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WO2008077247A1 - Revêtements pour dispositifs médicaux implantables comprenant du cholestérol - Google Patents

Revêtements pour dispositifs médicaux implantables comprenant du cholestérol Download PDF

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Publication number
WO2008077247A1
WO2008077247A1 PCT/CA2007/002325 CA2007002325W WO2008077247A1 WO 2008077247 A1 WO2008077247 A1 WO 2008077247A1 CA 2007002325 W CA2007002325 W CA 2007002325W WO 2008077247 A1 WO2008077247 A1 WO 2008077247A1
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WIPO (PCT)
Prior art keywords
cholesteryl
cholesterol
lipid
active agent
pharmaceutically active
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.)
Ceased
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PCT/CA2007/002325
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English (en)
Inventor
Deanmo Liu
Vlad Budzynski
Dorna Hakimi-Mehr
Manus Tsui
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MIV Therapeutics Inc
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MIV Therapeutics Inc
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Publication of WO2008077247A1 publication Critical patent/WO2008077247A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Definitions

  • the present invention relates to solid lipid film coatings for implantable medical devices comprising cholesterol and/or cholesterol derivatives, at least one additional solid lipid, and at least one pharmaceutically active agent. Also disclosed herein are methods of preparing film coatings and methods of treating diseases with the implantable devices.
  • a stent has an expandable tubular configuration that is inserted into the lumen of the vessel, often with the aid of a guide wire or catheter, to reopen or widen the lumen passageway.
  • the body can react to the reopening and to the stent itself with a complex restenosis response, including inflammation, reoccluding the vessel by smooth muscle tissue formation (neointima formation), formation of scar tissue, and/or clot formation (thrombus), among other responses.
  • drug eluting arterial stents have been developed that release drugs locally to the lumen and vessel wall, such as immunosuppressives, anti-inflammatory agents, antiproliferatives, and anticoagulants.
  • One embodiment provides an implantable medical device, comprising a solid film covering at least a portion of the device, the solid film comprising: at least one lipid selected from cholesterol and cholesterol derivatives, at least one additional solid lipid other than cholesterol and cholesterol derivatives, and a therapeutically effective amount of at least one pharmaceutically active agent.
  • Another embodiment provides a method of preparing a coating for an implantable medical device, comprising: combining to form a composition: at least one lipid selected from cholesterol and cholesterol derivatives at least one additional solid lipid other than cholesterol and cholesterol derivatives, and a therapeutic amount of at least one pharmaceutically active agent; and coating at least a portion of the device with the composition.
  • Another embodiment provides a method of treating at least one disease or condition comprising: implanting in a subject in need thereof a medical device comprising a solid film covering at least a portion of the device, the solid film comprising: at least one lipid selected from cholesterol and cholesterol derivatives, at least one additional solid lipid other than cholesterol and cholesterol derivatives, and a therapeutically effective amount of at least one pharmaceutically active agent.
  • FIG. 1 is a bar graph showing the cell growth inhibition by N- benzoyl staurosporine in the solid film formulations of Example 1 expressed as a percentage of cell growth inhibition as compared to the medium control.
  • One embodiment provides an implantable medical device, comprising a coating or film covering at least a portion of the device, where the coating or film comprises an implantable medical device, comprising a solid film covering at least a portion of the device, the solid film comprising: at least one lipid selected from cholesterol and cholesterol derivatives, at least one additional solid lipid other than cholesterol and cholesterol derivatives, and a therapeutically effective amount of at least one pharmaceutically active agent.
  • the solid film remains solid at body temperature.
  • the solid film comprises a crystalline (or semi- crystalline) phase comprising the cholesterol and/or cholesterol derivative uniformly distributed within an amorphous phase comprising the at least one additional solid lipid.
  • the solid film is uniform and homogeneous.
  • the solid film has a melting point greater than 37°C, a melting point greater than 4O 0 C, or a melting point greater than 50 0 C.
  • the solid film is substantially free of membrane bilayer sheets, vesicles, etc.
  • the solid film also has a total amount of solvent (e.g., water and/or organic solvents) of less than 5%, such as a total amount of less than 2%, or even a total amount of solvent less than 1%.
  • solvent e.g., water and/or organic solvents
  • Cholesterol has a structure well known in the art with a weakly polar hydroxyl group on the A ring of its rigid four-fused ring system and a short hydrocarbon tail on the D ring at the other end of the molecule.
  • Cholesterol with its fused ring structure has a molecular rigidity, which it can impart to the film.
  • the cholesterol can be present in an amount sufficient to impart a desired rigidity to the solid film.
  • cholesterol is present to improve long term blood compatibility of the solid film.
  • “Cholesterol derivatives” as used herein refer to those compounds compound having the four-fused-ring system of cholesterol, including esters and ethers of cholesterol, and a substituent on the D ring.
  • the substituent is a short hydrocarbon tail, such as a hydrocarbon tail having a C2- C11 , branched or straight chain, saturated or unsaturated (e.g., 1 , 2, or 3 double bonds) hydrocarbon.
