EP1868666A1 - Compositions de revetements bioactifs pour dispositifs medicaux - Google Patents

Compositions de revetements bioactifs pour dispositifs medicaux

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Publication number
EP1868666A1
EP1868666A1 EP05812405A EP05812405A EP1868666A1 EP 1868666 A1 EP1868666 A1 EP 1868666A1 EP 05812405 A EP05812405 A EP 05812405A EP 05812405 A EP05812405 A EP 05812405A EP 1868666 A1 EP1868666 A1 EP 1868666A1
Authority
EP
European Patent Office
Prior art keywords
composition
bioactive agent
poly
coating
topcoat
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05812405A
Other languages
German (de)
English (en)
Inventor
David M. Dewitt
Michael J. Finley
Laurie R. Lawin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Surmodics Inc
Original Assignee
Surmodics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/099,911 external-priority patent/US20050220841A1/en
Application filed by Surmodics Inc filed Critical Surmodics Inc
Publication of EP1868666A1 publication Critical patent/EP1868666A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials

Definitions

  • the present invention relates to a method of treating implantable medical devices with coating compositions to provide for the controlled release of bioactive (e.g., pharmaceutical) agents from the surface of the devices under physiological conditions.
  • bioactive e.g., pharmaceutical
  • the invention relates to the coating compositions, per se.
  • the invention relates to devices or surfaces coated with such compositions.
  • the present invention relates to the local administration of bioactive agents for the prevention and treatment of diseases, such as vascular and ocular diseases.
  • PTCA percutaneous transluminal coronary angioplasty
  • Many individuals suffer from circulatory disease caused by a progressive blockage of the blood vessels, which often leads to hypertension, ischemic injury, stroke, or myocardial infarction.
  • Percutaneous transluminal coronary angioplasty is a medical procedure performed to increase blood flow through a damaged artery and is now the predominant treatment for coronary vessel stenosis. The increasing use of this procedure is attributable to its relatively high success rate and its minimal invasiveness compared with coronary bypass surgery.
  • a limitation associated with PTCA is the abrupt closure of the vessel which can occur soon after angioplasty.
  • Insertion of small spring-like medical devices called stents into such damaged vessels has proved to be a better approach to keep the vessels open as compared to systemic pharmacologic therapy.
  • metal or polymeric devices e.g., stents, catheters
  • stents, catheters after placement in the body, can give rise to numerous physiological complications. Some of these complications include: increased risk of infection; initiation of a foreign body response resulting in inflammation and fibrous encapsulation; and initiation of a detrimental wound healing response resulting in hyperplasia and restenosis.
  • bioactive agents in the vicinity of the implant. By doing so, some of the harmful effects associated with the implantation of medical devices can be diminished.
  • antibiotics can be released from the surface of the device to minimize the possibility of infection, and antiproliferative drugs can be released to inhibit hyperplasia.
  • Another benefit to the local release of bioactive agents is the avoidance of toxic concentrations of drugs encountered when given systemically at sufficiently high doses to achieve therapeutic concentrations at the site where they are needed.
  • Implantable medical devices capable of delivering medicinal agents from hydrophobic polymer coatings have been described. See, for instance, U.S. Patent No. 6,214,901; U.S. Patent No. 6,344,035; U.S. Publication No. 2002-0032434; U.S. Publication No. 2002-0188037; U.S. Publication No. 2003-0031780; U.S. Publication No. 2003-0232087; U.S. Publication No. 2003-0232122; PCT Publication No. WO 99/55396; PCT Publication No. WO 03/105920; PCT Publication No. WO 03/105918; PCT Publication No.
  • WO 03/105919 which collectively disclose, inter alia, coating compositions having a bioactive agent in combination with a polymer component such as polyalkyl(meth)acrylate or aromatic poly(meth)acrylate polymer and another polymer component such as poly(ethylene-co-vinyl acetate) for use in coating device surfaces to control and/or improve their ability to release bioactive agents in aqueous systems.
  • the present invention provides a coating composition, and related methods for preparing and using the coating composition to coat a surface with a bioactive agent, for instance to coat the surface of an implantable medical device in a manner that permits the surface to release the bioactive agent over time when implanted in vivo.
  • the coating composition of this invention comprises one or more bioactive agents in combination with a plurality of polymers, including: (a) a first polymer component comprising a polymer selected from the group consisting of (i) ethylene copolymers with other alkylenes, (ii) polybutenes, (iii) aromatic group-containing copolymers, (iv) epichlorohydrin-containing polymers, (v) poly(alkylene-co-alkyl(meth)acrylates), and (vi) diolefm-derived, non-aromatic polymers and copolymers; and (b) a second polymer component comprising one or more polymers selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic (meth)acrylates), where "(meth)" will be understood by those skilled in the art to include such molecules in either the acrylic and/or methacrylic form (corresponding to the acrylates and/or methacrylates, respectively).
  • a coating composition of this invention may be provided in the form of a true solution by the use of one or more solvents.
  • solvents are not only capable of dissolving the polymers and bioactive agent in solution, as compared to dispersion or emulsion, but they are also sufficiently volatile to permit the composition to be effectively applied to a surface (e.g., as by spraying) and quickly removed (e.g., as by drying) to provide a stable and desirable coated composition.
  • the coated composition is itself homogeneous, with the first and second polymers effectively serving as cosolvents for each other, and bioactive agent substantially equally sequestered within them both.
  • the ability to form a true solution using the claimed polymer combinations is desirable when considering the inclusion of potentially significant amounts of bioactive agent with the polymer blend.
  • the coating composition is not only in the form of a true solution, but one in which bioactive agent is present at saturated or supersaturated levels. Without intending to be bound by theory, it appears that it is by virtue of the ability to achieve such solutions, that release of the bioactive agent from the coated composition is best accomplished and facilitated. In turn, it appears that the release of bioactive agent from such a system is due, at least in part, to its inherent instability within the coated composition itself, coupled with its physical/chemical preference for surrounding tissues and fluids. In turn, those skilled in the art will appreciate the manner in which the various ingredients and amounts in a composition of this invention can be adjusted to provide desired release kinetics and for any particular bioactive agent, solvent and polymer combination.
  • compositions of this invention meets or exceeds further criteria in its ability to be sterilized, stored, and delivered to a surface in a manner that preserves its desired characteristics, yet using conventional delivery means, such as spraying.
  • delivery involves spraying the composition onto a device surface in a manner that avoids or minimizes phase separation of the polymer components.
  • a composition of this invention permits polymer ratios to be varied in a manner that provides not only an optimal combination of such attributes as biocompatibility, durability, and bioactive agent release kinetics, but also, in some embodiments, provides a coated composition that is homogeneous, and hence substantially optically clear upon microscopic examination. Even more surprisingly, in some embodiments, the compositions of this invention will provide these and other features, with or without optional pretreatment of a metallic surface. The ability to achieve or exceed any of these criteria, let alone most if not all of them, was not expected.
  • compositions of the present invention provide properties that are comparable or better than those obtained with previous polymer blend compositions. This, in turn, provides a variety of new and further opportunities, including with respect to both the type and concentration of bioactive agents that can be coated, as well as the variety of medical devices, and surfaces, themselves.
  • the present invention also provides a combination that includes a medical device coated with a composition of this invention, as well as a method of preparing and using such a combination.
  • Figure 1 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in Example 1.
  • Figure 2 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Figure 3 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Figure 4 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Example 4 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Figure 6 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in Example 6.
  • Figure 7 depicts a graph illustrating the stress/strain measurements of first polymer components used in coating compositions according to the present invention, as described in Example 8.
  • Figure 8 depicts a 100 micron wide and 10 micron deep Raman image taken by measuring the Raman intensity at 2900 cm "1 of a coating composition according to the present invention.
  • Figure 9 depicts a 100 micron wide and 10 micron deep Raman image taken by measuring the Raman intensity at 1630 cm "1 for the same region of stent coating shown in Figure 9.
  • Figure 10 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Figure 1OA depicts a bar chart illustrating the durability profiles for coating compositions according to the present invention applied to stents, as described in Example 10.
  • Figure 11 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Example 11 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Figure 13 depicts a scanning electron microscope image a coated stent including a coating composition according to the present invention after conventional crimping and balloon expansion procedures.
  • Figure 14 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Example 15 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions according to the present invention applied to stents, as described in
  • Figure 16 depicts a graph illustrating the cumulative bioactive agent release profiles for coating compositions and topcoats according to the present invention applied to stents, as described in Example 16.
  • Figure 17 shows a medical device as described in Example 17.
  • Figure 18 shows a medical device as described in Example 17.
  • Figure 19A shows a plot of data as described in Example 17.
  • Figure 19B shows the plot of Figure 19A with tilt and curvature correction.
  • Figure 2OA shows a surface plot of a roughness test as described in Example 17.
  • Figure 2OB shows a 3D representation of Figure 2OA.
  • Figure 21 A shows a surface plot of a roughness test as described in Example 17.
  • Figure 2 IB shows a 3D representation of Figure 2 IA.
  • suitable first polymers for use in a composition of this invention provide an optimal combination of such properties as glass transition temperature (T g ) and diffusion constant for the particular bioactive agent of choice.
  • T g glass transition temperature
  • T m melting temperature
  • T g is an important parameter of a given polymer (including copolymer), and particularly amorphous polymers, that can be used to characterize its properties over a wide temperature range.
  • a polymer is typically brittle at temperatures below its T g , and flexible at temperatures above. Both T m and T g can be affected by such things as polymer structure and backbone flexibility, molecular weight, attractive forces, and pressure.
  • Tg can be measured by any suitable technique, e.g., dilatometry, refractive index, differential scanning calorimetry, dynamic mechanical measurement, and dielectric measurement.
  • Various second polymers e.g., poly (n-butyl methacrylate) of the present composition generally provide a T g in the range of room to body temperature (e.g., from about 20 0 C to about 40 0 C), and hence tend to be somewhat stiffer polymers, in turn, providing a slower diffusion constant for a number of bioactive agents.
  • Applicants have discovered the manner in which certain new polymers can be used as a first polymer component, to essentially balance, or temper the desired properties of the second polymer.
  • Such first polymers will generally provide a lower glass transition temperature (e.g., below room temperature, and in some embodiments in the range of about 0 0 C or less), together with a relatively high diffusion constant for the bioactive agent.
  • embodiments of the first polymer of this invention will generally provide an optimal combination of glass transition temperature (e.g., at or lower than that of the second polymer), compatibility with the bioactive agent of choice, acceptable solubility in the solvents of choice, as well as commercial availability and cost.
  • coating composition will refer to one or more vehicles (e.g., solutions, mixtures, emulsions, dispersions, blends, etc.) used to effectively coat a surface with bioactive agent, first polymer component and/or second polymer component, either individually or in any suitable combination.
  • vehicles e.g., solutions, mixtures, emulsions, dispersions, blends, etc.
  • coated composition will refer to the effective combination, upon the surface of a device, of bioactive agent, first polymer component and second polymer component, whether formed as the result of one or more coating vehicles or in one or more layers and/or steps.
  • coating will refer to the effective combination of bioactive agent, first polymer component and second polymer component, independent of the device surface, and whether formed as the result of one or more coating vehicles or in one or more layers.
