WO2002003890A1 - Enduits de diffusion de medicament, applications et procedes - Google Patents

Enduits de diffusion de medicament, applications et procedes Download PDF

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Publication number
WO2002003890A1
WO2002003890A1 PCT/US2001/041281 US0141281W WO0203890A1 WO 2002003890 A1 WO2002003890 A1 WO 2002003890A1 US 0141281 W US0141281 W US 0141281W WO 0203890 A1 WO0203890 A1 WO 0203890A1
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WO
WIPO (PCT)
Prior art keywords
therapeutic agent
membrane
coating composition
layer
polymeric matrix
Prior art date
Application number
PCT/US2001/041281
Other languages
English (en)
Inventor
Shigemasa Osaki
Paul O. Zamora
Meng Chen
Original Assignee
Biosurface Engineering Technologies, Inc.
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Filing date
Publication date
Application filed by Biosurface Engineering Technologies, Inc. filed Critical Biosurface Engineering Technologies, Inc.
Priority to AU2001279288A priority Critical patent/AU2001279288A1/en
Priority to US10/332,307 priority patent/US20040058056A1/en
Publication of WO2002003890A1 publication Critical patent/WO2002003890A1/fr

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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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D4/00—Coating compositions, e.g. paints, varnishes or lacquers, based on organic non-macromolecular compounds having at least one polymerisable carbon-to-carbon unsaturated bond ; Coating compositions, based on monomers of macromolecular compounds of groups C09D183/00 - C09D183/16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings

Definitions

  • the invention relates to compositions and methods for coating implantable medical device surfaces to provide controlled release of a therapeutic agent.
  • the invention relates to a polymeric composition applied to at least one surface of the device, the composition including a polymeric matrix and the therapeutic agent, wherein the therapeutic agent is a drug, peptide, biological agent or other bioactive molecule, which polymeric composition has applied thereto by plasma deposition a hydrocyclosiloxane-containing membrane.
  • siloxane membranes and coatings are known in the art, and is taught in U.S. Patent No. 5,463,010, Hydrocyclosiloxane Membrane Prepared by Plasma Polymerization Process, incorporated herein by reference.
  • These siloxane membranes provide a variety of benefits, and can be used to coat substrates to impart properties such as hydrophobicity, thromboresistance, gas permeability and biocompatability.
  • drugs or other therapeutic agents may be coated on a surface, or may alternatively comprise a part of a porous or degradable matrix, such that the drugs or other therapeutic agents are eluted over a period of time.
  • rate of elution is controlled by the design of the matrix, design of the binding elements contained in the coating material, or the like.
  • any change in the rate of elution requires, in most instances, a reformulation of the coating material, reformulation of the matrix material, or the like, with attendant testing and evaluation.
  • U.S. Patent Nos. 5,624,411 ; 5,679,400; and 5,464,650 disclose a method and device for delivery of a drug using an intraluminal stent, consisting of a first coating layer that includes a therapeutic substance and a second coating layer that includes a porous polymer.
  • the first coating layer also includes a porous polymer, which may be the same or different as the polymer of the second coat.
  • the polymer is porous and is applied by art conventional means, such as by application of a solution and optionally a solvent.
  • U.S. Patent Nos. 6,096,070; 5,824,049; and 5,609,629 disclose application of a bioactive substance layer on a medical device, but without any polymeric matrix, with subsequent deposition of a porous polymer over the bioactive substance layer.
  • the porous polymer is deposited by vapor deposition, and is from about 500 to about 25,000 nm thickness, and is optimally about 5,000 nm thick.
  • the polymeric layer is characterized in that it has defined pores.
  • U.S. Patent Nos. 5,569,463 and 5,447,724 disclose a method of drug release including a polymeric reservoir containing an elutable drug, with a surface layer that contains defined pores, such as a polyether urethane composition. These and other patents disclose a number of methods and devices for controlled release of drugs or other bioactive substances. However, none of the prior art methods meet all the requirements for the intended purpose, including a variable quantity of drug, a variable release rate, minimal thickness of the membrane for controlled release, and high strength and hardness of the topmost membrane, all in a biocompatible and thromboresistant material.
  • the invention provides a biocompatible coating composition for in vivo diffusion of a therapeutic agent, which composition includes a layer including a therapeutic agent dispersed in a polymeric matrix and a membrane posited over the layer, the membrane formed from the plasma polymerization of hydrocyclosiloxane monomer of the general formula:
  • R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10, wherein the membrane cross-links with the polymeric matrix of the layer.
  • the biocompatible coating composition includes a layer containing a therapeutic agent, with the membrane as set forth above posited over the layer.
  • no polymeric matrix is provided.
  • the invention further provides an implantable medical device, which medical device includes a structural component adapted for implantation is a patient, the structural component having at least one exterior surface.
  • a layer including a therapeutic agent is posited over at least a portion of the at least one exterior surface, and a membrane posited over the layer, the membrane formed from the plasma polymerization of hydrocyclosiloxane monomer of the general formula:
  • the implantable medical device further includes embodiments wherein the layer comprising a therapeutic agent includes a polymeric matrix, whereby the therapeutic agent is dispersed in the polymeric matrix and the membrane cross-links with the polymeric matrix.