  • the at least one additional solid lipid other than cholesterol and cholesterol derivatives can be selected from phospholipids, glycolipids, stearic acid, 12-hydroxyl stearic acid, glycerol behenate, hydrogenated castor oil, hydrogenated soybean oil, and hydrogenated vegetable oils.
  • Exemplary cholesterol derivatives include 7 ⁇ -hydroxycholesterol 7- ketocholesterol, 7-ketocholesteryl acetate, 25-hydroxycholesterol, 24,25- epoxycholesterol, diacetylenic cholesterol, cholest-4-ene-3,6-dione, cholest-4-en- 3-one, cholesteryl behenate, cholesteryl benzoate, cholesteryl butyrate, cholesteryl caprate, cholesteryl caproate, cholesteryl caprylate, cholesteryl-3,5- dinitrobenzoate, cholesteryl formate, cholesteryl- ⁇ -D-glucoside, cholesteryl hemisuccinate, cholesteryl heptylate, cholesteryl heptadecanoate, cholesteryl hydrogen phthalate, cholesteryl isobutyrate, cholesteryl isovalerate, cholesteryl laurate, cholesteryl linoleate, cholesteryl methyl succinates, cholesteryl
  • cholesterol derivatives include lanosterol, 14-nor- lanosterol, 14-nor,24,25-dihydrolanosterol, ⁇ 7-cholestenol, 4 ⁇ -methyl- ⁇ 7- cholestenol, 4 ⁇ -methyl- ⁇ 8-cholestenol, dehydrocholesterol, cholestenone, cholestanone, cholestanol, coprosterol (coprostanol), coprostanone, Ia- hydroxycholesterol, 7 ⁇ -hydroxy-4-cholesten-3 one, 5 ⁇ -cholestan-3 ⁇ ,7 ⁇ ,12 ⁇ ,26- tetrol, 7 ⁇ ,12 ⁇ -dihydroxy-4-cholesten-3-one, 5 ⁇ -cholestan-3 ⁇ ,7 ⁇ ,12 ⁇ -triol, 5 ⁇ - cholestan-3 ⁇ ,7 ⁇ -diol, 5 ⁇ -cholestan-3 ⁇ ,7 ⁇ ,26-triol, 5-cholestene-3 ⁇ ,7 ⁇ -diol
  • cholesterol derivatives include cholesterol acetate, cholesterol arachidonate, cholesterol behenate, cholesterol butyrate, cholesterol docosanoate, cholesterol dodecanoate, cholesterol eicosapentanoate, cholesterol elaidate, cholesterol erucate, cholesterol heptadecanoate, cholesterol heptanoate, cholesterol hexanoate, cholesterol linoleate, cholesterol ⁇ -linolenate, cholesterol ⁇ -linolenate, cholesterol nonanoate, cholesterol octanoate, cholesterol oleate, cholesterol palmitate, cholesterol palmitoleate, cholesterol pentanoate, cholesterol propanoate, cholesterol tetracosanoate, cholesterol tetracosenoate, cholesterol methyl ether, cholesterol ethyl ether, cholesterol n-propyl ether, cholesterol 2-propyl ether, cholesterol 1-n-butyl ether, cholesterol 2-n-butyl ether, cholesterol isobutyl ether
  • cholesterol derivatives include those derived from lanosterol, including lanosterol acetate, lanosterol arachidonate, lanosterol behenate, lanosterol butyrate, lanosterol docosanoate, lanosterol dodecanoate, lanosterol eicosapentanoate, lanosterol elaidate, lanosterol erucate, lanosterol heptadecanoate, lanosterol heptanoate, lanosterol hexanoate, lanosterol linoleate, lanosterol ⁇ -linolenate, lanosterol ⁇ -linolenate, lanosterol nonanoate, lanosterol octanoate, lanosterol oleate, lanosterol palmitate, lanosterol palmitoleate, lanosterol pent
  • Other cholesterol derivatives include those derived from 14-nor lanosterol, including 14-nor-lanosterol acetate, 14-nor-lanosterol arachidonate, 14-nor-lanosterol behenate, 14-nor-lanosterol butyrate, 14-nor-lanosterol docosanoate, 14-nor-lanosterol dodecanoate, 14-nor-lanosterol eicosapentanoate, 14-nor-lanosterol elaidate, 14-nor-lanosterol erucate, 14-nor- lanosterol heptadecanoate, 14-nor-lanosterol heptanoate, 14-nor-lanosterol hexanoate, 14-nor-lanosterol linoleate, 14-nor-lanosterol ⁇ -linolenate, 14-nor- lanosterol ⁇ -
  • cholesterol derivatives include those derived from delta-7- cholestenol, including delta-7-cholestenol acetate, delta-7-cholestenol arachidonate, delta-7-cholestenol behenate, delta-7-cholestenol butyrate, delta-7- cholestenol docosanoate, delta-7-cholestenol dodecanoate, delta-7-cholestenol eicosapentanoate, delta-7-cholestenol elaidate, delta-7-cholestenol erucate, delta-7-cholestenol heptadecanoate, delta-7-cholestenol heptanoate, delta-7- cholestenol hexanoate, delta-7-cholestenol linoleate, delta-7-cholestenol ⁇ - linolenate, delta-7-cholestenol ⁇ -linolenate, delta-7-cholestenol ⁇