  • weight average molecular weight As used herein "weight average molecular weight” or M w , is an absolute method of measuring molecular weight and is particularly useful for measuring the molecular weight of a polymer preparation.
  • the weight average molecular weight (M w ) can be defined by the following formula:
  • N represents the number of moles of a polymer in the sample with a mass of M
  • ⁇ is the sum of all N 1 M, (species) in a preparation.
  • the M w can be measured using common techniques, such as light scattering or ultracentrifugation. Discussion of M w and other terms used to define the molecular weight of polymer preparations can be found in, for example, Allcock, H. R. and Lampe, F. W., Contemporary Polymer Chemistry; pg 271 (1990).
  • a resultant composition can be coated using a plurality of individual steps or layers, including for instance, an initial layer having only bioactive agent (or bioactive agent with one or both of the polymer components), over which are coated one or more additional layers containing suitable combinations of bioactive agent, first polymer component and/or second polymer component, the combined result of which is to provide a coated composition of the invention.
  • 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 surface to which the composition is applied can itself be pretreated in a manner sufficient to improve attachment of the composition to the underlying (e.g., metallic) surface.
  • pretreatments include the use of compositions such as Parylene TM coatings, as described herein. Additional examples of such pretreatments include silane coupling agents, photografted polymers, epoxy primers, polycarboxylate resins, and physical roughening of the surface. It is further noted that the pretreatment compositions may be used in combination with each other or may be applied in separate layers to form a pretreatment coating on the surface of the medical device.
  • the release kinetics of the bioactive agent in vivo are thought to generally include both a short term (“burst”) release component, within the order of minutes to hours after implantation, and a longer term release component, which can range from on the order of hours to days or even months or years of useful release.
  • burst short term
  • the ability to coat a device in the manner of the present invention provides greater latitude in the composition of various coating layers, e.g., permitting more or less of the second polymer component (i.e., poly(alkyl (meth)acrylate) and/or poly(aromatic (meth)acrylate)) to be used in coating compositions used to form different layers (e.g., as a topcoat layer).
  • the second polymer component i.e., poly(alkyl (meth)acrylate) and/or poly(aromatic (meth)acrylate)
  • 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.
  • 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.
  • this approach permits the release rate to be adjusted and controlled by simply adjusting the relative concentrations of the polymers in the coating mixture.
  • Some embodiments of the invention include a method of coating a device comprising the step of applying the composition to the device surface under conditions of controlled relative humidity (at a given temperature), for instance, under conditions of increased or decreased relative humidity as compared to ambient humidity.
  • Humidity can be "controlled” in any suitable manner, including at the time of preparing and/or using (as by applying) the composition, for instance, by coating the surface in a confined chamber or area adapted to provide a relative humidity different than ambient conditions, and/or by adjusting the water content of the coating or coated composition itself.
  • the coating composition of this invention includes a mixture of two or more polymers having complementary physical characteristics, and a bioactive agent or agents applicable to the surface of an implantable medical device.
  • the device can be of any suitable type or configuration, and in some embodiments, is one that undergoes flexion and/or expansion upon implantation or use, as in the manner of a stent or catheter.
  • the applied coating composition is cured (e.g., by solvent evaporation) to provide a tenacious and flexible bioactive-releasing composition on the surface of the medical device.
  • Such coating compositions are particularly well suited for devices that are themselves sufficiently small, or have portions that are sufficiently small (as in the struts of an expandable stent or the twists of an ocular coil), to permit the coated composition to form a contiguous, e.g., circumferential, coating, thereby further improving the ability of the coating to remain intact (e.g., avoid delamination).
  • 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.
  • 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 coating composition may also be utilized with medical devices that have minimal or do not undergo flexion and/or expansion.
  • the structure and composition of the underlying device can be of any suitable, and medically acceptable, design and can be made of any suitable material that is compatible with the coating itself.
  • the natural or pretreated surface of the medical device is provided with a coating containing one or more bioactive agents.
  • a first polymer component of this invention provides an optimal combination of similar properties, and particularly when used in admixture with the second polymer component.
  • a first polymer is a polymer selected from the group consisting of (i) ethylene copolymers with other alkylenes, (ii) polybutenes, (iii) aromatic group-containing copolymers, (iv) epichlorohydrin-containing polymers (v) poly(alkylene- co-alkyl(meth)acrylates), and (vi) diolefin-derived, non-aromatic polymers and copolymers.
  • a first polymer component may be selected from one or more ethylene copolymers with other alkylenes.
  • Various first polymers for use in this invention comprise ethylene copolymers with other alkylenes, which in turn, can include straight chain and branched alkylenes, as well as substituted or unsubstituted alkylenes. Examples include copolymers prepared from alkylenes that comprise from 3 to 8 branched or linear carbon atoms, inclusive, in various embodiments, alkylene groups that comprise from 3 to 4 branched or linear carbon atoms, inclusive, and in some embodiments, the alkylene group contains 3 carbon atoms (e.g., propylene).
  • the other alkylene is a straight chain alkylene (e.g., 1 -alkylene).
  • copolymers of this type can comprise from about 20% to about 90% (based on moles) of ethylene, and in some embodiments, from about 35% to about 80% (mole) of ethylene. Such copolymers will have a molecular weight of between about 30 kilodaltons to about 500 kilodaltons. Examples of such copolymers are selected from the group consisting of poly(ethylene-co-propylene), poly(ethylene-co-l-butene), polyethylene-co- 1 -butene-co- 1 -hexene) and/or poly(ethylene-co- 1 -octene).
  • copolymers examples include poly(ethylene-co-propylene) random copolymers in which the copolymer contains from about 35% to about 65% (mole) of ethylene; and in some embodiments, from about 55% to about 65% (mole) ethylene, and the molecular weight of the copolymer is from about 50 kilodaltons to about 250 kilodaltons, in some embodiments from about 100 kilodaltons to about 200 kilodaltons.
  • Copolymers of this type can optionally be provided in the form of random terpolymers prepared by the polymerization of both ethylene and propylene with optionally one or more additional diene monomers, such as those selected from the group consisting of ethylidene norborane, dicyclopentadiene and/or hexadiene.
  • additional diene monomers such as those selected from the group consisting of ethylidene norborane, dicyclopentadiene and/or hexadiene.
  • Various terpolymers of this type can include up to about 5% (mole) of the third diene monomer .
  • suitable copolymers of this type are commercially available from sources such as Sigma-Aldrich and include the following products.
  • suitable copolymers of this type and their related descriptions may be found in the 2003- 2004 Aldrich Handbook of Fine Chemicals and Laboratory Equipment, the entire contents of which are incorporated by reference herein.
  • Examples of such copolymers include, but are not limited to poly(ethylene-co-propylene), poly(ethylene-co-l-butene), poly(ethylene- co-1-butene-co-l-hexene), poly(ethylene-co-l-octene) and poly(ethylene-co-propylene- co-5-methylene-2-norborene).
  • a first polymer component may be selected from one or more polybutenes.
  • Polybutenes suitable for use in the present invention include polymers derived by homopolymerizing or randomly interpolymerizing isobutylene, 1-butene and/or 2-butene.
  • the polybutene can be a homopolymer of any of the isomers or it can be a copolymer or a terpolymer of any of the monomers in any ratio.
  • the polybutene contains at least about 90% (wt) of isobutylene or 1 -butene, and in some embodiments, the polybutene contains at least about 90% (wt) of isobutylene.
  • the polybutene may contain non-interfering amounts of other ingredients or additives, for instance it can contain up to 1000 ppm of an antioxidant (e.g., 2,6-di-tert-butyl- methylphenol).
  • the polybutene has a molecular weight between about 100 kilodaltons and about 1,000 kilodaltons, in some embodiments, between about 150 kilodaltons and about 600 kilodaltons, and in some embodiments, between about 150 kilodaltons and about 250 kilodaltons. In other embodiments, the polybutene has a molecular weight between about 150 kilodaltons and about 1,000 kilodaltons, optionally, between about 200 kilodaltons and about 600 kilodaltons, and further optionally, between about 350 kilodaltons and about 500 kilodaltons.
  • Polybutenes having a molecular weight greater than about 600 kilodaltons, including greater than 1 ,000 kilodaltons are available but are expected to be more difficult to work with.
  • suitable copolymers of this type are commercially available from sources such as Sigma-Aldrich.
  • Additional alternative first polymers include aromatic group-containing copolymers, including random copolymers, block copolymers and graft copolymers.
  • the aromatic group is incorporated into the copolymer via the polymerization of styrene
  • the random copolymer is a copolymer derived from copolymerization of styrene monomer and one or more monomers selected from butadiene, isoprene, acrylonitrile, a Ci-C 4 alkyl (meth)acrylate (e.g., methyl methacrylate) and/or butene (e.g., isobutylene).
  • Useful block copolymers include copolymer containing (a) blocks of polystyrene, (b) blocks of a polyolefin selected from polybutadiene, polyisoprene and/or polybutene (e.g., polyisobutylene), and (c) optionally a third monomer (e.g., ethylene) copolymerized in the polyolefin block.
  • the aromatic group-containing copolymers may contain about 10% to about 50% (wt) of polymerized aromatic monomer and the molecular weight of the copolymer may be from about 50 kilodaltons to about 500 kilodaltons. In some embodiments, the molecular weight of the copolymer may be from about 300 kilodaltons to about 500 kilodaltons. In other embodiments, the molecular weight of the copolymer may be from about 100 kilodaltons to about 300 kilodaltons.
  • suitable copolymers of this type are commercially available from sources such as Sigma- Aldrich and include, but are not limited to, poly(styrene-co- butadiene) (random), polystyrene-block-polybutadiene, polystyrene-block-polybutadiene- block-polystyrene, polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene, polystyrene-block-polyisoprene-block-polystyrene, polystyrene-block-polyisobutylene- block-polystyrene, poly(styrene-co-acrylonitrile), poly(styrene-co-butadiene-co- acrylonitrile) and poly(styrene-co-butadiene-co-methyl methacrylate).
  • Additional alternative first polymers include epichlorohydrin homopolymers and poly(epichlorohydrin-co-alkylene oxide) copolymers.
  • the copolymerized alkylene oxide is ethylene oxide.
  • epichlorohydrin content of the epichlorohydrin-containing polymer is from about 30% to 100% (wt), and in some embodiments from about 50% to 100% (wt).
  • the epichlorohydrin-containing polymers have a Mw from about 100 kilodaltons to about 300 kilodaltons.
  • a first polymer component may be selected from one or more poly(alkylene-co-alkyl(meth)acrylates.
  • Various poly(alkylene-co-alkyl(meth)acrylates) include those copolymers in which the alkyl groups are either linear or branched, and substituted or unsubstituted with non-interfering groups or atoms.
  • such alkyl groups comprise from 1 to 8 carbon atoms, inclusive, and in some embodiments, from 1 to 4 carbon atoms, inclusive.
  • the alkyl group is methyl.
  • copolymers that include such alkyl groups comprising from about 15 % to about 80% (wt) of alkyl acrylate.
  • the alkyl group is methyl
  • the polymer may contain from about 20% to about 40% methyl acrylate, and in some embodiments from about 25 to about 30% methyl acrylate.
