis, and hydrogels and biological materials made therefrom
DE60316579D1 (en) 2002-08-13 2007-11-08 Medtronic Inc A system for delivery of drugs with a hydrophobic cellulose derivative
EP1530489A1 (en) 2002-08-13 2005-05-18 Medtronic, Inc. Active agent delivery system including a hydrophilic polymer, medical device, and method
US20040086569A1 (en) 2002-08-13 2004-05-06 Medtronic, Inc. Active agent delivery systems, medical devices, and methods
CA2500067A1 (en) 2002-09-26 2004-04-08 Endovascular Devices, Inc. Apparatus and method for delivery of mitomycin through an eluting biocompatible implantable medical device
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
WO2004075943A1 (en) 2003-02-28 2004-09-10 Biointeractions Ltd. Polymeric network system for medical devices and methods of use
US8313759B2 (en) 2003-03-06 2012-11-20 Boston Scientific Scimed, Inc. Implantable or insertable medical devices containing miscible polymer blends for controlled delivery of a therapeutic agent
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
US20040230298A1 (en) 2003-04-25 2004-11-18 Medtronic Vascular, Inc. Drug-polymer coated stent with polysulfone and styrenic block copolymer
US7279174B2 (en) 2003-05-08 2007-10-09 Advanced Cardiovascular Systems, Inc. Stent coatings comprising hydrophilic additives
US7186789B2 (en) 2003-06-11 2007-03-06 Advanced Cardiovascular Systems, Inc. Bioabsorbable, biobeneficial polyester polymers for use in drug eluting stent coatings
WO2004112746A1 (en) * 2003-06-26 2004-12-29 Korea Research Institute Of Chemical Technology Controlled release-drug delivery system for oral administration
WO2006063021A3 (en) 2004-12-07 2006-10-12 Ralph A Chappa Coatngs with crystallized active agents (s)

Patent Citations (101)