  • cholesterol derivatives include those derived from delta-8- cholestenol, including 4-alpha-methyl-delta-8-cholestenol acetate, 4-alpha- methyl-delta-8-cholestenol arachidonate, 4-alpha-methyl-delta-8-cholestenol behenate, 4-alpha-methyl-delta-8-cholestenol butyrate, 4-alpha-methyl-delta-8- cholestenol docosanoate, 4-alpha-methyl-delta-8-cholestenol dodecanoate, 4- alpha-methyl-delta-8-cholestenol eicosapentanoate, 4-alpha-methyl-delta-8- cholestenol elaidate, 4-alpha-methyl-delta-8-cholestenol erucate, 4-alpha-methyl-delta-8-cholestenol heptadecanoate, 4-alpha-methyl-delta-8-cholestenol heptanoate
  • Other cholesterol derivatives include those derived from dehydrocholesterol, including dehydrocholesterol acetate, dehydrocholesterol arachidonate, dehydrocholesterol behenate, dehydrocholesterol butyrate, dehydrocholesterol docosanoate, dehydrocholesterol dodecanoate, dehydrocholesterol eicosapentanoate, dehydrocholesterol elaidate, dehydrocholesterol erucate, dehydrocholesterol heptadecanoate, dehydrocholesterol heptanoate, dehydrocholesterol hexanoate, dehydrocholesterol linoleate, dehydrocholesterol ⁇ -linolenate, dehydrocholesterol ⁇ -linolenate, dehydrocholesterol nonanoate, dehydrocholesterol octanoate, dehydrocholesterol oleate, dehydrocholesterol palm
  • cholesterol derivatives include those derived from coprostanol, including coprostanol acetate, coprostanol arachidonate, coprostanol behenate, coprostanol butyrate, coprostanol docosanoate, coprostanol dodecanoate, coprostanol eicosapentanoate, coprostanol elaidate, coprostanol erucate, coprostanol heptadecanoate, coprostanol heptanoate, coprostanol hexanoate, coprostanol linoleate, coprostanol ⁇ -linolenate, coprostanol ⁇ -linolenate, coprostanol nonanoate, coprostanol octanoate, coprostanol oleate, coprostanol palmitate, coprostanol palmitoleate, coprostanol pent
  • cholesterol derivatives include those derived from cholestanol, including cholestanol acetate, cholestanol arachidonate, cholestanol behenate, cholestanol butyrate, cholestanol docosanoate, cholestanol dodecanoate, cholestanol eicosapentanoate, cholestanol elaidate, cholestanol erucate, cholestanol heptadecanoate, cholestanol heptanoate, cholestanol hexanoate, cholestanol linoleate, cholestanol ⁇ -linolenate, cholestanol ⁇ - linolenate, cholestanol nonanoate, cholestanol octanoate, cholestanol oleate, cholestanol
  • cholesterol derivatives include those derived from sitosterol, including alphal -sitosterol acetate, alphal -sitosterol arachidonate, alphal - sitosterol behenate, alphal -sitosterol butyrate, alphal -sitosterol docosanoate, alphal -sitosterol dodecanoate, alphal -sitosterol eicosapentanoate, alphal - sitosterol elaidate, alphal -sitosterol erucate, alphal -sitosterol heptadecanoate, alphal -sitosterol heptanoate, alphal -sitosterol hexanoate, alphal -sitosterol linoleate, alphal -sitosterol ⁇ -linolenate, alphal -sitosterol ⁇ -linolenate, alphal -s
  • Other cholesterol derivatives include those derived from stigmasterol, including stigmasterol acetate, stigmasterol arachidonate, stigmasterol behenate, stigmasterol butyrate, stigmasterol docosanoate, stigmasterol dodecanoate, stigmasterol eicosapentanoate, stigmasterol elaidate, stigmasterol erucate, stigmasterol heptadecanoate, stigmasterol heptanoate, stigmasterol hexanoate, stigmasterol linoleate, stigmasterol ⁇ -linolenate, stigmasterol ⁇ -linolenate, stigmasterol nonanoate, stigmasterol octanoate, stigmasterol oleate, stigmasterol palmitate, stigmasterol palmitoleate, stigmasterol pentanoate, stigmasterol propanoate, stigmasterol tetracosanoate, stigmasterol tetracosenoate, stigmasterol methyl
  • Other cholesterol derivatives include those derived from stigmastanol, including stigmastanol acetate, stigmastanol arachidonate, stigmastanol behenate, stigmastanol butyrate, stigmastanol docosanoate, stigmastanol dodecanoate, stigmastanol eicosapentanoate, stigmastanol elaidate, stigmastanol erucate, stigmastanol heptadecanoate, stigmastanol heptanoate, stigmastanol hexanoate, stigmastanol linoleate, stigmastanol ⁇ - linolenate, stigmastanol ⁇ -linolenate, stigmastanol nonanoate, stigmastanol octanoate, stigmastanol oleate, stigmastanol palmitate, stigmastanol palmitoleate, stigmastanol pentanoate, stigmastanol propanoate, stigmastanol tetrac