  • the alkyl group is ethyl
  • the polymer in some embodiments, contains from about 15% to about 40% ethyl acrylate
  • the alkyl group is butyl
  • the polymer in some embodiments, contains from about 20% to about 40% butyl acrylate.
  • the alkylene groups are selected from ethylene and/or propylene, and more in various embodiments, the alkylene group is ethylene.
  • the (meth)acrylate comprises an acrylate (i.e., no methyl substitution on the acrylate group).
  • Various copolymers provide a molecular weight (Mw) of about 50 kilodaltons to about 500 kilodaltons, and in some embodiments, Mw is 50 kilodaltons to about 200 kilodaltons.
  • Mw molecular weight
  • the glass transition temperature for these copolymers varies with ethylene content, alkyl length on the (meth)acrylate and whether the first copolymer is an acrylate or methacrylate. At higher ethylene content, the glass transition temperature tends to be lower, and closer to that of pure polyethylene (-120 0 C). A longer alkyl chain also lowers the glass transition temperature.
  • a methyl acrylate homopolymer has a glass transition temperature of about 1O 0 C while a butyl acrylate homopolymer has one of -54 0 C.
  • Copolymers such as poly(ethylene-co-methyl acrylate), poly(ethylene-co-butyl acrylate) and poly(ethylene-co-2-ethylhexyl acrylate) copolymers are available commercially from sources such as Atofina Chemicals, Inc., Philadelphia, PA, and can be prepared using methods available to those skilled in the respective art.
  • suitable polymers of this type are commercially available from sources such as Sigma-Aldrich and include, but are not limited to, poly(ethylene-co- methyl acrylate), poly(ethylene-co-ethyl acrylate), and poly(ethylene-co-butyl acrylate).
  • a butadiene polymer can include one or more butadiene monomer units which can be selected from the monomeric unit structures (a), (b), or (c):
  • An isoprene polymer can include one or more isoprene monomer units which can be selected from the monomeric unit structures (d), (e), (f) or (g):
  • the polymer is a homopolymer derived from diolefin monomers or is a copolymer of diolefin monomer with non-aromatic mono-olefin monomer, and optionally, the homopolymer or copolymer can be partially hydrogenated.
  • Such polymers can be selected from the group consisting of polybutadienes containing polymerized cis-, trans- and/or 1 ,2- monomer units, and in some embodiments, a mixture of all three co-polymerized monomer units, and polyisoprenes containing polymerized cis- 1,4- and/or trans- 1,4- monomer units, polymerized 1,2-vinyl monomer units, polymerized 3,4-vinyl monomer units and/or others as described in the Encyclopedia of Chemical Technology, Vol. 8, page 915 (1993), the entire contents of which is hereby incorporated by reference.
  • the first polymer is a copolymer, including graft copolymers, and random copolymers based on a non-aromatic mono-olef ⁇ n co-monomer such as acrylonitrile, an alkyl (meth)acrylate and/or isobutylene.
  • a non-aromatic mono-olef ⁇ n co-monomer such as acrylonitrile, an alkyl (meth)acrylate and/or isobutylene.
  • the mono-olef ⁇ n monomer is acrylonitrile
  • the interpolymerized acrylonitrile is present- at up to about 50% by weight
  • the diolefin monomer is isoprene (e.g., to form what is commercially known as a "butyl rubber").
  • the polymers and copolymers have a Mw between about 50 kilodaltons and about 1,000 kilodaltons. In other embodiments, the polymers and copolymers have a Mw between about 100 kilodaltons and about 450 kilodaltons. In yet other embodiments the polymers and copolymers have a Mw between about 150 kilodaltons and about 1 ,000 kilodaltons, and optionally between about 200 kilodaltons and about 600 kilodaltons.
  • first polymers of this type are commercially available from sources such as Sigma-Aldrich, and include, but are not limited to, polybutadiene, poly(butadiene-co-acrylonitrile), polybutadiene-block-polyisoprene, polybutadiene-graft- poly(methyl acrylate-co-acrylonitrile), polyisoprene, and partially hydrogenated polyisoprene.
  • a second polymer component of this invention provides an optimal combination of various structural/functional properties, including hydrophobicity, durability, bioactive agent release characteristics, biocompatibility, molecular weight, and availability.
  • the composition comprises at least one second polymer component selected from the group consisting of poly(alkyl (meth)acrylates) and poly(aromatic (meth)acrylates).
  • the second polymer component is a poly(alkyl)methacrylate, that is, an ester of a methacrylic acid.
  • suitable poly(alkyl (meth)acrylates) include those with alkyl chain lengths from 2 to 8 carbons, inclusive, and with molecular weights from 50 kilodaltons to 900 kilodaltons.
  • the polymer mixture includes a poly(alkyl (meth)acrylate) with a molecular weight of from about 100 kilodaltons to about 1000 kilodaltons, in some embodiments, from about 150 kilodaltons to about 500 kilodaltons, and in some embodiments from about 200 kilodaltons to about 400 kilodaltons.
  • a particular second polymer is poly (n-butyl methacrylate).
  • Such polymers are available commercially (e.g., from Sigma-Aldrich, Milwaukee, WI) with molecular weights ranging from about 150 kilodaltons to about 350 kilodaltons, and with varying inherent viscosities, solubilities and forms (e.g., as slabs, granules, beads, crystals or powder).
  • poly(aromatic (meth)acrylates) examples include poly(aryl (meth)acrylates), poly(aralkyl (meth)acrylates), poly(alkaryl (meth)acrylates), poly(aryloxyalkyl (meth)acrylates), and poly (alkoxyaryl (meth)acrylates).
  • Such terms are used to describe polymeric structures wherein at least one carbon chain and at least one aromatic ring are combined with (meth)acrylic groups, typically esters, to provide a composition of this invention.
  • a poly(aralkyl (meth)acrylate) can be made from aromatic esters derived from alcohols also containing aromatic moieties, such as benzyl alcohol.
  • a poly(alkaryl (meth)acrylate) can be made from aromatic esters derived from aromatic alcohols such as p-anisole.
  • Suitable poly(aromatic (meth)acrylates) include aryl groups having from 6 to 16 carbon atoms and with molecular weights from about 50 to about 900 kilodaltons.
  • poly(aryl (meth)acrylates) examples include poly(9-anthracenyl methacrylate), poly(chlorophenyl acrylate), poly(methacryloxy-2-hydroxybenzophenone), poly(methacryloxybenzotriazole), poly(naphthyl acrylate), poly(naphthylmethacrylate), poly-4-nitrophenylacrylate, poly(pentachloro(bromo, fluoro) acrylate) and methacrylate, poly(phenyl acrylate) and poly(phenyl methacrylate).
  • suitable poly(aralkyl (meth)acrylates) include poly(benzyl acrylate), poly(benzyl methacrylate), poly(2-phenethyl acrylate), poly(2- phenethyl methacrylate) and poly(l-pyrenylmethyl methacrylate).
  • suitable poly(alkaryl(meth)acrylates include poly(4-sec-butylphenyl methacrylate), poly(3- ethylphenyl acrylate), and poly(2-methyl-l-naphthyl methacrylate).
  • suitable poly(aryloxyalkyl (meth)acrylates) include poly(phenoxyethyl acrylate), poly(phenoxyethyl methacrylate), and poly(polyethylene glycol phenyl ether acrylate) and poly(polyethylene glycol phenyl ether methacrylate) with varying polyethylene glycol molecular weights.
  • suitable poly(alkoxyaryl(meth)acrylates) include poly(4- methoxyphenyl methacrylate), poly(2-ethoxyphenyl acrylate) and poly(2- methoxynaphthyl acrylate).
  • Acrylate or methacrylate monomers or polymers and/or their parent alcohols are commercially available from Sigma-Aldrich (Milwaukee, WI) or from Polysciences, Inc, (Warrington, PA).
  • the coating composition may include one or more additional polymers in combination with the first and second polymer components, the additional polymers being, for example, selected from the group consisting of (i) poly(alkylene-co- alkyl(meth)acrylates, (ii) ethylene copolymers with other alkylenes, (iii) polybutenes, (iv) diolefin-derived, non-aromatic polymers and copolymers, (v) aromatic group-containing copolymers, (vi) epichlorohydrin-containing polymers, including each as disclosed and described above in the sections describing first polymers, and (vii) poly (ethylene-co-vinyl acetate).
  • additional polymers being, for example, selected from the group consisting of (i) poly(alkylene-co- alkyl(meth)acrylates, (ii) ethylene copolymers with other alkylenes, (iii) polybutenes, (iv) diolefin-derived, non-aromatic
  • the one or more additional polymers are different from the first polymer component used in the coating composition.
  • the additional polymers may substitute up to about 25% of the first polymer. In other embodiments, the additional polymers may substitute up to about 50% of the first polymer.
  • a suitable additional polymer that may be utilized in the coating composition of the present invention includes poly(ethylene-co-vinyl acetate) (pEVA).
  • pEVA poly(ethylene-co-vinyl acetate)
  • suitable polymers of this type are available commercially and include poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations of from about 8% and about 90%, in some embodiments, from about 20 to about 40 weight percent and in some embodiments, from about 30 to about 34 weight percent.
  • Such polymers are generally found in the form of beads, pellets, granules, etc. It has generally been found that pEVA co-polymers with lower percent vinyl acetate become increasingly insoluble in typical solvents.
  • coating compositions for use in this invention includes mixtures of first and second polymer components as described herein.
  • first and second polymer components are purified for such use to a desired extent and/or provided in a form suitable for in vivo use.
  • biocompatible additives may be added, such as dyes and pigments (e.g., titanium dioxide, Solvent Red 24, iron oxide, and Ultramarine Blue); slip agents (e.g., amides such as oleyl palmitamide, N,N'-ethylene bisoleamide, erucamide, stearamide, and oleamide); antioxidants (e.g.
  • butylated hydroxytoluene BHT
  • vitamin E tocopherol
  • BNXTM BNXTM
  • dilauryl thiodipropionate DLTDP
  • IrganoxTM series phenolic and hindered phenolic antioxidants
  • organophosphites e.g., trisnonylphenyl phosphite, IrgafosTM 168
  • lactones e.g., substituted benzofuranone
  • hydroxylamine and MEHQ (monomethyl ether of hydroquinone)
  • surfactants e.g., anionic fatty acid surfactants (e.g., sodium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium stearate, and sodium palmitate), cationic fatty acid surfactants (e.g., quaternary ammonium salts and amine salts), and nonionic ethoxylated surfactants (
  • the polymer mixture includes a first polymer component comprising one or more polymers selected from the group consisting of (i) ethylene copolymers with other alkylenes, (ii) polybutenes, (iii) aromatic group-containing copolymers, (iv) epichlorohydrin-containing polymers, (v) poly(alkylene-co- alkyl(meth)acrylates), and (vi) diolefin-derived, non-aromatic polymers and copolymers, and a second polymer component selected from the group consisting of poly (alkyl(meth)acrylates) and poly (aromatic(meth)acrylates) and having a molecular weight of from about 150 kilodaltons to about 500 kilodaltons, and in some embodiments from about 200 kilodaltons to about 400 kilodaltons.
  • a first polymer component comprising one or more polymers selected from the group consisting of (i) ethylene copolymers with other
  • polymers have proven useful with absolute polymer concentrations (i.e., the total combined concentrations of both polymers in the coating composition), of between about 0.1 and about 50 percent (by weight), and in some embodiments, between about 0.1 and about 35 percent (by weight).