  • the invention further provides a method of applying a biocompatible coating composition to a structural component for in vivo diffusion of a therapeutic agent, the method including the steps of providing a structural component adapted for introduction into a patient, the structural component having at least one exterior surface; positing a layer including a therapeutic agent over at least a portion of the at least one exterior surface; and plasma depositing a membrane over the layer including the therapeutic agent, the membrane formed from the plasma polymerization of hydrocyclosiloxane monomer of the general formula:
  • the step of positing the layer comprising a therapeutic agent may further consist of positing a layer including a polymeric matrix and the therapeutic agent.
  • n may be between 7 to 10, between 4 to 6 or between 2 to 3.
  • the hydrocyclosiloxane monomer may be 1 ,3,5,7-tetramethylhydrocyclotetrasiloxane, 1 ,3,5,7,9-pentamethylhydrocyclopentasiloxane, 1 ,3,5,7,9,11-hexamethylhydrocyclohexasiloxane, or a mixture of 1 ,3,5,7, 9-pentamethylcyclopentasiloxane and 1 ,3,5,6,9,11-hexamethylcyclohexasiloxane monomers.
  • the polymeric matrix may include poly(2-hydroxyethyl methacrylate), polycaprolactone or cellulose acetate butyrate.
  • the membrane has a thickness of between about
  • the layer including the therapeutic agent contains between about 0.01 g and about 5.0 mg of therapeutic agent per cm 2 , and preferably between about 0.1 mg and about 0.5 mg of therapeutic agent per cm 2 .
  • a primary object of the present invention is to provide a method and device for drug diffusion for use with implantable medical devices.
  • Another object of the present invention is to provide a method and device for drug diffusion wherein the rate of diffusion is controlled by a plasma-deposited hydrocyclosiloxane membrane that is from about 20 to about 450 nm, and preferably about 20 to about 250 nm, in thickness.
  • Another object of the invention is to provide a polymeric matrix through which a therapeutic drug is dispersed, which polymeric matrix has a first rate of diffusion, with a plasma-deposited hydrocyclosiloxane membrane posited thereover, and preferably cross-linked with the polymeric matrix, most preferably highly cross-linked, the plasma-deposited hydrocyclosiloxane membrane having a second rate of diffusion.
  • a primary advantage of the present invention is that it provides a very hard and thin membrane, with a thickness of from about 20 to about 450 nm thickness, and preferably about 20 to about 250 nm thickness, that controls the rate of diffusion.
  • Another advantage of the present invention is that plasma-deposited hydrocyclosiloxane forms a highly cross-linked and dense membrane, which membrane is also hard and flexible, but not elastic, such that it provides surface protection, is highly biocompatible, and controls diffusion.
  • Fig. 1 is a plot illustrating the thickness of a hydrocyclosiloxane coating of this invention
  • Fig. 2 is plot illustrating the rate of elution of NPC-15199 as a function of hydrocyclosiloxane coating time
  • Fig. 3 is a plot illustrating the rate of elution of daunomycin as a function of hydrocyclosiloxane coating time.
  • the present invention provides methods and coatings for the formation and use of a plasma- deposited aliphatic polymerized hydrocyclosiloxane membrane as a diffusion control barrier for drugs and therapeutic agents coated on a surface or contained within a matrix, preferably a polymeric matrix.
  • the drugs or therapeutic agents together with the membrane and, if provided, the matrix, form the drug delivery component of the invention.
  • the plasma-polymerized hydrocyclosiloxane membrane coats all or substantially all of the drug delivery component that is in contact or communication with the exterior surface, whereby all or substantially all of any drug or therapeutic agent must transit the membrane in order to be released.
  • the membrane has a variety of characteristics in addition to serving as a diffusion control membrane, including thromboresistance, gas permeability and biocompatibility.
  • the present invention is particular useful with medical devices.
  • the membrane is formed through plasma polymerization of suitable aliphatic hydrocyclosiloxane monomers or plasma copolymerization of aliphatic hydrocyclosiloxane monomers and co-monomers, depending on the desired characteristics.
  • Aliphatic hydrocyclosiloxane monomers have the general formula:
  • R is alkyl group of 1 to about 5 carbon atoms and n is an integer from 2 to about 10.
  • Monomers include those where n is 7 to 10, where n is 4 to 6 and where n is 2 to 3.
  • Co-monomers such as fluorocarbons, organo-based monomers, or functional group terminated monomers can be utilized to change the properties of the membrane to adjust for varied applications. Definitions. For purposes of this patent, the following terms are defined:
  • biocompatible polymer refers to polymers which, in the amounts employed, are not toxic and are substantially non-immunogenic when placed internally in the patient.
  • bioabsorbable polymer refers to biocompatible polymers that are degradable, and preferably biodegradable, with a definable degradation rate.
  • a bioabsorbable polymer is capable of being broken down, in the body, into smaller constituents.
  • the bioabsorbable polymer is, as it degrades into smaller constituents, metabolized or excreted through normal biological systems.
  • Hydrolysis is one mechanism by which some bioabsorbable materials are broken down following implantation within a living organism.
  • Some bioabsorbable polymers may be composites, and may have a bioabsorption rate that varies over time.