  • Other cholesterol derivatives include those derived from fucosterol, including fucosterol acetate, fucosterol arachidonate, fucosterol behenate, fucosterol butyrate, fucosterol docosanoate, fucosterol dodecanoate, fucosterol eicosapentanoate, fucosterol elaidate, fucosterol erucate, fucosterol heptadecanoate, fucosterol heptanoate, fucosterol hexanoate, fucosterol linoleate, fucosterol ⁇ -linolenate, fucosterol ⁇ -linolenate, fucosterol nonanoate, fucosterol octanoate, fucosterol oleate, fucosterol palmitate, fucosterol palmitoleate, fucosterol pentanoate, fucosterol propanoate, fucosterol tetraco
  • Other cholesterol derivatives include those derived from campesterol, including campesterol acetate, campesterol arachidonate, campesterol behenate, campesterol butyrate, campesterol docosanoate, campesterol dodecanoate, campesterol eicosapentanoate, campesterol elaidate, campesterol erucate, campesterol heptadecanoate, campesterol heptanoate, campesterol hexanoate, campesterol linoleate, campesterol ⁇ -linolenate, campesterol ⁇ -linolenate, campesterol nonanoate, campesterol octanoate, campesterol oleate, campesterol palmitate, campesterol palmitoleate, campesterol pentanoate, campesterol propanoate, campesterol tetracosanoate, campesterol tetracosenoate, campesterol methyl
  • Other cholesterol derivatives include those derived from dinosterol, including dinosterol acetate, dinosterol arachidonate, dinosterol behenate, dinosterol butyrate, dinosterol docosanoate, dinosterol dodecanoate, dinosterol eicosapentanoate, dinosterol elaidate, dinosterol erucate, dinosterol heptadecanoate, dinosterol heptanoate, dinosterol hexanoate, dinosterol linoleate, dinosterol ⁇ -linolenate, dinosterol ⁇ -linolenate, dinosterol nonanoate, dinosterol octanoate, dinosterol oleate, dinosterol palmitate, dinosterol palmitoleate, dinosterol pentanoate, dinosterol propanoate, dinosterol tetraco
  • the at least one additional solid lipid is biocompatible and/or biodegradable.
  • the at least one additional solid lipid has at least one fatty acid comprising C 4 -C 32 hydrocarbon chains, such as C 8 -C 2 S hydrocarbon chains or C 6 -C 24 hydrocarbon chains, Ci 2 - C 32 hydrocarbon chains, or even Ci 2 -C 24 hydrocarbon chains.
  • the at least one additional solid lipid can have two identical fatty acid chains.
  • the fatty acids can comprise C 4 -C 32 hydrocarbon chains, such as C 8 -C 28 hydrocarbon chains or C 6 - C 24 hydrocarbon chains, Ci 2 -C 32 hydrocarbon chains, or even Ci 2 -C 24 hydrocarbon chains.
  • the lipids can be identical or different, saturated or unsaturated (e.g., containing up to 6 double bonds in cis or trans configurations).
  • the phospholipid is natural lecithin.
  • the at least one additional solid lipid is selected from hydrogenated vegetable oils.
  • exemplary hydrogenated vegetable oils include hydrogenated soybean oil, hydrogenated sesame oil, hydrogenated corn oil, hydrogenated sunflower oil, hydrogenated cottonseed oil, hydrogenated coconut oil, hydrogenated palm oil and margarine.
  • a coating for an implantable medical device is prepared by a method comprising: combining to form a composition: at least one lipid selected from cholesterol and cholesterol derivatives at least one additional solid lipid other than cholesterol and cholesterol derivatives, and a therapeutic amount of at least one pharmaceutically active agent; and coating at least a portion of the device with the composition.
  • the combining comprises forming non-aqueous solution, such as a water-insoluble non-aqueous solution.
  • the at least one pharmaceutically active agent is hydrophobic or amphipathic. A hydrophobic agent generally dissolves more readily in oils or solvents (polar or nonpolar) than in water or aqueous solutions, but may have some solubility in water or aqueous solutions.
  • the combining comprises forming a first solution comprising the cholesterol and/or cholesterol derivative dissolved in a first non-aqueous solvent, forming a second solution comprising the at least one additional solid lipid in a second non-aqueous solvent, and combining the first and second solutions.