  • Various polymer mixtures contain at least about 10 percent by weight of either the first polymer or the second polymer.
  • the polymer composition may comprise about 5% to about 95% of the first and/or second polymers based on the total weights of the first and second polymers. In a another group of embodiments, the composition may comprise about 15% to about 85% of the first and/or second polymers. In some embodiments, the composition may include about 25% to about 75% of the first and/or second polymers.
  • the bioactive agent may comprise about 1% to about 75% of the first polymer, second polymer, and bioactive agent mixture (i.e., excluding solvents and other additives). In some embodiments, the bioactive agent may comprise about 5% to about 60% of such a mixture. In some embodiments, the bioactive agent may comprise about 25% to about 45% of such a mixture.
  • the concentration of the bioactive agent or agents dissolved or suspended in the coating mixture can range from about 0.01 to about 90 percent, by weight, based on the weight of the final coating composition, and in some embodiments, from about 0.1 to about 50 percent by weight.
  • bioactive agent and "active agent”, as used herein, will refer to a wide range of biologically active materials or drugs that can be incorporated into a coating composition of the present invention.
  • the bioactive agent(s) to be incorporated do not chemically interact with the coating composition during fabrication or during the bioactive agent release process.
  • the bioactive agents as described herein may also be included in one or more additional layers or coatings, such as, for example, a pretreatment coating and/or protective coating.
  • the bioactive agent in the coating composition may be the same as or different than the bioactive agent included in the pretreatment coating and/or protective coating. Further, such bioactive agents may sometimes be referred to herein as the "pretreatment coating bioactive agent” or the "protective coating bioactive agent.”
  • An amount of biologically active agent can be applied to the device to provide a therapeutically effective amount of the agent to a patient receiving the coated device.
  • Particularly useful agents include those that affect cardiovascular function or that can be used to treat cardiovascular-related disorders.
  • the active agent includes estradiol.
  • the active agent includes rapamycin.
  • the active agent includes paclitaxel.
  • Active agents useful in the present invention can include many types of therapeutics including thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, anticoagulants, anti-platelet agents, vasospasm inhibitors, calcium channel blockers, steroids, vasodilators, anti-hypertensive agents, antimicrobial agents, antibiotics, antibacterial agents, antiparasite and/or antiprotozoal solutes, antiseptics, antifungals, angiogenic agents, anti-angiogenic agents, inhibitors of surface glycoprotein receptors, antimitotics, microtubule inhibitors, antisecretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti-metabolites, miotic agents, antiproliferatives, anticancer chemotherapeutic agents, anti-neoplastic agents, antipolymerases, antivirals, anti-AIDS substances, anti-inflammatory steroids or nonsteroidal anti-inflammatory agents, analgesics, antipyretics, immunosuppressive
  • the active agent can include heparin, covalent heparin, synthetic heparin salts, or another thrombin inhibitor; hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or another antithrombogenic agent; urokinase, streptokinase, a tissue plasminogen activator, or another thrombolytic agent; a fibrinolytic agent; a vasospasm inhibitor; a calcium channel blocker, a nitrate, nitric oxide, a nitric oxide promoter, nitric oxide donors, dipyridamole, or another vasodilator; HYTRIN® or other antihypertensive agents; a glycoprotein Ilb/IIIa inhibitor (abciximab) or another inhibitor of surface glycoprotein receptors; aspirin, ticlopidine, clopidogrel or another
  • ACE growth factor signal transduction kinase inhibitor
  • enzyme inhibitors including growth factor signal transduction kinase inhibitors
  • ascorbic acid alpha tocopherol, superoxide dismutase, deferoxamine, a 21-aminosteroid (lasaroid) or another free radical scavenger, iron chelator or antioxidant
  • a 14 C-, 3 H-, 13 H-, 32 P- or 36 S-radiolabelled form or other radiolabeled form of any of the foregoing an estrogen (such as estradiol, estriol, estrone, and the like) or another sex hormone
  • AZT or other antipolymerases acyclovir, famciclovir, rimantadine hydrochloride, ganciclovir sodium, Norvir, Crixivan, or other antiviral agents; 5-aminolevulinic acid, meta-tetrahydroxyphenylchlorin, hexadecafluorozinc phthal
  • Other biologically useful compounds that can also be included in the coating material include, but are not limited to, hormones, (3 -blockers, anti-anginal agents, cardiac inotropic agents, corticosteroids, analgesics, anti-inflammatory agents, anti-arrhythmic agents, immunosuppressants, anti-bacterial agents, anti-hypertensive agents, antimalarials, anti-neoplastic agents, anti-protozoal agents, anti-thyroid agents, sedatives, hypnotics and neuroleptics, diuretics, antiparkinsonian agents, gastro-intestinal agents, anti-viral agents, anti-diabetics, anti-epileptics, anti-fungal agents, histamine H-receptor antagonists, lipid regulating agents, muscle relaxants, nutritional agents such as vitamins and minerals, stimulants, nucleic acids, polypeptides, and vaccines.
  • hormones 3 -blockers, anti-anginal agents, cardiac inotropic agents, corticosteroids, analgesic
  • Antibiotics are substances which inhibit the growth of or kill microorganisms. Antibiotics can be produced synthetically or by microorganisms. Examples of antibiotics include penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycin, geldanamycin, geldanamycin analogs, cephalosporins, or the like.
  • cephalosporins examples include cephalothin, cephapirin, cefazolin, cephalexin, cephradine, cefadroxil, cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid, ceforanide, cefotaxime, moxalactam, ceftizoxime, ceftriaxone, and cefoperazone.
  • Antiseptics are recognized as substances that prevent or arrest the growth or action of microorganisms, generally in a nonspecific fashion, e.g., either by inhibiting their activity or destroying them.
  • antiseptics include silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds.
  • Antiviral agents are substances capable of destroying or suppressing the replication of viruses.
  • anti-viral agents examples include a-methyl-ladamantanemethylamine, hydroxy-ethoxymethylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, and adenine arabinoside.
  • Enzyme inhibitors are substances that inhibit an enzymatic reaction.
  • enzyme inhibitors include edrophonium chloride, N-methylphysostigmine, neostigmine bromide, physostigmine sulfate, tacrine HCL, tacrine, 1 -hydroxy maleate, iodotubercidin, p-bromotetramisole, 10-(a-diethylaminopropionyl)-phenothiazine hydrochloride, calmidazolium chloride, hemicholinium-3,3,5-dinitrocatechol, diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor II, 3-phenylpropargylaminie, N-monomethyl-L- arginine acetate, carbidopa, 3-hydroxybenzylhydrazine HCl, hydralazine HCl, clorgyline HCl, deprenyl
  • Anti-pyretics are substances capable of relieving or reducing fever.
  • Antiinflammatory agents are substances capable of counteracting or suppressing inflammation. Examples of such agents include aspirin (salicylic acid), indomethacin, sodium indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodium salicylamide.
  • Local anesthetics are substances that have an anesthetic effect in a localized region.
  • Examples of such anesthetics include procaine, lidocaine, tetracaine and dibucaine.
  • Imaging agents are agents capable of imaging a desired site, e.g., tumor, in vivo.
  • imaging agents include substances having a label that is detectable in vivo, e.g., antibodies attached to fluorescent labels.
  • the term antibody includes whole antibodies or fragments thereof.
  • Cell response modifiers are chemotactic factors such as platelet-derived growth factor (PDGF).
  • Other chemotactic factors include neutrophil-activating protein, monocyte chemoattractant protein, macrophage-inflammatory protein, SIS (small inducible secreted), platelet factor, platelet basic protein, melanoma growth stimulating activity, epidermal growth factor, transforming growth factor alpha, fibroblast growth factor, platelet-derived endothelial cell growth factor, insulin-like growth factor, nerve growth factor, bone growth/cartilage-inducing factor (alpha and beta), and matrix metalloproteinase inhibitors.
  • neutrophil-activating protein neutrophil-activating protein
  • monocyte chemoattractant protein macrophage-inflammatory protein
  • SIS small inducible secreted
  • platelet factor platelet basic protein
  • melanoma growth stimulating activity epidermal growth factor
  • transforming growth factor alpha transforming growth factor alpha
  • fibroblast growth factor platelet-derived endothelial
  • cell response modifiers are the interleukins, interleukin receptors, interleukin inhibitors, interferons, including alpha, beta, and gamma; hematopoietic factors, including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor; tumor necrosis factors, including alpha and beta; transforming growth factors (beta), including beta-1, beta-2, beta-3, inhibin, activin, and DNA that encodes for the production of any of these proteins, antisense molecules, androgenic receptor blockers and statin agents.
  • interleukins interleukin receptors
  • interleukin inhibitors interferons
  • interferons including alpha, beta, and gamma
  • hematopoietic factors including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating
  • the active agent can be in a microparticle.
  • microparticles can be dispersed on the surface of the substrate.
  • weight of the coating attributable to the active agent can be in any range desired for a given active agent in a given application. In some embodiments, weight of the coating attributable to the active agent is in the range of about 1 microgram to about 10 milligrams of active agent per cm of the effective surface area of the device.
  • 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.
  • the weight of the coating attributable to the active agent is between about 0.01 mg and about 0.5 mg of active agent per cm 2 of the gross surface area of the device. In an embodiment, the weight of the coating attributable to the active agent is greater than about 0.01 mg.
  • more than one active agent can be used in the coating.
  • co-agents or co-drugs can be used.
  • a co-agent or co-drug can act differently than the first agent or drug.
  • the co-agent or co-drug can have an elution profile that is different than the first agent or drug.
  • the active agent can be hydrophilic.
  • the active agent can have a molecular weight of less than 1500 daltons and can have a water solubility of greater than lOmg/mL at 25 0 C.
  • the active agent can be hydrophobic.
  • the active agent can have a water solubility of less than 10mg/mL at 25 0 C.
  • Some embodiments of the invention include a stent coated with a coating compositon including a first polymer, a second polymer, and at least one bioactive agent selected from the group of steroids and antiproliferatives.
  • the invention includes a wound dressing coated with a coating composition including a first polymer, a second polymer, and at least one bioactive agent selected from the group consisting of anesthetics, such as procaine, lidocaine, tetracaine and/or dibucaine.
  • Bioactive agents are commercially available from Sigma Aldrich (e.g., vincristine sulfate).
  • concentration of the bioactive agent or agents dissolved or suspended in the coating mixture can range from about 0.01 to about 90 percent, by weight, based on the weight of the final coated composition.
  • Additives such as inorganic salts, BSA (bovine serum albumin), and inert organic compounds can be used to alter the profile of bioactive agent release, as known to those skilled in the art.
  • a coating composition is prepared to include one or more solvents, a combination of complementary polymers dissolved in the solvent, and the bioactive agent or agents dispersed in the polymer/solvent mixture.
  • the solvent in some embodiments, is one in which the polymers form a true solution.
  • the pharmaceutical agent itself may either be soluble in the solvent or form a dispersion throughout the solvent.