  • suitable bioabsorbable polymers may include poly-L-lactide, poly-D-lactide, polyglycolide, poly(dioxanone), polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, glycosaminogylcans including hyluronic acid and cross-linked hyaluronic acid, fibrin, elastin, silk, poly(hydroxybutyrate), polyanhydride, polyphosphoester, poly(amino acids), poly(alpha- hydroxy acid) and combinations thereof.
  • plasma polymerization refers to the formation of polymeric materials under the influence of plasma, consisting of ionized gases, free radicals and electrons.
  • plasma glow zone refers to the region in which the glow discharge in the plasma polymerization process takes place.
  • therapeutic agent refers to any substance used as a drug, to effect a biochemical change in an organism, or to confer a benefit to an organism. The term thus includes art conventional drugs, compounds, molecules, peptides, peptidomimetics, antibodies and fragments and mimics thereof, and the like.
  • a therapeutic drug may, but need not, bind to a receptor in the organism, be a receptor for an endogenous substance found in an organism, or be an agonist, antagonist, or a mixed agonist-antagonist of a receptor-mediated process or reaction.
  • the coatings may be applied to any of a wide variety of structural components of medical devices. Suitable structural components with a surface include medical devices that are intended to contact blood or other tissues, such as a stent, catheter, shunt, graft, artificial blood vessel, nerve-growth guide, artificial heart valve, prosthetic, pacemaker lead, in- dwelling catheter, cardiovascular graft, bone replacement, wound healing device, cartilage replacement device, urinary tract replacement and other medical devices known in the art. Other examples of medical devices that would benefit from the application of the present invention will be readily apparent to those skilled in the art of surgical and medical procedures and are therefore contemplated by the instant invention.
  • the structural component may include a mesh, coil, wire, inflatable balloon, or any other device or structure which is capable of being implanted at a target location, including intravascular target locations, intralumenal target locations, target locations within solid tissue, such as for the treatment of tumors, and the like.
  • the implantable device can be intended for permanent or temporary implantation. Such devices may be delivered by or incorporated into intravascular and other medical catheters.
  • Suitable surfaces of the structural component include stainless steel, nitinol, titanium, other metal alloys, polyvinyl chloride, polyethylene, polylactide, poly glycolide, poly caprolactone, poly methyl methacrylate, poly hydroxylethyl methacrylate, polyurethane, polystyrene, polycarbonate, dacron, extended poly tetrafluoroethylene (Teflon®), related fluoropolymer composites (Gore-Tex®), or combinations thereof. All or part of the available surface can be modified.
  • substrate materials can also be used, including poly(acrylate), poly(bisphenol A carbonate), polybutadiene, poly utylene terephthalate), poly(butryl methacrylate), polydimethylsiloxane, polyester, polyethyleneimine, polysulfone, poly(vinyl acetate), polyvinylidine fluoride, polylactide, polyglycolide, polycaprolactone and copolymers and variants thereof.
  • the structural component may be a biodegradable or bioerodible material, which after controlled release of a therapeutic drug degrades or erodes.
  • biodegradable or bioerodible materials to provide sustained or controlled release of chemotherapeutic or other drugs, including bioactive drugs, has been known for a number of years.
  • Biodegradable implants for the controlled release of hormones, such as contraceptive hormones were developed over twenty years ago, and have been used as birth control devices.
  • Biodegradable or bioerodible materials employed for controlled release of drugs include polyanhydrides, polyglycolic acid, polylactic/polyglycolic acid copolymers, polyhydroxybutyrate-valerate and other aliphatic polyesters, among a wide variety of polymeric substrates employed for this purpose.
  • Biodegradable implantable materials some of which have been used in drug delivery systems, are described in U.S. Patent Nos.
  • U.S. Patent No. 5,876,452 describes biodegradable polymeric material, such as polyanhydrides and aliphatic polyesters, providing substantially continuous release of bioactive drugs, including bi-phasic release of bioactive drugs.
  • a bioabsorbable polymeric structural component is made from a biocompatible polymeric material such as polycaprolactone, poly(D,L-lactide) poly(L-lactide), polyglycolide, poly(dioxanone), poly(glycolide-co-trimethylene carbonate), poly(L-lactide-co- glycolide), poly(D,L-lactide-co-glycolide), poly(L-lactide-co-D,L-lactide) or poly(glycolide-co- trimethylene carbonate-co-dioxanone).
  • the persistence of the bioabsorbable polymeric structural component within a living organism is in excess of the anticipated period over which the therapeutic agent will diffuse in an effective amount, and preferably in excess of at least two such anticipated periods.
  • the drug delivery component includes any drug suitable for treatment of the disease condition for which the device is employed.
  • this includes any known chemotherapeutic agent including but not limited to bleomycin, busulfan, carboplatin, carmustine, cisplatin, dactinomycin, daunorubicin, doxorubicin, estramustine, interferon, levamisole, methotrexate, mitomycin, paclitaxel, pentostatin, plicamycin, tamoxifen, vinblastine, vindesine and the like.
  • radiosensitizers including 5-halo-uracils, anti-angiogenesis compounds including thalidomide and tranilast, natural or synthetic peptide hormones including octreotide, and compounds that induce apoptosis including butyrate and nitric oxide donors. Any drugs or therapeutic agents can be used singly or in combination.
  • the therapeutic agent used in the present invention can be virtually any therapeutic agent that possesses desirable therapeutic characteristics for application to a tissue.