  • the first and second non-aqueous solutions can be the same or different and can be selected from, but not limited to, methylene chloride, chloroform, ethyl ether and derivatives, ethyl acetate, tetrahydrofuran, hexanes, toluene, xylene, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetone, alcohols such as methanol, ethanol, 1- and 2-propanol, and t-butanol, and combinations thereof.
  • DMA dimethylacetamide
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • alcohols such as methanol, ethanol, 1- and 2-propanol, and t-butanol, and combinations thereof.
  • the first and second solutions can be mixed at a pre-determined concentration with respect to the lipids and then combined with a third solution comprising at least one pharmaceutically active agent.
  • the at least one pharmaceutically active agent can be dissolved in either the first or second solutions followed by combining the two solutions.
  • the combining comprises mixing the cholesterol and/or cholesterol derivative, at least one additional solid lipid, and at least one pharmaceutically active agent in one solution comprising one or more of the non-aqueous solvents disclosed herein.
  • the non- aqueous solution can be formed from more polar solvents such as DMF, DMA, and DMSO.
  • the combining comprises forming a water-in-oil emulsion.
  • the water-in-oil emulsion comprises at least one hydrophilic (e.g., dissolves more readily in water or polar solvents than in oils or non-polar solvents) or amphipathic pharmaceutically active agent.
  • the at least one lipid selected from cholesterol and/or cholesterol derivative and at least one additional lipid is dissolved in an organic solvent immiscible with water, e.g., one or more low boiling point organic solvents such as dichloromethane, diethyl ether, and chloroform.
  • the at least one pharmaceutically active agent can be dissolved in an aqueous medium and combined with the lipid-containing solution to form a water-in-oil emulsion.
  • the droplet size ranges from 0.1 ⁇ m to 10 ⁇ m.
  • at least one additional surfactant can be added to aid in forming the emulsion and/or stabilizing the emulsion to ensure a homogenous dispersion of the emulsified phase.
  • the at least one additional surfactant is chosen from nonionic hydrophobic surfactants, such as sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), glyceryl monoleate, triglyceryl monoleate, stearic glycerides, propylene glyceryl monolaurate, glyceryl monocaprylate.
  • nonionic hydrophobic surfactants such as sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), glyceryl monoleate, triglyceryl monoleate, stearic glycerides, propylene glyceryl monolaurate, glyceryl monocaprylate.
  • the lipid composition can be applied onto the medical device by any means known in the art.
  • the medical device can be dipped in the solution, suspension, or emulsion containing the drug and lipid-containing composition.
  • the lipid/drug-containing solution, suspension, or emulsion can be sprayed or brushed on the surface of the stent.
  • the coating can then be dried, e.g., by applying a vacuum, to form the solid film on the stent.
  • Other coating methods include rolling, brushing, electrostatic plating, spinning, or inject printing.
  • the compositions can be applied by these methods either as a solid (e.g., film or particles), a suspension, as a solution.
  • the lipid composition can be formed into particles and applied to the medical device by any technique known in the art, such as, injection, dipping, solvent evaporation from emulsions, and spraying, such as air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle.
  • one or more layers of solid film can be coated onto the stent.
  • one layer can contain a first pharmaceutically active agent
  • a second layer can contain a second pharmaceutically active agent. Additional agents can be contemplated in the first or second layer or in one or more additional layers.
  • the lipid/drug-containing composition is applied to the surface of the medical device.
  • the device can be coated with a first substance that is capable of absorbing the lipid/drug-containing composition.
  • the device can be constructed from a material comprising a biocompatible polymer, as disclosed herein.
  • the at least one pharmaceutically acceptable agent can be selected from one or more therapeutically effective agents known in the industry. They can take the form of organic compounds and pharmaceuticals, recombinant DNA and RNA products, collagens and derivatives, proteins and analogs, saccharides and analogs and derivatives thereof.
  • the at least one pharmaceutically active agent is selected from anti-inflammatory agents, anti-proliferatives, pro-healing agents, gene therapy agents, extracellular matrix modulators, anti-thrombotic agents/anti- platelet agents, antiangioplastic agents, antisense agents, anticoagulants, antibiotics, bone morphogenetic proteins, integrins (peptides), and disintegrins (peptides and proteins).
  • anti-inflammatory agents include pimecrolimus, adrenocortical steroids (e.g., Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives such as aspirin, para-aminophenol derivatives such as acetaminophen, indole and indene acetic acids (e.g., indomethacin, sulindac, and etodalac), heteroaryl acetic acids (e.g., tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, pheny
  • Exemplary anti-proliferatives include sirolimus, everolimus, actinomycin D (ActD), taxol, and paclitaxel.
  • Exemplary pro-healing agents include estradiol.
  • Exemplay gene therapy agents include gene delivering vectors e.g., VEGF gene, and c-myc antisense.
  • Exemplary extracellular matrix modulators include batimastat.