  • Suitable solvents include, but are not limited to, alcohols (e.g., methanol, butanol, propanol and isopropanol), alkanes (e.g., halogenated or unhalogenated alkanes such as hexane, cyclohexane, methylene chloride and chloroform), amides (e.g., dimethylformamide), ethers (e.g., tetrahydrofuran (THF ), dioxolane, and dioxane), ketones (e.g., methyl ethyl ketone), aromatic compounds (e.g., toluene and xylene), nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate).
  • alcohols e.g., methanol, butanol, propanol and isopropanol
  • alkanes e.g.
  • a coating composition of this invention can be used to coat the surface of a variety of devices, and is particularly useful for those devices that will come in contact with aqueous systems. Such devices are coated with a coating composition adapted to release bioactive agent in a prolonged and controlled manner, generally beginning with the initial contact between the device surface and its aqueous environment.
  • the coated composition provides a means to deliver bioactive agents from a variety of biomaterial surfaces.
  • biomaterials include those formed of synthetic polymers, including oligomers, homopolymers, and copolymers resulting from either addition or condensation polymerizations.
  • suitable addition polymers include, but are not limited to, acrylics such as those polymerized from methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic acid, glyceryl acrylate, glyceryl methacrylate, methacrylamide, and acrylamide; vinyls, such as those polymerized from ethylene, propylene, styrene, vinyl chloride, vinyl acetate, vinyl pyrrolidone, and vinylidene difluoride.
  • condensation polymers include, but are not limited to, nylons such as polycaprolactam, poly(lauryl lactam), poly(hexamethylene adipamide), and poly(hexamethylene dodecanediamide), and also polyurethanes, polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co- glycolic acid), polydimethylsiloxanes, polyetheretherketone, poly(butylene terephthalate), poly(butylene terephthalate-co-polyethylene glycol terephthalate), esters with phosphorus containing linkages, non-peptide polyamino acid polymers, polyiminocarbonates, amino acid-derived polycarbonates and polyarylates, and copolymers of polyethylene oxides with amino acids or peptide sequences.
  • nylons such as polycaprolactam, poly(lauryl lactam), poly(hexamethylene a
  • biomaterials including human tissue such as bone, cartilage, skin and teeth; and other organic materials such as wood, cellulose, compressed carbon, and rubber.
  • 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, such as nitinol (e.g. MP35), 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.
  • Yet other suitable biomaterials include combinations of ceramics and metals, as well as biomaterials that are fibrous or porous in nature.
  • the surface of some biomaterials can be pretreated (e.g., with a silane and/or Parylene TM coating composition in one or more layers) in order to alter the surface properties of the biomaterial.
  • a layer of silane may be applied to the surface of the biomaterial followed by a layer of ParleneTM.
  • Parylene TM C is the polymeric form of the low-molecular- weight dimer of para-chloro-xylylene.
  • Silane and/or Parylene TM C (a material supplied by Specialty Coating Systems (Indianapolis)) can be deposited as a continuous coating on a variety of medical device parts to provide an evenly distributed, transparent layer.
  • the deposition of Parylene TM is accomplished by a process termed vapor deposition polymerization, in which dimeric Parylene TM C is vaporized under vacuum at 150°C, pyrolyzed at 680°C to form a reactive monomer, then pumped into a chamber containing the component to be coated at 25°C. At the low chamber temperature, the monomeric xylylene is deposited on the part, where it immediately polymerizes via a free- radical process. The polymer coating reaches molecular weights of approximately 500 kilodaltons.
  • Deposition of the xylylene monomer takes place in only a moderate vacuum (0.1 torr) and is not line-of-sight. That is, the monomer has the opportunity to surround all sides of the part to be coated, penetrating into crevices or tubes and coating sharp points and edges, creating what is called a "conformal" coating. With proper process control, it is possible to deposit a pinhole-free, insulating coating that will provide very low moisture permeability and high part protection to corrosive biological fluids. Adherence is a function of the chemical nature of the surface to be coated. It has been reported, for instance, that tantalum and silicon surfaces can be overcoated with silicon dioxide, then with plasma-polymerized methane, and finally with Parylene TM C to achieve satisfactory adherence.
  • Parylene TM C coating in the medical device industry are for protecting sensitive components from corrosive body fluids or for providing lubricity to surfaces.
  • Typical anticorrosion applications include blood pressure sensors, cardiac-assist devices, prosthetic components, bone pins, electronic circuits, ultrasonic transducers, bone-growth stimulators, and brain probes.
  • Applications to promote lubricity include mandrels, injection needles, cannulae, and catheters.
  • the surface to which the composition is applied can itself be pretreated in other manners sufficient to improve attachment of the composition to the underlying (e.g., metallic) surface. Additional examples of such pretreatments include photografted polymers, epoxy primers, polycarboxylate resins, and physical roughening of the surface. It is further noted that the pretreatment compositions and/or techniques may be used in combination with each other or may be applied in separate layers to form a pretreatment coating on the surface of the medical device. As described above, the surface of a medical device may be roughened to increase adhesion of the coating composition to the medical device and/or alter elution profiles.
  • the roughening of the surface provides for a greater surface area between the coating composition and the surface of the medical device, which may increase adhesion. Further, in embodiments with relatively aggressive roughening and/or relatively thin coatings, the peaks and valleys of the roughened surface may transfer through the coating composition, thereby increasing the surface area of the coating. Such increased surface area may alter the bioactive agent release profile in situ.
  • the surface of the medical device may be roughened by any suitable method. In some embodiments, the surface of the medical device may be roughened by projecting silica particles at the surface. The extent of the roughening may be characterized by peak to valley distances.
  • the extent of roughening may be characterized by the distance between the average of the ten highest peaks and the ten lowest valleys. In some embodiments, the extent of roughening may range from about 2 ⁇ m to about 20 ⁇ m. Optionally, the extent of roughening may range from about 5 ⁇ m to about 15 ⁇ m. In some embodiments, the extent of roughening may range from about 6.5 ⁇ m to about 12 ⁇ m.
  • a tie-in layer may be utilized to facilitate one or more physical and/or covalent bonds between layers.
  • the pretreatment layer may include a multi-interface system to facilitate adhesion and cohesion interaction relative to the different materials positioned at the interface of each layer.
  • the application of Parylene pretreatments to metal surfaces may be aided by a first application of a reactive organosilane reagent.
  • a reactive organosilane reagent containing an unsaturated pendant group is capable of participating with the Parylene radicals as they deposit on the surface from the vapor phase. After cleaning of the metal surface, an organosilane reagent with an unsaturated pendant group may be applied to the metal oxide surface on a metal substrate.
  • the silicon in the organosilane reagent couples covalently to the metal oxide, linking the organosilane group to the surface.
  • the substrate may then be placed in a Parylene reactor and exposed to the vapor-phase Parylene process.
  • the unsaturated pendant groups on the organosilane-treated surface can react with the Parylene diradicals depositing from the vapor phase. This forms a covalent link between the Parylene and the organosilane layer.
  • the Parylene also forms covalent bonds to itself as it deposits.
  • this process yields a layered surface in which the layers are covalently bonded to each other.
  • the Parylene may physically bond with the bioactive agent delivery coating or may include a reactive acrylate group that can be reacted with the bioactive agent delivery coating to improve durability to mechanical challenges.
  • the coating composition of the present invention can be used in combination with a variety of devices, including those used on a temporary, transient, or permanent basis upon and/or within the body.
  • Compositions of this invention can be used to coat the surface of a variety of implantable devices, for example: drug-delivering vascular stents (e.g., self-expanding stents typically made from nitinol, balloon-expanded stents typically prepared from stainless steel); other vascular devices (e.g., grafts, catheters, valves, artificial hearts, heart assist devices); implantable defibrillators; blood oxygenator devices (e.g., tubing, membranes); surgical devices (e.g., sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds); membranes; cell culture devices; chromatographic support materials; biosensors; shunts for hydrocephalus; wound management devices; endoscopic devices; infection control devices; orthopedic devices (e.g., for joint implants, fracture repairs); dental devices (e.g
  • ocular coils ocular coils
  • glaucoma drain shunts synthetic prostheses (e.g., breast); intraocular lenses; respiratory, peripheral cardiovascular, spinal, neurological, dental, ear/nose/throat (e.g., ear drainage tubes); renal devices; and dialysis (e.g., tubing, membranes, grafts).
  • synthetic prostheses e.g., breast
  • intraocular lenses respiratory, peripheral cardiovascular, spinal, neurological, dental, ear/nose/throat (e.g., ear drainage tubes); renal devices; and dialysis (e.g., tubing, membranes, grafts).
  • dialysis e.g., tubing, membranes, grafts
  • useful devices include urinary catheters (e.g., surface-coated with antimicrobial agents such as vancomycin or norfloxacin), intravenous catheters (e.g., treated with antithrombotic agents (e.g., heparin, hirudin, Coumadin), small diameter grafts, vascular grafts, artificial lung catheters, atrial septal defect closures, electrostimulation leads for cardiac rhythm management (e.g., pacer leads), glucose sensors (long-term and short-term), degradable coronary stents (e.g., degradable, non-degradable, peripheral), blood pressure and stent graft catheters, birth control devices, benign prostate and prostate cancer implants, bone repair/augmentation devices, breast implants, cartilage repair devices, dental implants, implanted drug infusion tubes, intravitreal drug delivery devices, nerve regeneration conduits, oncological implants, electrostimulation leads, pain management implants, spinal/orthopedic repair devices, wound dressings, embolic protection filters, abdominal a
  • vena cava filters examples include, but are not limited to, vena cava filters, urinary dialators, endoscopic surgical tissue extractors, atherectomy catheters, clot extraction catheters, percutaneous transluminal angioplasty catheters, PTCA catheters, stylets (vascular and non-vascular), coronary guidewires, drug infusion catheters, esophageal stents, circulatory support systems, angiographic catheters, transition sheaths and dilators, coronary and peripheral guidewires, hemodialysis catheters, neurovascular balloon catheters, tympanostomy vent tubes, cerebro-spinal fluid shunts, defibrillator leads, percutaneous closure devices, drainage tubes, thoracic cavity suction drainage catheters, electrophysiology catheters, stroke therapy catheters, abscess drainage catheters, biliary drainage products, dialysis catheters, central venous access catheters, and parental feeding catheters.
  • medical devices suitable for the present invention include, but are not limited to catheters, implantable vascular access ports, blood storage bags, vascular stents, blood, tubing, arterial catheters, vascular grafts, intraaortic balloon pumps, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such as pancreas or liver and artificial lungs, as well as filters adapted for deployment in a blood vessel in order to trap emboli (also known as "distal protection devices").
  • catheters implantable vascular access ports
  • blood storage bags such as blood storage bags, vascular stents, blood, tubing, arterial catheters, vascular grafts, intraaortic balloon pumps, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such
  • compositions are particularly useful for those devices that will come in contact with aqueous systems, such as bodily fluids.
  • Such devices are coated with a coating composition adapted to release bioactive agent in a prolonged and controlled manner, generally beginning with the initial contact between the device surface and its aqueous environment.
  • a coating composition adapted to release bioactive agent in a prolonged and controlled manner, generally beginning with the initial contact between the device surface and its aqueous environment.
  • bioactive agents may be utilized to treat a wide variety of conditions utilizing any number of medical devices, or to enhance the function and/or life of the device.