  • useful bioactive agents of the present invention include antithrombogenic agents, antibiotic agents, anti-tumor agents, antioxidants, antimetabolite agents, antiviral agents, anti-angiogenic agents, angiogenic agents, anti-mitotic agents, anti-inflammatory agents, angiostatin agents, endostatin agents, cell cycle regulation agents, bioactive peptides, peptide mimetics, protein fragments, genetic agents, including hormones, such as estrogen; and homologs, analogs, derivatives, fragments, pharmaceutical salts and mixtures of any of the foregoing.
  • the therapeutic agent includes both solid substances and liquid substances.
  • Antithrombogenic agents include, for example, glucocorticoids (e.g. dexamethasone, betamethasone), hirudin, tocopherol, coumadin, angiopeptin, aspirin, ACE inhibitors and dipyridamole.
  • Antimitotic agents and antimetabolite agents include drugs such as methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin, daunomycin, taxanes including paclitaxel, rapamycin, and mutamycin.
  • the therapeutic agent of the present invention can include organic acid functional group-containing antibiotics.
  • antibiotics include rifampicin, penicillins, cephalosporins, vancomycins, aminoglycosides, quinolones, polymyxins, erythromycins, tetracyclines, chloramphenicols, clindamycins, lincomycins, and sulfonamides, and homologs, analogs, fragments, derivatives, pharmaceutical salts and mixtures of any of the foregoing.
  • the therapeutic agent of the present invention can also include organic acid functional group-containing anti-tumor agents.
  • anti-tumor agents include paclitaxel, docetaxel, alkylating agents including mechlorethamine, chlorambucil, cyclophosphamide, melphalan and ifosfarnide; antimetabolites including methotrexate, 6-mercaptopurine, 5-fluorouracil and cytarabine; plant alkaloids including colchicines, vinblastine, vincristine and etoposide; antibiotics including doxorubicin, daunomycin, bleomycin, and mitomycin; nitrosureas including carmustine and lomustine; inorganic ions including cisplatin; hormones including somatostatin, LHRH, progesterone, and estrogen; steroid hormones including hydrocortisone, tamoxifen, and flutamide; and homologs, analogs, fragments, derivatives, pharmaceutical salts and
  • the therapeutic agent of the present invention can also include organic acid functional group- containing anti-viral agents.
  • anti-viral agents include amantadines, rimantadines, ribavirins, idoxuridines, vidarabines, trifluridines, acyclovirs, ganciclovirs, zidovudines and foscarnets, and homologs, analogs, fragments, derivatives, pharmaceutical salts and mixtures of any of the foregoing.
  • the coating includes the therapeutic drug which is dispersed within and throughout a polymeric matrix, preferably a matrix formed from a biocompatible polymer, and in one embodiment a matrix formed from a bioabsorbable polymer.
  • Bioabsorbable polymers that may be employed include poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co- trimethyle ⁇ e carbonate), polyp osphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g.
  • polyalkylene oxalates polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid.
  • biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters can be employed, and other polymers can also be employed, provided they can be dissolved in the selected solvent and cured or polymerized on the surface of the structural component such as polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such as poly
  • PHEMA poly(2-hydroxyethyl methacrylate)
  • PHEMA poly(2-hydroxyethyl methacrylate)
  • This solvent system can also be employed with many therapeutic agents, and is thus a preferred polymeric matrix material, particularly for therapeutic agents soluble in ethanol and water, or in acetone and water.
  • polymeric matrix materials include polycaprolactone and cellulose acetate butyrate, both of which are soluble in solvents compatible with many therapeutic agents.
  • the polymeric matrix material is preferably soluble in a solvent in which the therapeutic agent is also soluble.
  • solvents include, without limitation, water, alcohols, chloroform, acetone, xylene, and the like.
  • the polymeric matrix material, therapeutic agent and solvent must be compatible, such that there is no adverse chemical change in the therapeutic agent affecting efficacy of the therapeutic agent. It is preferred that the therapeutic agent also be soluble in the solvent, such that both the polymeric matrix material and the therapeutic agent are both in solution. However, in an alternative embodiment, the therapeutic agent may be dispersed through the solution of the polymeric matrix material and the solvent.
  • the therapeutic material is most preferably in the form of fine particulates.
  • the solution comprising a solvent, the therapeutic agent and the polymeric matrix material may be applied to the structural component by any means known in the art. This can include dip coating, painting, spraying, partial immersion and the like. Following application, the coated structural component may be incubated at a constant temperature, such as between about 37° C and about 80° C, and preferably between about 45° C and 65° C, to facilitate evaporation of the solvent and curing of the polymeric matrix. Multiple coats of the solution may be applied to the structural component, optionally with curing between applications. In this way, the thickness of the coating, and the quantity of therapeutic agent per unit area, may be precisely controlled.
  • the quantity of polymeric matrix material placed in solution depends, in part, on the solubility of the polymeric matrix material.
  • PHEMA in an ethanol and water solvent between about 5% and 20% PHEMA, preferably between about 7% and 10% PHEMA, may be placed in solution.
  • the maximum and optimal concentration in the selected solvent may be easily and empirically ascertained.
  • the quantity of the therapeutic agent per unit area is dependent, in part, on the solubility of the therapeutic agent in the solvent, the quantity of therapeutic agent either in solution or dispersed therein, the thickness of the coating and the number of coats applied.