* 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
US5741551A (en) * 1982-09-29 1998-04-21 Bsi Corporation Preparation of polymeric surfaces
US4722906A (en) * 1982-09-29 1988-02-02 Bio-Metric Systems, Inc. Binding reagents and methods
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
US5624975A (en) * 1985-11-04 1997-04-29 Biocompatibles Limited Plastics
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
US4994071A (en) * 1989-05-22 1991-02-19 Cordis Corporation Bifurcating stent apparatus and method
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
US5301559A (en) * 1991-09-26 1994-04-12 Mazda Motor Corporation Torque detecting system
US5591227A (en) * 1992-03-19 1997-01-07 Medtronic, Inc. Drug eluting stent
US20030039675A1 (en) * 1993-01-28 2003-02-27 Angiotech Pharmaceuticals, Inc. 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
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
US20030004209A1 (en) * 1993-07-19 2003-01-02 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
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
US6214370B1 (en) * 1995-02-10 2001-04-10 Medtronic, Inc. Method and device for administering analgesics
US5618552A (en) * 1995-03-06 1997-04-08 Ethicon, Inc. Absorbable polyoxaesters
US5607687A (en) * 1995-03-06 1997-03-04 Ethicon, Inc. Polymer blends containing absorbable polyoxaesters
US5859150A (en) * 1995-03-06 1999-01-12 Ethicon, Inc. Prepolymers of 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
US20020004101A1 (en) * 1995-04-19 2002-01-10 Schneider (Usa) Inc. Drug coating with topcoat
US20020032477A1 (en) * 1995-04-19 2002-03-14 Michael N. Helmus Drug release coated stent
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
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
US5722424A (en) * 1995-09-29 1998-03-03 Target Therapeutics, Inc. Multi-coating stainless steel guidewire
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
US5895407A (en) * 1996-08-06 1999-04-20 Jayaraman; Swaminathan Microporous covered stents and method of coating
US6689803B2 (en) * 1996-12-02 2004-02-10 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating surgical adhesions
US20020013298A1 (en) * 1996-12-02 2002-01-31 William L. Hunter Compositions and methods for treating or preventing inflammatory diseases
US6042875A (en) * 1997-04-30 2000-03-28 Schneider (Usa) Inc. Drug-releasing coatings for medical devices
US5879697A (en) * 1997-04-30 1999-03-09 Schneider Usa Inc Drug-releasing coatings for medical devices
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
US6348152B1 (en) * 1997-10-09 2002-02-19 Teijin Limited Medical material containing fluorinated polysulfone having excellent antithrombotic activity
US20050042293A1 (en) * 1997-10-29 2005-02-24 The University Of British Columbia Polymeric systems for drug delivery and uses thereof
US20020032434A1 (en) * 1998-04-27 2002-03-14 Chudzik Stephen J. Bioactive agent release coating
US20060067968A1 (en) * 1998-04-27 2006-03-30 Surmodics, Inc. Bioactive agent release coating
US6214901B1 (en) * 1998-04-27 2001-04-10 Surmodics, Inc. Bioactive agent release coating
US7008667B2 (en) * 1998-04-27 2006-03-07 Surmodics, Inc. Bioactive agent release coating
US20030031780A1 (en) * 1998-04-27 2003-02-13 Chudzik Stephen J. Bioactive agent release coating
US6344035B1 (en) * 1998-04-27 2002-02-05 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
US20040059408A1 (en) * 1999-01-12 2004-03-25 Quanam Medical Corporation Polymer compositions for intraluminal stent
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
US6537312B2 (en) * 1999-12-22 2003-03-25 Ethicon, Inc. Biodegradable stent
US20030045924A1 (en) * 1999-12-22 2003-03-06 Arindam Datta Biodegradable stent
US20020026236A1 (en) * 2000-01-25 2002-02-28 Helmus Michael N. 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
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
US20020007215A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US6545097B2 (en) * 2000-12-12 2003-04-08 Scimed Life Systems, Inc. Drug delivery compositions and medical devices containing block copolymer
US6517520B2 (en) * 2000-12-21 2003-02-11 Ethicon Endo Surgery, Inc. Peripherally inserted catheter with flushable guide-tube
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
US20030039689A1 (en) * 2001-04-26 2003-02-27 Jianbing Chen Polymer-based, sustained release drug delivery system
US20040022853A1 (en) * 2001-04-26 2004-02-05 Control Delivery Systems, Inc. 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
US20040058056A1 (en) * 2001-07-06 2004-03-25 Shigemasa Osaki Drug diffusion coatings, applications and methods
US20030065377A1 (en) * 2001-09-28 2003-04-03 Davila Luis A. Coated medical devices
US20040030380A1 (en) * 2002-04-24 2004-02-12 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7097850B2 (en) * 2002-06-18 2006-08-29 Surmodics, Inc. Bioactive agent release coating and controlled humidity method
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
US20070053835A1 (en) * 2002-08-19 2007-03-08 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
US20040054104A1 (en) * 2002-09-05 2004-03-18 Pacetti Stephen D. Coatings for drug delivery devices comprising modified poly(ethylene-co-vinyl alcohol)
US20060013835A1 (en) * 2003-05-02 2006-01-19 Anderson Aron B Controlled release bioactive agent delivery device
US20050019371A1 (en) * 2003-05-02 2005-01-27 Anderson Aron B. Controlled release bioactive agent delivery device
US20050025830A1 (en) * 2003-06-23 2005-02-03 Technische Universiteit Eindhoven Drug delivery device comprising an active compound and method for releasing an active compound from a drug delivery device
US20050033417A1 (en) * 2003-07-31 2005-02-10 John Borges Coating for controlled release of a therapeutic agent
US20050025802A1 (en) * 2003-07-31 2005-02-03 Richard Robert E. Implantable or insertable medical devices containing acrylic copolymer for controlled delivery of therapeutic agent
US20050037047A1 (en) * 2003-08-11 2005-02-17 Young-Ho Song Medical devices comprising spray dried microparticles
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
US20050064005A1 (en) * 2003-08-13 2005-03-24 Dinh Thomas Q. Active agent delivery systems including a miscible polymer blend, medical devices, and methods
US20050064038A1 (en) * 2003-08-13 2005-03-24 Dinh Thomas Q. Active agent delivery systems including a single layer of a miscible polymer blend, medical devices, and methods
US20050037052A1 (en) * 2003-08-13 2005-02-17 Medtronic Vascular, Inc. Stent coating with gradient porosity
US20060057277A1 (en) * 2004-09-10 2006-03-16 Chappa Ralph A Methods, devices, and coatings for controlled active agent release
US7833584B2 (en) * 2005-04-13 2010-11-16 Dsm Ip Assets B.V. Aqueous vinyl coating compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chien, "Novel Drug Delivery Systems", Informa Health Care, Chapter 1, page 29, 1991 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013123206A1 (en) * 2012-02-14 2013-08-22 Allegiance Corporation Antimicrobial elastomeric articles
US9386772B2 (en) 2012-02-14 2016-07-12 Allegiance Corporation Antimicrobial elastomeric articles

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