  • any type of medical device may be coated in some fashion with one or more bioactive agents that enhances treatment over use of the individual use of the device or bioactive agent.
  • 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.
  • 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.
  • vascular stents such as self- expanding stents and balloon expandable stents.
  • self-expanding stents useful in the present invention are illustrated in U.S. Pat. Nos. 4,655,771 and 4,954,126 issued to Wallsten and 5,061,275 issued to Wallsten et al.
  • suitable balloon-expandable stents are shown in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco and U.S. Pat. No. 4,886,062 issued to Wiktor.
  • the coating composition can also be used to coat ophthalmic devices, e.g. ocular coils.
  • ophthalmic devices e.g. ocular coils.
  • a therapeutic agent delivery device that is particularly suitable for delivery of a therapeutic agent to limited access regions, such as the vitreous chamber of the eye and inner ear is described in U.S. patent number 6,719,750 and U.S. Patent Application Publication No. 2005/0019371 Al.
  • the resultant coating composition can be applied to the device in any suitable fashion (e.g., the coating composition can be applied directly to the surface of the medical device, or alternatively, to the surface of a surface-modified medical device, by dipping, spraying, ultrasonic deposition, or using any other conventional technique).
  • the coating comprises at least two layers which are themselves different.
  • a base layer may be applied having bioactive agent(s) alone, or together with or without one or more of the polymer components, after which one or more topcoat layers are coated, each with either first and/or second polymers as described herein, and with or without bioactive agent.
  • These different layers can cooperate in the resultant composite coating to provide an overall release profile having certain desired characteristics, and in some embodiments, for use with bioactive agents of high molecular weight.
  • the composition is coated onto the device surface in one or more applications of a single composition that includes first and second polymers, together with bioactive agent.
  • a pretreatment layer or layers may be first applied to the surface of the device, wherein subsequent coating with the composition may be performed onto the pretreatment layer(s).
  • the method of applying the coating composition to the device is typically governed by the geometry of the device and other process considerations.
  • the coating is subsequently cured by evaporation of the solvent.
  • the curing process can be performed at room or elevated temperature, and optionally with the assistance of vacuum and/or controlled humidity.
  • one or more additional layers may be applied to the coating layer(s) that include bioactive agent.
  • Such layer(s) or topcoats can be utilized to provide a number of benefits, such as biocompatibility enhancement, delamination protection, durability enhancement, bioactive agent release control, to just mention a few.
  • the topcoat may include one or more of the first, second, and/or additional polymers described herein without the inclusion of a bioactive agent.
  • the topcoat includes a second polymer that is a poly(alkyl(meth)acrylate).
  • An example of one embodiment of a poly(alkyl(meth)acrylate) includes poly (n-butyl methacrylate).
  • the first or second polymers could further include functional groups (e.g. hydroxy, thiol, methylol, amino, and amine-reactive functional groups such as isocyanates, thioisocyanates, carboxylic acids, acyl halides, epoxides, aldehydes, alkyl halides, and sulfonate esters such as mesylate, tosylate, and tresylate) that could be utilized to bind the topcoat to the adjacent coating composition.
  • one or more of the pretreatment materials e.g. Parylene TM
  • biocompatible topcoats e.g.
  • biocompatible topcoats may be adjoined to the coating composition of the present invention by utilizing photochemical or thermochemical techniques known in the art. Additionally, release layers may be applied to the coating composition of the present invention as a friction barrier layer or a layer to protect against delamination. Examples of biocompatible topcoats that may be used include those disclosed in U.S. Patent No. U.S. Patent No. 4,979,959 and 5,744,515.
  • a hydrophilic topcoat may be provided.
  • Such topcoats may provide several advantages, including providing a relatively more lubricious surface to aid in medical device placement in situ, as well as to further increase biocompatibility in some applications.
  • hydrophilic agents that may be suitable for a topcoat in accordance with the invention includes polyacrylamide(36%)co-methacrylic acid(MA)- (10%)co-methoxy PEG1000MA-(4%)co-BBA-APMA compounds such as those described in example 4 of US Patent Application Publication No. 2002/0041899, photoheparin such as described in example 4 of US Patent No. 5,563,056, and a photoderivatized coating as described in Example 1 of US Patent No. 6,706,408, the contents of each of which is hereby incorporated by reference.
  • the topcoat may be used to control the elution rate of a bioactive agent from a medical device surface.
  • topcoats may be described as the weight of the topcoat relative to the weight of the underlying bioactive agent containing layer.
  • the topcoat may be about 1 percent to about 50 percent by weight relative to the underlying layer.
  • the topcoat may be about 2 percent to about 25 percent by weight relative to the underlying layer.
  • the topcoat may be about 5 percent to about 12 percent by weight relative to the underlying layer. Applicants have found that providing a relatively thin topcoat compared to the underlying layer may significantly reduce initial drug elution rates to provide for longer elution times.
  • providing a topcoat weighing about 5% of the underlying layer may reduce initial elution rates (e.g., less than 20 hours) by more than about 50%.
  • the topcoat layer comprises a polymer that is also included in the underlying layer (e.g., first, second, and/or additional polymers as described above). Such topcoats may provide for superior adhesion between the top coat and the underlying layer.
  • one or more bioactive agents may be provided in a topcoat (sometimes referred to herein as a topcoat bioactive agent).
  • the topcoat bioactive agent may be the same as or distinguishable from the bioactive agent included in an underlying layer. Providing bioactive agent within the topcoat allows for the bioactive agent to be in contact with surrounding tissue in situ while providing a longer release profile compared to coating compositions provided without topcoats.
  • Such topcoats may also be used to further control the elution rate of a bioactive agent from a medical device surface, such as by varying the amount of bioactive agent in the topcoat.
  • the degree to which the bioactive agent containing topcoat affects elution will depend on the specific bioactive agent within the topcoat as well as the concentration of the bioactive agent within the topcoat. Any suitable amount of a bioactive agent may be included in the topcoat. For example, the upper limit of the amount of bioactive agent in the topcoat may be limited only by the ability of the topcoat to hold additional bioactive agent. In some embodiments, the bioactive agent may comprise about 1 to about 75 percent of the topcoat. Optionally, the bioactive agent may comprise about 5 to about 50 percent of the topcoat. In yet other embodiments, the bioactive agent may comprise about 10 to about 40 percent of the topcoat.
  • the polymer composition for use in this invention is generally biocompatible, e.g., such that it results in no significant induction of inflammation or irritation when implanted.
  • the polymer combination is generally useful throughout a broad spectrum of both absolute concentrations and relative concentrations of the polymers. This means that the physical characteristics of the coating, such as tenacity, durability, flexibility and expandability, will typically be adequate over a broad range of polymer concentrations. In turn, the ability of the coating to control the release rates of a variety of bioactive agents can be manipulated by varying the absolute and relative concentrations of the polymers.
  • the coatings of the present invention are generally hydrophobic and limit the intake of aqueous fluids.
  • many embodiments of the present invention are coating compositions including two or more hydrophobic polymers wherein the resulting coating shows ⁇ 10% (wt) weight change when exposed to water, and in some embodiments ⁇ 5% (wt) weight change when exposed to water.
  • 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.
  • polymer combinations of this invention are capable of being provided in the form of a true solution, and in turn, can be used to provide a coating that is both optically clear (upon microscopic examination), while also containing a significant amount of bioactive agent.
  • 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.
  • a further example of a coating composition embodiment may include a configuration of one or more bioactive agents within an inner matrix structure, for example, bioactive agents within or delivered from a degradable encapsulating matrix or a microparticle structure formed of semipermeable cells and/or degradable polymers.
  • One or more inner matrices may be placed in one or more locations within the coating composition and at one or more locations in relation to the substrate. Examples of inner matrices, for example degradable encapsulating matrices formed of semipermeable cells and/or degradable polymers, are disclosed and/or suggested in U.S. Publication No. 20030129130, U.S. Patent Application Serial No. 60/570,334 filed May 12, 2004, U.S. Patent Application Serial No.
  • the overall weight of the coating upon the surface may vary depending on the application. However, in some embodiments, the weight of the coating attributable to the bioactive agent is in the range of about one microgram to about 10 milligram (mg) of bioactive agent per cm 2 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.
  • the weight of the coating attributable to the bioactive agent is between about 0.005 mg and about 10 mg, and in some embodiments between about 0.01 mg and about 1 mg of bioactive agent per cm 2 of the gross surface area of the device. This quantity of bioactive agent is generally required to provide desired activity under physiological conditions.
  • the final coating thickness of a coated composition will typically be in the range of about 0.1 micrometers to about 100 micrometers, and in some embodiments, between about 0.5 micrometers and about 25 micrometers. This level of coating thickness is generally required to provide an adequate concentration of drug to provide adequate activity under physiological conditions.
  • Stainless steel stents used in the following examples were manufactured by Laserage Technology Corporation, Waukegan, IL.
  • the metal surface of the stents may be coated without any pretreatment beyond washing.
  • a primer may be applied to the stents by first cleaning the stents with aqueous base, then pre- treating with a silane followed by vapor deposition of ParyleneTM polymer.
  • the silane used may be [3-(methacroyloxy)propyl] trimethoxysilane, available from Sigma- Aldrich Fine Chemicals as Product No. 44,015-9.
  • the silane may be applied as essentially a monolayer by mixing the silane at a low concentration in 50/50 (vol) isopropanol/water, soaking the stents in the aqueous silane solution for a suitable length of time to allow the water to hydrolyze the silane and produce some cross-linking, washing off residual silane, then baking the silane-treated stent at 100 0 C for conventional periods of time.
  • ParyleneTM C coating available from Union Carbide Corporation, Danbury, CT
  • the stents Prior to coating, the stents should be weighed on a microbalance to determine a tare weight.
  • Bioactive agent/polymer solutions may be prepared at a range of concentrations in an appropriate solvent (typically tetrahydrofuran or chloroform), in the manner described herein.
  • an appropriate solvent typically tetrahydrofuran or chloroform
  • the coating solutions are applied to respective stents by spraying, and the solvent is allowed to evaporate under ambient conditions.
  • the coated stents are then re-weighed to determine the mass of coating and consequently the mass of polymer and bioactive agent. Rapamycin Release Assay Procedure
  • the Rapamycin Release Assay Procedure was used to determine the extent and rate of release of an exemplary bioactive agent, rapamycin, under in vitro elution conditions.
  • Spray-coated stents prepared using the Sample Preparation Procedure were placed in sample baskets into 10 milliliters of SotaxTM dissolution system (elution media containing 2% (wt) surfactant/water solution, available from Sotax Corporation, Horsham, PA). Amount of bioactive agent elution was monitored by UV spectrometry over the course of several days. The elution media was held at 37 0 C. After the elution measurements, the stents were removed, rinsed, dried, and weighed to compare measured bioactive agent elution to weighed mass loss. Dexamethasone Release Assay Procedure
  • the Dexamethasone Release Assay Procedure may be used to determine the extent and rate of dexamethasone release under in vitro conditions.
  • Spray- coated stents made using the Sample Preparation Procedure are placed in 10 milliliters of pH 7 phosphate buffer solution ("PBS") contained in an amber vial.