  • the coating including all applications thereof, may thus contain between about 0.01 mg per cm 2 and about 5.0 mg per cm 2 of therapeutic agent, and preferably between about 0.1 mg per cm 2 and about 0.5 mg per cm 2 of therapeutic agent.
  • the ratio of therapeutic drug to polymeric matrix material depends, in large part, on the polymer selected, the desired rate of release of the therapeutic drug, and the like. This parameter may be altered as required to obtain a desired result.
  • the polymeric matrix material forms a cross-linked polymer, and accordingly contains appropriate reactive groups that may be cross-linked.
  • PHEMA for example, contains hydrogen atoms along its carbon backbone, and may thus be cross-linked to both itself and to a plasma-deposited hydrocyclosiloxane membrane that contains Si-H groups.
  • a cross- linkable polymeric matrix material is preferred for several reasons, including increased adherence to the structural component, and of more significance, forming a cross-linked connection with the plasma-deposited hydrocyclosiloxane membrane. Cross-linking between the polymeric matrix material and the plasma-deposited hydrocyclosiloxane membrane is believed to more precisely control the rate of diffusion, increase adherence of the membrane to the coating, and define a harder and more protective membrane.
  • the polymeric matrix material may also cross-link with the surface of the structural component.
  • the structural component may be selected such that cross-linking is possible, or may be modified to enhance cross-linking. Such modifications include, but are not limited to, introduction of amine groups such as by plasma etching with NH 3 or other nitrogen-containing gases.
  • the coating including the polymeric matrix may optionally have a predefined release rate as a result of the coating composition, which may be a continuous, bi-phasic or an otherwise modulated release rate.
  • the therapeutic drug is locally released at the site of the device, and is cleared from the patient by normal clearance and excretory function.
  • the drug and other components, including a polymeric matrix is selected such that it may be coated with a hydrocyclosiloxane membrane by plasma polymerization.
  • the device may itself consist solely of a polymeric matrix and the drug or other therapeutic agent, and preferably a biodegradable polymeric matrix, which is then coated with a hydrocyclosiloxane membrane by plasma polymerization, wherein the length of plasma polymerization determines the thickness of the siloxane membrane, and accordingly the rate of diffusion of the drug or other therapeutic agent.
  • the polymeric matrix will remain substantially intact for a predetermined persistence period, such persistence period being at least equal to the maximum length of time of drug diffusion.
  • hydrocyclosiloxane Monomer Plasma Polymerization The hydrocyclosiloxane monomers are polymerized directly on the drug delivery component surface using plasma-state polymerization techniques.
  • the general process of plasma-state polymerization is known to those in the art. See Yasuda, Plasma Polymerization, Academic Press Inc., New York (1985), incorporated herein by reference.
  • hydrocyclosiloxane monomers are polymerized onto a surface by activating the monomer from a gaseous state in a plasma state composed of electrons, ions, gas atoms, free radicals and molecules.
  • the plasma state generates highly reactive species of the hydrocyclosiloxane monomer, which forms a characteristically highly cross-linked, ultra-thin polymer membrane, which is deposited on the substrate surface as it moves through the area of most intense energy density, the plasma glow zone.
  • an electric discharge from a radio frequency (R.F.) generator is applied to the "hot" electrodes of plasma reactor.
  • the selected monomers are introduced into the reactor and energized into a plasma, saturating the plasma glow zone with an abundance of energetic free radicals and lesser amounts of ions and free electrons produced by the monomers.
  • the surface of the material is continually bombarded with free radicals, resulting in the polymerized membrane coating.
  • the plasma-state polymerized hydrocyclosiloxane membrane is highly adherent to most organic and inorganic materials, providing a smooth and hard membrane coating.
  • the monomer or monomer mixture When the plasma glow zone is activated, the monomer or monomer mixture is continually passed through the plasma glow zone.
  • the material to be coated such as the structural component to which is adhered a therapeutic drug, and preferably a therapeutic drug in a polymeric matrix, is placed within the plasma glow zone. This results in a flow of plasma state monomer or monomer mixture in and around the structural component, thereby resulting in deposition on exposed surfaces.
  • the monomer or monomer mixture that does not deposit is removed under vacuum from the plasma field.
  • the plasma state monomer or monomer mixture deposition may be controlled by varying the plasma conditions, including primarily the power level of the R.F. generator and the length of time the target material is in the plasma glow zone, typically the total length of time of plasma generation.
  • Aliphatic hydrocyclosiloxane monomers may be used to create a homogeneous membrane coating.
  • aliphatic hydrocyclosiloxane monomers and co-monomers may be mixed to create membrane coatings having properties different from the properties of a homogenous membrane prepared using aliphatic hydrocyclosiloxane monomers.
  • reactive functionalizing monomers, or organo-based monomers, orfluorocarbon monomers together with the aliphatic hydrocyclosiloxane monomers in the plasma polymerization system, chemical affinity of the plasma copolymerized aliphatic hydrocyclosiloxane membrane with selective monomers can be controlled.
  • Type A refers to membrane coatings that are deposited on the substrate surface through the plasma state polymerization process using aliphatic hydrocyclosiloxane monomers of the general formula:
  • R is an aliphatic group and n is an integer from 2 to about 10, preferably 4 to 6.