  • Exemplary anti-thrombotic agents/anti-platelet agents include sodium heparin, low molecular weight heparin, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogs, dextran, D-phe-pro-arg- chloromethylketone (e.g., synthetic antithrombin), dipyridamole, glycoprotein llb/llla platelet membrane receptor antagonist, recombinant hirudin, and thrombin inhibitor.
  • Exemplary antiangioplastic agents include thiphosphoramide.
  • Exemplary antisense agents include oligonucleotides and combinations.
  • Exemplary anticoagulants include hirudin, heparin, synthetic heparin salts and other inhibitors of thrombin.
  • Exemplary antibiotics include vancomycin, dactinomycin (e.g., actinomycin D), daunorubicin, doxorubicin, and idarubicin.
  • Exemplary disintegrins include saxatilin peptide. Derivatives and analogs thereof of these examples are also included.
  • agents that inhibit restenosis include agents that inhibit restenosis, smooth muscle cell inhibitors, immunosuppressive agents, and anti- antigenic agents.
  • Exemplary drugs include sirolimus, paclitaxel, tacrolimus, heparin, pimecrolimus, imatinib mesylate (gleevec), and bisphosphonates.
  • the pharmaceutically active agent is staurosporine, which has exhibited inhibitory activity against a variety of protein kinase C (PKC) isoforms with additional activity against PDGF and FGF tyrosine kinases. It has been isolated from Streptomyces stauroporeus cultures. Moreover, a number of staurosporine derivatives have been prepared that target primarily protein kinase C with less activity against other protein kinases. Such derivatives can be useful in targeting tumor-inhibiting, inflammation-inhibiting, immunomodulating, and antibacterial substances, as well as diseases of cardiovascular systems, e.g., arteriosclerosis.
  • PLC protein kinase C
  • the pharmaceutically active agent is selected from staurosporine derivatives N-(3-carboxypropionyl staurosporine, N-benzoyl staurosporine, and N-methylaminothiocarbonyl staurosporine.
  • concentration of the drug in the lipid film is tailored depending on the specific target cell, disease extent, lumen type, etc. In one embodiment, the concentration of drug in the lipid film can range from 0.001% to 75% by weight relative to the total weight of the solid film, such as a concentration of 0.1% to 50% by weight relative to the total weight of the solid film.
  • the concentration of drug in the lipid film can range from 0.01% to 40% by weight, such as a concentration ranging from 0.1% to 20% by weight relative to the total weight of the solid film. In another embodiment, the concentration of drug in the lipid film range from 1% to 50%, 2% to 45%, 5% to 40%, or 10% to 35% by weight, relative to the total weight of the solid film.
  • the drug load can range from 0.1 ng to 5 ⁇ g per mm length of a given stent configuration, such as a drug load ranging from 1 ng to 5 ⁇ g, or from 0.1 ng to 1 ⁇ g, or from 1 ng to 1 ⁇ g, or from 0.1 ng to 100 ng or from 0.1 ⁇ g to 5 ⁇ g, or from 0.1 ⁇ g to 1 ⁇ g, or from or from 1 ⁇ g to 5 ⁇ g.
  • the film comprises cholesterol and/or cholesterol derivatives in a concentration ranging from 0.1% to 99% by weight (e.g., 10% to 99% by weight), and at least one additional solid lipid, such as hydrogenated oils (e.g., hydrogenated soybean oil and/or hydrogenated castor oil), in a concentration ranging from 1 % to 99% (e.g., 1% to 90%) by weight, relative to the total weight of the solid film.
  • the film comprises cholesterol and/or cholesterol derivatives in a concentration ranging from 0.1% to 50% by weight and at least one additional solid lipid in a concentration ranging from 50% to 99.9% by weight, relative to the total weight of the solid film.
  • the film comprises: cholesterol in a concentration ranging from 10-50% (e.g., 30-50%) by weight, relative to the total weight of the film; hydrogenated castor oil in a concentration ranging from 50- 90% (e.g., 50-70%) by weight, relative to the total weight of the film; and N- benzoyl staurosporine in a concentration ranging from 1-50% (e.g., 1-5%).
  • the N- benzoyl staurosporine is present in a dose ranging from 0.1 ⁇ g to 100 ⁇ g per stent, e.g., a 22 mm stent.
  • the N-benzoyl staurosporine is released at a rate of 3 ng to 100 ng per day over a period of weeks (e.g., 2-4 weeks) to months (e.g. 1 month to 6 months or even up to a year).
  • One embodiment provides a method of treating at least one disease or condition comprising: implanting in a subject in need thereof a medical device comprising a solid film covering at least a portion of the device, the solid film comprising: at least one lipid selected from cholesterol and cholesterol derivatives, at least one additional solid lipid other than cholesterol and cholesterol derivatives, and a therapeutically effective amount of at least one pharmaceutically active agent.
  • the at least one disease or condition is a proliferative disorder (e.g., a tumor), an inflammatory disease, or an autoimmune disease.