  • PBS pH 7 phosphate buffer solution
  • a magnetic stirrer bar is added to the vial, and the vial with its contents are placed into a 37°C water bath. After a sample interval, the stent is removed and placed into a new buffer solution contained in a new vial.
  • Dexamethasone concentration in the buffer is measured using ultraviolet spectroscopy and the concentration converted to mass of bioactive agent released from the coating. After the experiment, the stent is dried and weighed to correlate actual mass loss to the loss measured by the elution experiment.
  • the durability of the coated composition can be determined by the following manner. To simulate use of the coated devices, the coated stents are placed over sample angioplasty balloons. The stent is then crimped onto the balloon using a laboratory test crimper (available from Machine Solutions, Brooklyn, NY). The stent and balloon are then placed in a phosphate buffer bath having a pH of 7.4 and temperature of 37°C. After 5 minutes of soaking, the balloon is expanded using air at 5 atmospheres (3800 torr) of pressure. The balloon is then deflated, and the stent is removed. The stent is then examined by optical and scanning electron microscopy to determine the amount of coating damage caused by cracking and/or delamination and a rating may be assigned.
  • Coatings with extensive damage are considered unacceptable for a commercial medical device.
  • the "Rating" is a qualitatitive scale used to describe the amount of damage to the coating from the stent crimping and expansion procedure based on optical microscopy examination by an experienced coating engineer.
  • a low rating indicates a large percentage of the coating cracked, smeared, and/or delaminated from the surface. For example, a coating with a rating often shows no damage while one with a rating of 1 will show a majority of the coating damaged to the point where clinical efficacy maybe diminished.
  • Commercially attractive coatings typically have a rating of nine or higher. Stress-Strain Measurement Test Procedure
  • Polymer films can be prepared by hot pressing polymer beads at 100°C in a constant film maker kit to a thickness of approximately 0.5 mm. The resulting films are cut into strips using a razor blade.
  • a Q800 Dynamic Mechanical Analyzer (available from Texas Instruments, Dallas, TX) may be fitted with a film tension clamp. Each sample is equilibrated at 35°C for five minutes prior to straining the sample. Then the sample is loaded into the clamp such that the sample length is between 5 and 7 mm in length. A static force of 0.0 IN is applied to each sample throughout the measurements. Simultaneously, a 0.5 N/min force is applied to the sample until the movable clamp reaches its maximum position. Films are elongated at constant stress and the average tensile modulus (i.e., the initial slope of the stress-strain curve, in MPa) can be determined.
  • Example 1 Release of Rapamvcin from Polyfethylene-co-propylene ⁇ and PolyCbutyl methacrylate Three solutions were prepared for coating the stents. The solutions included mixtures of poly(ethylene-co-propylene) ("PEPP", available from Sigma- Aldrich Fine Chemicals, Milwaukee, WI, as Product No. 18,962-6, contains 60% (mole) ethylene, having Mw of approximately 170 kilodaltons ), "PBMA” and “RAPA” (“PBMA”, available from Sigma- Aldrich Fine Chemicals as Product No.
  • PEPP poly(ethylene-co-propylene)
  • PBMA poly(ethylene-co-propylene)
  • RAPA PBMA
  • the solutions were prepared to include the following ingredients at the stated weights per milliliter of THF: 1) 16 mg/ml PEPP / 4 mg/ml PBMA / 10 mg/ml RAPA
  • Results demonstrate the ability to control the elution rate of rapamycin, a pharmaceutical agent, from a coated stent surface by varying the relative concentrations of PEPP and PBMA in the polymer mixture as described herein.
  • Example 2 Release of Rapamycin from PoMepichlorohydrin) and Polyfbutyl methacrylate
  • the solutions included mixtures of poly(epichlorohydrin) ("PECH”, available from Scientific Polymer Products as Catalog #127, CAS #24969-06-0, Mw approximately 700 kilodaltons), poly(butyl methacrylate) (“PBMA”, available from Sigma- Aldrich Fine Chemicals as Product No. 18,152-8, having a weight average molecular weight (Mw) of about 337 kilodaltons), and rapamycin (“RAPA”, available from LC Laboratories, Woburn, MA) dissolved in tetrahydrofuran (THF) to form a homogeneous solution.
  • PCH poly(epichlorohydrin)
  • PBMA poly(butyl methacrylate)
  • RAPA rapamycin
  • THF tetrahydrofuran
  • the solutions included mixtures of poly(isobutylene) ("PIB”, available from Scientific Polymer Products as Catalog #681, CAS #9003-27 r -4, Mw approx. 85 kilodaltons), ("PBMA”, available from Sigma- Aldrich Fine Chemicals as Product No. 18,152-8, having a weight average molecular weight (Mw) of about 337 kilodaltons), and rapamycin (“RAPA”, available from LC Laboratories, Woburn, MA) dissolved in THF to form a homogeneous solution.
  • PIB poly(isobutylene)
  • PBMA poly(isobutylene)
  • RAPA rapamycin
  • the solutions were prepared to include the following ingredients at the stated weights per milliliter of THF: 1 ) 16 mg/ml PIB / 4 mg/ml PBMA / 10 mg/ml RAPA
  • Results demonstrate the ability to control the elution rate of rapamycin, a pharmaceutical agent, from a coated stent surface by varying the relative concentrations of PIB and PBMA in the polymer mixture as described herein.
  • Example 4
  • the solutions included mixtures of poly(styrene-co-butadiene) copolymer ("SBR", available from Scientific Polymer Products, Inc. Catalog #100, contains 23% (wt) styrene), poly(butyl methacrylate) (“PBMA”, available from Sigma-Aldrich Fine Chemicals as Product No. 18,152-8, having a weight average molecular weight (Mw) of about 337 kilodaltons), and rapamycin (“RAPA”, available from LC Laboratories, Woburn, MA) dissolved in THF to form a homogeneous solution.
  • SBR poly(styrene-co-butadiene) copolymer
  • PBMA poly(butyl methacrylate)
  • RAPA rapamycin
  • the solutions were prepared to include the following ingredients at the stated weights per milliliter of THF:
  • Results demonstrate the ability to control the elution rate of rapamycin, a pharmaceutical agent, from a coated stent surface by varying the relative concentrations of SBR and PBMA in the polymer mixture as described herein.
  • Example 5
  • the solutions were prepared to include the following ingredients at the stated weights per milliliter of THF: 1) 16 mg/ml PEMA / 4 mg/ml PBMA / 10 mg/ml RAPA 2) 10 mg/ml PEMA / 10 mg/ml PBMA / 10 mg/ml RAPA 3) 4 mg/ml PEMA / 16 mg/ml PBMA / 10 mg/ml RAPA
  • Results demonstrate the ability to control the elution rate of dexamethasone, a pharmaceutical agent, from a stent surface by varying the relative concentrations of PEMA and PBMA in the polymer mixture.
  • stents were sprayed with a coating of second polymer/poly(butyl methacrylate)("PBMA”)/rapamycin("RAPA”), mixed at a weight ratio of 33/33/33 at 10 mg/ml each of THF.
  • the first polymer was poly(ethylene- co-methyl acrylate) ("PEMA", available from Focus Chemical Corp. Portsmouth, NH, containing 28% (wt) methyl acrylate).
  • the second polymer used was PBMA from Sigma- Aldrich Fine Chemicals as Product No. 18,152-8, having a weight average molecular weight (Mw) of about 337 kilodaltons.
  • Stents were either used as received (i.e., uncoated metal), were pre-treated with a silane/ParyleneTM primer using the primer procedure described in the Sample Preparation Procedure, were not pre-treated with primer but were given a subsequent PBMA topcoat using the spraying process described in the Sample Preparation Procedure, or were given both a silane/ParyleneTM pre-treatment primer and subsequent PBMA topcoat.
  • the stents were examined with an optical microscope under both "bright field” and "dark field” conditions. All coatings were optically transparent (i.e., clear, showing no cloudiness).
  • the coated stents were crimped down on balloons and were expanded following the Durability Test Procedure, which showed that, overall, all the coatings remained intact (i.e., the coating did not peel off or flake off, etc.), with only a few localized sites where coating delaminated from the metal stent.
  • primer coatings were used, essentially no delamination was evident and cracks were all smaller than about 10 microns in width. Almost all stents had some degree of cracking of the coating around bends in the struts, as well as some mechanical damage caused by handling or balloon expansion. Adding a PBMA topcoat did not adversely affect the mechanical integrity of the coating on the stent after crimping and expansion, as might be expected with an overall thicker stent coating.
  • coatings containing bioactive agents incorporated into blends of PBMA with PEMA as the first polymer are viable candidates for commercial applications in drug-eluting stents and are expected to be particularly effective in minimizing the onset of restenosis after stent implantation.
  • first polymers and additional polymers of this invention were tested and average tensile modulus calculated using the Stress-Strain Measurement Test Procedure.
  • the first and/or additional polymers evaluated were poly(ethylene-co-methyl acrylate) ("PEMA”, same as used in Example 5), poly(ethylene- c'o-butyl acrylate) ("PEBA”, containing 35% (wt) butyl acrylate, available from Focus Chemical Corp., Portsmouth, NH), polybutadiene (“PBD”, available from Scientific Polymers Products, Inc., Ontario, NY, as Catalog # 688; CAS #31567-90-5; 7% cis 1 ,4; 93% vinyl 1,2; Mw approx.
  • PEMA poly(ethylene-co-methyl acrylate)
  • PEBA poly(ethylene- c'o-butyl acrylate)
  • PBD polybutadiene
  • PEVA poly(ethylene-co-vinyl acetate)
  • Poly(ethylene-co-vinyl acetate) (“PEVA”, available as Product No. 34,691-8 from Sigma- Aldrich Fine Chemicals).
  • PEVA was run as a comparative example. Stress-strain curves are shown in Figure 7. The calculated average tensile modulus for each of the tested polymers is shown in Table 1.
  • Raman measurements were made with a WITec CRM200 scanning confocal Raman microscope.
  • the Raman microscope can optically dissect a layer of coating on a stent, looking into the coating and imaging the distribution of the coating composition ingredients within the thin coating. Since no Raman signal is obtained from air and steel materials, the air above the coating surface is black as is the steel substrate upon which the coating is deposited.
  • Figure 8 shows a 100 micron wide and 10 micron deep image (including a 10 micron bar in the lower left-hand corner for scale) taken by measuring the Raman intensity at 2900 cm '1 for a stent with a 33/33/33 PEMA/PBMA/rapamycin coating. Since each of the composition ingredients, including first and second polymers as well as bioactive agent, contribute signal at this wavenumber, the image obtained is one of the entire coating.
  • Figure 9 shows Raman intensity at 1630 cm "1 for the same region of stent coating shown in Figure 8.
  • the solutions included mixtures of poly(l,2-butadiene) ("PBD”, available from Scientific Polymers Products, Inc., Ontario, NY, as Catalog # 688; CAS #31567-90-5; 7% cis 1,4; 93% vinyl 1,2; Mw approx. 100 kilodaltons), poly(butyl methacrylate) (“PBMA”, available from Sigma- Aldrich Fine Chemicals as Product No. 18,152-8, having a weight average molecular weight (Mw) of about 337 kilodaltons), and rapamycin (“RAPA”, available from LC Laboratories, Woburn, MA) dissolved in THF to form a homogeneous solution.