  • Preferred aliphatic hydrocyclosiloxane monomers include: 1 ,3,5,7-tetramethylcyclotetrasiloxane ("TMCTS”); 1 ,3,5,7,9-pentamethylhydrocyclopentasiloxane (“PMCTS”); 1 ,3,5,7,9,11- hexamethylhydrocyclohexasiloxane (“HMCHS”) and a mixture of 1 ,3,5,7,9- pentamethylcyclopentasiloxane and 1 ,3,5,6,9,11-hexamethylcyclohexasiloxane monomers (“XMCXS").
  • radio frequency power greater than 5 Watts (“W”), a system pressure less than 300 mTorr, and a monomer flow rate greater than about 1 standard cm 3 per minute (“seem”), will cause a homogeneous, hard, hydrophobic, biocompatible, gas permeable membrane to form on the surface passing through the plasma glow zone.
  • Type B refers to membrane coatings that are produced by plasma co-polymerization process of mixtures of the same aliphatic hydrocyclosiloxane monomers used in Type A membrane coatings and fluorocarbon monomers.
  • Suitable fluorocarbon monomers would include CF 4 , C 2 F 6 , C 3 F 6 , C 3 F 8 , C 2 F 4 , hexafluoropropene, perfluorobenzene, ditrifluoromethylbenzene, perfluoro-2- butyltetrahydrofuran, and pentafluorostyrene.
  • the linear alkyl-type fluorocarbon monomers should have C/F ratio greater than 1/4, for example, C 3 F 6 .
  • Type C refers to membrane coatings which are produced by plasma co-polymerization process of mixtures of the same aliphatic hydrocyclosiloxane monomers used in Type A membrane coatings and organo-based monomers.
  • Suitable organo-based monomers would include ethylene, allylamine, and N-trimethylsilylallylamine, hydrocarbons, unsaturated amines (both N-protected and N-un protected), cyclic aliphatic amines (both N-protected and N-unprotected), mercaptans (organosulfur), nitrites and organophosphorous compounds.
  • Type D refers to membrane coatings that are produced by plasma co-polymerization process of mixtures of the same aliphatic hydrocyclosiloxane monomers used in Type A membrane coatings and reactive functionalizing monomers.
  • Suitable functionalizing monomers include N 2 , C0 2 , NH 3 and S0 2 .
  • the thickness of the membrane can be controlled precisely during the plasma polymerization process, and in general the thickness of the membrane coating is a direct function of the length of time of plasma polymerization, assuming a constant flow rate of monomer. Thus the thickness of the membrane may be controlled by the length of time of plasma polymerization.
  • the diffusion rate of the drug or therapeutic agent through the membrane is, in turn, related to the specific composition of the membrane and the thickness of the membrane.
  • the thickness of the membrane is no more than about 450 nm, and is preferably from about 20 nm to about 250 nm in thickness, depending on the rate of diffusion desired with the specific drug or therapeutic agent, and the specific composition of the membrane.
  • the plasma polymerization process parameters may be varied, so long as a polymer with the desired characteristics is obtained.
  • the RF generator power may be varied from about 5 Wto about 200 W or higher, depending on the desired rate of plasma deposition, the configuration of the plasma apparatus and the like.
  • the mass flow rate of the monomer or monomer mixture may be altered as desired.
  • the mass flow rate setting and the R.F. power setting are synchronized, such that there is sufficient monomer available to polymerize, without requiring excessive removal of unutilized material.
  • the molecular size, configuration, net charge, polarity and solubility of the therapeutic agent also affect the rate of diffusion.
  • one therapeutic agent may diffuse at one rate through a plasma-polymerized hydrocyclosiloxane membrane of a given thickness, while another therapeutic agent diffuses through a membrane of the same thickness at a different rate.
  • the diffusion characteristics for any given therapeutic agent may be easily determined by empirical means, as may the thickness of membrane required to result in diffusion at the desired rate. Since the rate of diffusion is proportional to thickness, only minimal empirical data is required to specify the thickness required for a desired rate of diffusion.
  • the hydrocyclosiloxanes of this invention are characterized in part by a high density of cross-linked sidechains when polymerized, specifically when polymerized by plasma deposition. This is believed to result in a very high-density membrane, wherein the density of molecular packing with the cross-linked polysiloxanes is high. This is believed to be related, in part, to the cyclic nature of hydrocyclosiloxanes, as opposed to linear siloxanes, which form a simple homogenous monolayer.
  • the polymerized hydrocyclosiloxanes are further characterized by the presence of Si-H groups, which presence may be conveniently detected by use of infrared ("IR") spectroscopy.
  • siloxane polymers such as polydimethylsiloxane, do not contain Si-H groups detectable by IR spectroscopy, even though such groups may be present in the monomer prior to polymerization.
  • the Si-H groups in plasma-polymerized hydrocyclosiloxanes are believed to contribute to cross-linking, both within the polymer and between the polymer and any substrate, such as a therapeutic agent or a polymeric matrix containing a therapeutic agent.
  • plasma polymerized hydrocyclosiloxanes are characterized by forming, under the plasma deposition conditions disclosed hereunder, a hard yet elastic, highly cross-linked and dense membrane, which is not significantly elastic. Further, the plasma-polymerized hydrocyclosiloxanes of this invention are only minimally soluble in most solvents, including water.