  • the device is useful for treating diseases or conditions associated with the narrowing or obstruction of a body passageway in a subject in need thereof.
  • the disease or condition is associated with restenosis.
  • the at least one disease or condition is neointima and neointimal hyperplasia.
  • the at least one disease or condition is selected from thrombosis, embolism, and platelet accumulation.
  • the disease or disorder is the proliferation of smooth muscle cells.
  • the film comprises N-benzoyl staurosporine in a concentration ranging from 0.1 ⁇ g to 100 ⁇ g per stent for treating the proliferation of smooth muscle cells.
  • the cholesterol (and/or derivatives) and lipids in the solid film can be varied with respect to type and/or amount for a particular drug application.
  • a solid film containing lipids with short chain backbones e.g., C 4 -Ci 6 , such as lauric acid, myristic acid and palmitic acid
  • C-i 6 long chain backbones
  • hydrogenated castor oil e.g., hydrogenated castor oil.
  • lipids can be useful short-term drug delivery purpose (e.g., days or less). For other applications requiring long-term delivery (e.g., weeks to months), the presence of less degradeable lipids may be useful. Accordingly, one embodiment provides a slow release solid film for releasing the at least one pharmaceutically active agent over a period of 7 days or less, such as a period of 3 days or less or less than 2 days. In another embodiment, the solid film releases the at least one pharmaceutically active agent over a longer course of time, e.g., at least 7 days, or at least 10 days and even up to a period of 1 year, e.g., over a period ranging from 1 week to 1 year, such as a period ranging from 2 weeks to 6 months.
  • a slow release solid film for releasing the at least one pharmaceutically active agent over a period of 7 days or less, such as a period of 3 days or less or less than 2 days.
  • the solid film releases the at least one pharmaceutically active agent over a longer course of time
  • the solid film releases at least 50% of the at least one pharmaceutically active agent over a period ranging from 7 days to 6 months, from 7 days to 3 months, from 7 days to 2 months, from 7 days to 1 month, from 10 days to 1 year, from 10 days to 6 months, from 10 days to 2 months, or from 10 days to 1 month.
  • the solid film can also release drug by mechanisms other than degradation of the lipids, such as diffusion of the drug out into the aqueous phase with or without degradation, and solubilization of the intact lipids into the aqueous phase allowing drug now exposed at the surface to dissolve. Shorter chain lipids would be more soluble than longer chain lipids leading to faster release of drug. A solid film of shorter chain lipid would probably be less viscous than longer chains and allow faster diffusion of drug out of the film. I know I am on shaky ground here trying to characterize the viscosity of a solid lipid.
  • the device comprises an inner coating that contacts the device and serves as a substrate for the at least one lipid coating.
  • the inner coating can comprise one or more polymers typically used for implantable medical devices, as disclosed above.
  • the inner coating can be a ceramic, such as those ceramics known in the art to be biocompatible, e.g., hydroxyapatite, titanium oxide, and silicon carbide. Exemplary treatments/coatings of a surface with a ceramic material that improves the performance of subsequently deposited polymer layer is disclosed in
  • the inner coating can be an inorganic coating, such as metals (e.g. gold), or carbon.
  • the substrate is porous.
  • the porous substrate can have pores and voids sufficiently large enough to contain a drug yet have passageways that permit the drug to be released from the pores of the substrate and enter the aqueous solution.
  • a porous substrate is provided that can act as a drug reservoir.
  • the size and volume fraction of the substrate porosity can also be adjusted to influence the release rate of the therapeutic agent, e.g., by adjusting the porosity volume and/or pore diameter.
  • a porous substrate possessing nano- size porosity is expected to decrease the release rate of the therapeutic agent compared to a porous substrate having micro-size porosity.
  • the substrate is porous and has a porosity volume ranging from 30 to 70% and an average pore diameter ranging from
  • the porosity volume ranges from 30 to 60%, from 40 to 60%, from 30 to 50%, or from 40 to 50%, or even a porosity volume of 50%.
  • the average pore diameter ranges from 0.4 to 0.6 ⁇ m, from 0.3 to 0.5 ⁇ m, from 0.4 to 0.5 ⁇ m, or the average pore diameter can be 0.5 ⁇ m.
  • calcium phosphates displaying various combinations of the disclosed thicknesses, porosity volumes or average pore diameters can also be prepared.
  • a porous substrate may offer an opportunity for a single drug type to exhibit dual functionality.
  • a film comprising a lipid bilayer and at least one pharmaceutically active agent can coat a top surface of the substrate.
  • a medical device comprising at least one coating covering at least a portion of the device, the at least one coating comprising a porous substrate and a solid film as described herein.
  • the substrate e.g., a ceramic, is biocompatible so as to provide a surface that can promote growth of endothelial cells of the vascular intima, i.e., endothelialization.
  • drug eluting stents have been developed to elute anti-proliferative drugs from a non-degradable aromatic polymer coating and are currently used to further reduce the incidence of restenosis.