  • PPD poly(l,2-butadiene)
  • PBMA poly(butyl methacrylate)
  • RAPA rapamycin
  • the stents were not given a primer pre-treatment.
  • Results demonstrate the ability to control the elution rate of rapamycin, a pharmaceutical agent, from a coated stent surface by varying the relative concentrations of PBD and PBMA in the polymer mixture as described herein.
  • the lines in Figure 10 and similar figures are expressed in terms of percent by weight of the first and second polymers, respectively, in the coated compositions. This can be compared to the amounts provided above, which are stated in terms of "mg/ml" of the respective polymers in the coating compositions themselves, which are applied to the stents.
  • “54/13” corresponds to the coated compositions that results from the use of the first coating composition above, which upon removal of the solvent provides a coated composition having 54% PBD and 13% PBMA respectively, by weight.
  • solutions such as the second solution above, e.g., which includes equal amounts (by weight) of the ingredients will alternatively be referred to herein as "33/33/33", representing the weight ratio of ingredients to each other.
  • PBD/PBMA coatings were also analyzed. Stents were coated with PBD and PBMA in a procedure as described above but without any bioactive agent. The stents were then tested according to the method described in the Durability Test Procedure section. The results are displayed in Figure 1 OA.
  • the PBD/PBMA coatings showed very little damage in the form of some small cracks that did not appear to reach the stent surface. These coatings were applied to bare metal stents before ethylene oxide sterilization ("sterilization"), Parylene TM coated stents before sterilization, and Parylene TM coated stents after sterilization.
  • PBDA poly(butadiene-co-acrylonitrile)
  • PBMA PBMA
  • RAPA PBMA and RAPA
  • Results demonstrate the ability to control the elution rate of dexamethasone, a pharmaceutical agent, from a stent surface by varying the relative concentrations of PBD and PBMA in the polymer mixture.
  • Example 13 Surface Characterization of Coated Stents after Crimping and Expansion Using the Sample Preparation Procedure, stents were sprayed with a coating of second polymer/poly(butyl methacrylate)("PBMA”)/rapamycin("RAPA”), mixed at a weight ratio of 33/33/33 at 10 mg/ml each of THF.
  • the first polymer was polybutadiene ("PBD", available from Scientific Polymers Products, Inc., Ontario, NY, as Catalog # 688; CAS #31567-90-5; 7% cis 1,4; 93% vinyl 1,2; Mw approx. 100 kilodaltons), and a polymer from the additional polymer class was poly(ethylene-co-methyl acrylate)
  • the second polymer used was PBMA from Sigma-Aldrich Fine Chemicals as Product No. 18,152-8, having a weight average molecular weight (Mw) of about 337 kilodaltons.
  • Stents were either used as received (i.e., uncoated metal), were pre- treated with a silane/ParyleneTM primer using the primer procedure described in the Sample Preparation Procedure, were not pre-treated with primer but were given a subsequent PBMA topcoat using the spraying process described in the Sample Preparation Procedure, or were given both a silane/ParyleneTM pre-treatment primer and subsequent PBMA topcoat.
  • the coated stents were crimped down on balloons and were expanded following the Durability Test Procedure, which showed that, overall, all the coatings remained intact (i.e., the coating did not peel off or flake off, etc.), with only a few localized sites where coating delaminated from the metal stent.
  • primer coatings were used, essentially no delamination was evident and cracks were all smaller than about 10 microns in width. Almost all stents had some degree of cracking of the coating around bends in the struts, as well as some mechanical damage caused by handling or balloon expansion. Adding a PBMA topcoat did not adversely affect the mechanical integrity of the coating on the stent after crimping and expansion, as might be expected with an overall thicker stent coating.
  • coatings containing bioactive agents incorporated into blends of PBMA with either PEMA or PBD as the other polymer are viable candidates for commercial applications in drug-eluting stents and are expected to be particularly effective in minimizing the onset of restenosis after stent implantation.
  • Scanning Electron Microscopy can be used to observe coating quality and uniformity on stents at any suitable point in their manufacture or use. Crimped and expanded stents were examined for coating failures in fine microscopic detail using a scanning electron microscope (SEM) at magnifications varying from 150X to 5000X. Various coating defects tend to affect the manufacture and use of most polymer coated stents in commercial use today, including the appearance of cracks or tears within the coating, smearing or displacement of the coating, as well as potentially even delamination of the coating in whole or in part.
  • SEM scanning electron microscope
  • Such defects can occur upon formation of the coating itself, or more commonly, in the course of its further fabrication, including crimping the stent upon an inflatable balloon, or in surgical use, which would include manipulating the stent and expanding the balloon to position the stent in vivo.
  • Figure 13 shows a scanning electron microscope image from a LEO Supra-35 VP at 250X of a 33/33/33 PBD/PBMA/rapamycin coating on a stent after conventional crimping and balloon expansion procedures.
  • the image shows that the coated composition maintains integrity after expansion, showing no evidence of delamination or cracks.
  • polybutadiene-containing coatings exhibited less cracking and in one case no cracks, and when cracks occurred, they were typically smaller in size in comparison with the cracks found in PEMA or PEVA-containing coatings.
  • cracks which opened up and delaminated from the metal stent surface were found in coatings containing PEMA and PEVA in the absence of a Parylene TM primer coating.
  • Polybutadiene-containing coatings without Parylene TM primer, as well as comparative PEMA (or comparative PEVA)-containing coatings with Parylene TM primer showed cracks which tended to not result in delamination.
  • Results illustrates several elution rates of rapamycin, a pharmaceutical agent, from a coated stent surface by varying the relative concentrations of rapamycin, PBD, and PBMA with and without utilizing a topcoat. Further, Figure 15 demonstrates the ability to control the elution rate of a bioactive agent by varying the amount of topcoat provided relative to the coating composition.
  • Stainless steel BX velocity stents manufactured by Cordis Corporation, Miami Lakes, FL were used in the following examples.
  • the stents were Parylene treated and weighted before coating.
  • Bioactive agent/polymer solutions were prepared at a range of concentrations in an appropriate solvent, in the manner described herein.
  • the coating solutions were applied to respective stents by spraying procedures using an ultrasonic sprayer as described in U.S. Published Application 2004/0062875 (Chappa et al.); and in U.S. Application Serial No. 11/102,465, filed April 8, 2005 and entitled "Medical Devices and Methods for Producing Same.”
  • the solvent was allowed to evaporate.
  • the coated stents were weighed to determine the mass of coating and consequently the mass of polymer and bioactive agent.
  • the coating thickness can be measured using any suitable means, e.g. optical interferometry.
  • the Bioactive Agent Release Assay was used to determine the extent and rate of drug release in vitro conditions.
  • a Sotax dissolution system (Sotax Corporation, Horsham, PA) was utilized. The system used a 2wt% surfactant/water solution as elution media.
  • the coated stents were placed in the sample baskets, and the drug elution monitored by UV spectrometry over the course of several days. The elution media was held at 37 0 C. After the elution measurement, the stents were removed, rinsed, dried, and weighed to compare measured drug elution to mass loss.
  • One basecoat solution was prepared for coating the stents.
  • This solution included mixtures of "PBD” poly(butadiene), “PBMA” poly(butyl methacrylate), and sirolimus dissolved in tetrahydrofuran (THF).
  • the basecoat solution contained 6 mg/ml PBD, 6 mg/ml PBMA, and 6 mg/ml Sirolimus for a total "solids" concentration of 18 mg/ml. Stents were coated with approximately 435 micrograms of total coating. The basecoat was allowed to dry before the topcoats were applied.
  • Eye coils were roughened by blasting 50 ⁇ m silica particles at the surface of the coils under high pressure and velocity.
  • the roughness of the coil surfaces, particularly the peak to valley distance, was measured with the VSI (Vertical Scanning Interferometry) mode of an Optical Interferometer.
  • the VSI mode of the optical interferometer was used to look at the surface topography of uncoated eye coils over an area approximately 155 um x 120 ⁇ m. Three separate areas were measured on each coil on two sides of each coil, to get an average for each. Each measurement comprised of a 30 ⁇ m scan to acquire the raw data, after which R 3 , R t , and R z roughness parameters were calculated.
  • R a the roughness average, is the arithmetic mean of the absolute values of the surface departures from the mean plane.
  • R t the maximum height (peak to valley distance), is the vertical distance between the highest and lowest points over the entire dataset (highest and lowest single pixels)
  • R z the average maximum height (average peak to valley distance), is the average of the difference of the ten highest and ten lowest points in the dataset (10 highest and 10 lowest pixels at least 4.6 ⁇ m apart from each other laterally).
  • the R z value measures the average peak to valley distance from multiple locations to prevent a misrepresentation of the data caused by single data pixels that are random noise, or uncommon surface features like scratches or pits.
  • Table 2 shows the roughness statistics for coil 1
  • Table 3 shows the roughness statistics for coil 2.
  • Figure 2OA shows a surface plot of test A-2 of coil 1
  • Figure 2OB shows a 3D representation of Figure 2OA
  • Figure 21 A shows a surface plot of test A-2 of coil 2
  • Figure 2 IB shows a 3D representation of Figure 2 IA.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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Abstract

La présente invention concerne une composition de revêtement et un procédé afférent à utiliser dans l'application d'un agent bioactif sur une surface d'une manière qui permettra à l'agent bioactif d'être libéré du revêtement in vivo. La composition est particulièrement bien adaptée pour enduire la surface de dispositifs médicaux implantables, tels que des stents ou des cathéters, afin de permettre au dispositif de libérer un agent bioactif dans le tissu environnant au cours du temps. La composition comprend une pluralité de polymères compatibles ayant différentes propriétés leur permettant d'être combinés ensemble pour fournir une combinaison optimale de propriétés telles que la durabilité, la biocompatibilité et la cinétique de libération.
EP05812405A 2005-04-06 2005-10-06 Compositions de revetements bioactifs pour dispositifs medicaux Withdrawn EP1868666A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US11/099,911 US20050220841A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11/099,796 US7544673B2 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11/099,939 US20050220843A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11/099,997 US20050244459A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11/099,935 US20050220842A1 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
US11/099,910 US7541048B2 (en) 2004-04-06 2005-04-06 Coating compositions for bioactive agents
PCT/US2005/035957 WO2006107336A1 (fr) 2005-04-06 2005-10-06 Compositions de revetements bioactifs pour dispositifs medicaux

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US7828840B2 (en) 2007-11-15 2010-11-09 Med Institute, Inc. Medical devices and methods for local delivery of angiotensin II type 2 receptor antagonists
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AU3664693A (en) * 1992-02-13 1993-09-03 Bio-Metric Systems, Inc. Immobilization of chemical species in crosslinked matrices
US6254634B1 (en) * 1998-06-10 2001-07-03 Surmodics, Inc. Coating compositions
US7097850B2 (en) * 2002-06-18 2006-08-29 Surmodics, Inc. Bioactive agent release coating and controlled humidity method
CA2494187A1 (fr) * 2002-08-13 2004-02-19 Medtronic, Inc. Systeme d'administration de principe actif, dispositif medical et methode
DE602004028638D1 (de) * 2003-05-02 2010-09-23 Surmodics Inc System zur kontrollierten Freisetzung eines bioaktiven Wirkstoffs im hinteren Bereich des Auges
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