  • the density of a diffusion medium and the solubility of the diffusant in the diffusion medium are parameters that control the diffusion flux, including the rate of diffusion.
  • Prior art plasma-deposited siloxanes have employed polydimethylsiloxanes, which are comparatively significantly less dense, less cross-linked and substantially more soluble than the polymers of this invention.
  • the use of the polymers of this invention thus provides much harder and denser membranes, which will control diffusion at a rate comparable to that obtainable with polymer described in the prior art, such as polydimethylsiloxane, but at a thickness of between about one- tenth and about one-one hundredth or less than that required for polydimethylsiloxane.
  • the membranes of this invention can be 20 nm in thickness or thinner, and still provide a significant decrease in diffusion of a therapeutic agent posited thereunder.
  • the maximum thickness required for a membrane of this invention is between about 250 and 450 nm in thickness.
  • a membrane of this invention that is substantially thicker is relative impermeable, such that therapeutic agents will not diffuse across such membrane in meaningful quantities or rates.
  • the diffusion control barrier siloxane membrane may be applied to a device that consists of the drug delivery component.
  • the drug delivery component may be an implantable structure forming the device, which may be a biodegradable structure.
  • the therapeutic agent may be dissolved in a solvent, and directly applied to the structural component without use of a polymeric matrix material. More than one coat of the therapeutic agent may be applied, optionally with curing by incubation as for the polymeric matrix material. A plasma-deposited hydrocyclosiloxane membrane is then applied over the therapeutic agent, with the composition of the membrane and thickness of the membrane controlled so as to obtain the desired rate of diffusion, and thus rate of release of the therapeutic agent.
  • the plasma-deposited hydrocyclosiloxane cross-links with the topmost portions of the therapeutic agent in this embodiment, and the therapeutic agent is selected such that it may be cross-linked.
  • Table 1 summarizes the time of plasma deposition using TMCTS and the thickness of the resulting membrane as determined using atomic force microscopy (AFM) following plasma deposition of TMCTS on a silicone substrate.
  • the plasma was generated at 83 W and 55 mTorr with a mass flow rate of 84 seem.
  • Fig. 1 graphically depicts the data of the foregoing table, illustrating the thickness of TMCTS on a silicon wafer as a function of plasma deposition time.
  • NPC-15199 N-(9-fluorenylmethoxycarbonyl)-L-leucine
  • PHEMA poly(2-hydroxyethyl methacrylate)
  • the plasma was generated at 83 W and 55 mTorr with a mass flow rate of 84 seem; under these conditions a micro-thin siloxane membrane is deposited on the targeted surface, with the thickness directly related to the length of time of plasma deposition.
  • the coating thickness could be precisely controlled by plasma deposition time, with a coating thickness in the range of 5 to 200 nm.
  • the coupons were eluted in buffered saline at pH 7.4.
  • the eluted drug was measured spectrophotometrically at 480 nm for daunomycin.
  • the absorbance change was proportional to the concentration of daunomycin.
  • Fig. 3 shows the time course of the absorbance at 480 nm of the coupons with different plasma deposition times.
  • the drug diffusion time was controlled by the TMCTS coating thickness.
  • EXAMPLE 4 The elution time of rapamycin from the surface of stainless steel coupons was evaluated as a function of plasma deposition time.
  • One side of stainless steel coupons was coated with 100 ⁇ 10 ⁇ g of rapamycin dissolved in chloroform (0.2%, w/v). After air drying at room temperature, the coated surfaces were plasma coated with TMCTS. The plasma was generated at 83 W and 55 mTorr with a mass flow rate of 84 seem at various time lengths between 30 and 300 seconds.
  • the coated coupons were extracted with porcine serum mixed with 0.02% NaN 3 as the preservative at 37° C.

Abstract

L'invention concerne des procédés, des enduits et des dispositifs médicaux enduits. Selon cette invention, une membrane d'hydrocyclosiloxane polymérisé aliphatique déposé par plasma est déposée en tant que barrière de régulation de diffusion d'un composant d'administration de médicament, ce dernier consistant en un ou plusieurs agents thérapeutiques enduits sur une surface ou contenus dans une matrice, de préférence une matrice polymère, enduite sur une surface. La membrane d'hydrocyclosiloxane polymérisé par plasma recouvre tout ou essentiellement tout le composant d'administration de médicament en contact ou en communication avec la surface extérieure, de manière que tous ou essentiellement tous les agents médicamenteux ou thérapeutiques doivent se diffuser à travers la membrane pour pouvoir être libérés.
PCT/US2001/041281 2000-07-06 2001-07-06 Enduits de diffusion de medicament, applications et procedes WO2002003890A1 (fr)

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WO2005030287A1 (fr) * 2003-09-19 2005-04-07 Julius-Maximilians- Universität Würzburg Prothese vacsulaire a liberation de substances actives
WO2005061003A1 (fr) * 2003-12-12 2005-07-07 Medtronic, Inc. Dispositif medical anti-infectieux
WO2006031532A2 (fr) * 2004-09-10 2006-03-23 Surmodics, Inc. Methodes, dispositifs et enrobages pour une liberation controlee d'un principe actif
US8691258B2 (en) 2003-12-12 2014-04-08 Medtronic, Inc. Anti-infective medical device
US8871883B2 (en) 2002-12-11 2014-10-28 Abbott Cardiovascular Systems Inc. Biocompatible coating for implantable medical devices
US8871236B2 (en) 2002-12-11 2014-10-28 Abbott Cardiovascular Systems Inc. Biocompatible polyacrylate compositions for medical applications
US8961588B2 (en) 2002-03-27 2015-02-24 Advanced Cardiovascular Systems, Inc. Method of coating a stent with a release polymer for 40-O-(2-hydroxy)ethyl-rapamycin
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
US9056155B1 (en) 2007-05-29 2015-06-16 Abbott Cardiovascular Systems Inc. Coatings having an elastic primer layer
US9067000B2 (en) 2004-10-27 2015-06-30 Abbott Cardiovascular Systems Inc. End-capped poly(ester amide) copolymers
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US9364498B2 (en) 2004-06-18 2016-06-14 Abbott Cardiovascular Systems Inc. Heparin prodrugs and drug delivery stents formed therefrom
US9561351B2 (en) 2006-05-31 2017-02-07 Advanced Cardiovascular Systems, Inc. Drug delivery spiral coil construct
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US10064982B2 (en) 2001-06-27 2018-09-04 Abbott Cardiovascular Systems Inc. PDLLA stent coating
US10076591B2 (en) 2010-03-31 2018-09-18 Abbott Cardiovascular Systems Inc. Absorbable coating for implantable device

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Cited By (26)

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US10064982B2 (en) 2001-06-27 2018-09-04 Abbott Cardiovascular Systems Inc. PDLLA stent coating
US8961588B2 (en) 2002-03-27 2015-02-24 Advanced Cardiovascular Systems, Inc. Method of coating a stent with a release polymer for 40-O-(2-hydroxy)ethyl-rapamycin
US9084671B2 (en) 2002-06-21 2015-07-21 Advanced Cardiovascular Systems, Inc. Methods of forming a micronized peptide coated stent
US8986726B2 (en) 2002-12-11 2015-03-24 Abbott Cardiovascular Systems Inc. Biocompatible polyacrylate compositions for medical applications
US8871883B2 (en) 2002-12-11 2014-10-28 Abbott Cardiovascular Systems Inc. Biocompatible coating for implantable medical devices
US8871236B2 (en) 2002-12-11 2014-10-28 Abbott Cardiovascular Systems Inc. Biocompatible polyacrylate compositions for medical applications
US9175162B2 (en) 2003-05-08 2015-11-03 Advanced Cardiovascular Systems, Inc. Methods for forming stent coatings comprising hydrophilic additives
WO2005030287A1 (fr) * 2003-09-19 2005-04-07 Julius-Maximilians- Universität Würzburg Prothese vacsulaire a liberation de substances actives
US9114198B2 (en) 2003-11-19 2015-08-25 Advanced Cardiovascular Systems, Inc. Biologically beneficial coatings for implantable devices containing fluorinated polymers and methods for fabricating the same
USRE45744E1 (en) 2003-12-01 2015-10-13 Abbott Cardiovascular Systems Inc. Temperature controlled crimping
US8691258B2 (en) 2003-12-12 2014-04-08 Medtronic, Inc. Anti-infective medical device
WO2005061003A1 (fr) * 2003-12-12 2005-07-07 Medtronic, Inc. Dispositif medical anti-infectieux
US9101697B2 (en) 2004-04-30 2015-08-11 Abbott Cardiovascular Systems Inc. Hyaluronic acid based copolymers
US9561309B2 (en) 2004-05-27 2017-02-07 Advanced Cardiovascular Systems, Inc. Antifouling heparin coatings
US9375445B2 (en) 2004-06-18 2016-06-28 Abbott Cardiovascular Systems Inc. Heparin prodrugs and drug delivery stents formed therefrom
US9364498B2 (en) 2004-06-18 2016-06-14 Abbott Cardiovascular Systems Inc. Heparin prodrugs and drug delivery stents formed therefrom
US9580558B2 (en) 2004-07-30 2017-02-28 Abbott Cardiovascular Systems Inc. Polymers containing siloxane monomers
US7709049B2 (en) 2004-09-10 2010-05-04 Surmodics, Inc. Methods, devices, and coatings for controlled active agent release
WO2006031532A3 (fr) * 2004-09-10 2006-06-08 Surmodics Inc Methodes, dispositifs et enrobages pour une liberation controlee d'un principe actif
WO2006031532A2 (fr) * 2004-09-10 2006-03-23 Surmodics, Inc. Methodes, dispositifs et enrobages pour une liberation controlee d'un principe actif
US9067000B2 (en) 2004-10-27 2015-06-30 Abbott Cardiovascular Systems Inc. End-capped poly(ester amide) copolymers
US9339592B2 (en) 2004-12-22 2016-05-17 Abbott Cardiovascular Systems Inc. Polymers of fluorinated monomers and hydrocarbon monomers
US9561351B2 (en) 2006-05-31 2017-02-07 Advanced Cardiovascular Systems, Inc. Drug delivery spiral coil construct
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
US9056155B1 (en) 2007-05-29 2015-06-16 Abbott Cardiovascular Systems Inc. Coatings having an elastic primer layer
US10076591B2 (en) 2010-03-31 2018-09-18 Abbott Cardiovascular Systems Inc. Absorbable coating for implantable device

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