  • Commercially available drug eluting stents such as the Cypher ® stent, which elutes sirolimus, and the Taxus ® stent, which elutes paclitaxel, do not promote endothelialization, most likely because of the non-degradable polymer.
  • the surface of the biocompatible ceramic upon resorption of the solid film by the aqueous solution or body fluid, the surface of the biocompatible ceramic is exposed to the body fluid. Ceramics can persist in the body for one or more years, and a stable, persistent coating is not undesirable in the body since endothelialization has been demonstrated on biocompatible ceramics, such as a hydro xyapatite coating.
  • the thickness of the porous substrate coating can be adjusted so that it provides the necessary volume for deposition of the composition comprising one or more lipids and one or more pharmaceutically active agents.
  • the adhesion of the porous substrate coating to the surface of the medical device is such that the porous substrate does not delaminate from the surface of the medical device during implantation.
  • the porous substrate has a thickness of 10 ⁇ m or less. In other embodiments, e.g., where the device is an orthopedic implant, the porous substrate can have a thickness ranging from 10 ⁇ m to 5 mm, such as a thickness ranging from 100 ⁇ m to 1 mm.
  • the substrate is well bonded to the stent surface and neither forms significant cracks nor flakes off the stent during mounting on a balloon catheter and placement in an artery by expansion.
  • a substrate that does not form significant cracks can have still present minor crack formation so long as it measures less than 300 nm, such as cracks less than 200 nm, or even less than 100 nm.
  • the substrate is a ceramic, such as any ceramic known in the art to be biocompatible, e.g., metal oxides such as titanium oxide, aluminum oxide, silica, and indium oxide, metal carbides such as silicon carbide, and one or more calcium phosphates such as hydroxyapatite, octacalcium phosphate, ⁇ - and ⁇ -tricalcium phosphates, amorphous calcium phosphate, dicalcium phosphate, calcium deficient hydroxyapatite, and tetracalcium phosphate.
  • metal oxides such as titanium oxide, aluminum oxide, silica, and indium oxide
  • metal carbides such as silicon carbide
  • calcium phosphates such as hydroxyapatite, octacalcium phosphate, ⁇ - and ⁇ -tricalcium phosphates, amorphous calcium phosphate, dicalcium phosphate, calcium deficient hydroxyapatite, and tetracalcium phosphate.
  • the substrate is a calcium phosphate coating, such as hydroxyapatite.
  • the calcium phosphate coating may be deposited by electrochemical deposition (ECD) or electrophoretic deposition (EPD).
  • ECD electrochemical deposition
  • EPD electrophoretic deposition
  • the coating may be deposited by a sol gel (SG) or an aero-sol gel (ASG) process.
  • the coating may be deposited by a biomimetic (BM) process.
  • BM biomimetic
  • the coating may be deposited by a calcium phosphate cement (CPC) process.
  • the inner coating comprises a hydroxyapatite.
  • Hydroxyapatites are often used in medical devices as they may have one or more of the following properties: stability, biocompatibility, rapid integration with the human body, non-toxicity, non-thrombogenicity, angiogenicity, and is not likely to induce inflammatory reactions.
  • Exemplary hydroxyapatites include those disclosed in U.S. Patent No. 6,426,114, U.S. Publication No. 20060134160, and Tsui M., 2007, "Calcium phosphate coatings on coronary stents by electrophoretic deposition," M.A.Sc. Thesis, Department of Materials Engineering, University of British Columbia, Vancouver, BC, the disclosures of which are incorporated herein by reference.
  • the hydroxyapatite is a porous hydroxyapatite.
  • the method comprises inserting the device into the passageway, the device comprising a generally tubular structure, the surface of the structure being coated with a composition disclosed herein, such that the passageway is expanded and/or prevented from contracting or being obstructed.
  • the body passageway may be selected from arteries, veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal passages, sinuses, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina, the vasdeferens, and the ventricular system.
  • Exemplary devices include sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, urological implants, tissue adhesives and sealants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.
  • the device can be a cardiovascular device, such as venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemakers and pace maker leads, and implantable defibrillators.
  • the device can be a neurologic/neurosurgical device such as ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post-laminectomy, devices for continuous subarachnoid infusions, and biodegradable discs eluting i.e. imatinib, implanted after brain tumor removal.
  • the device can be a gastrointestinal device, such as chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, and suspensions or dry implants to prevent surgical adhesions.
  • the device can be a genitourinary device, such as uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
  • IUDs intrauterine devices
  • devices to prevent endometrial hyperplasia include reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
  • IUDs intrauterine devices
  • Other exemplary devices include prosthetic heart valves, vascular grafts ophthalmologic implants (e.g., multino (multeno) implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk corneal transplants), otolaryngology devices (e.g., ossicular implants, Eustachian tube splints or stents for glue ear or chronic otitis as an alternative to transtempanic drains), plastic surgery implants (e.g., breast implants or chin implants), and catheter cuffs and orthopedic implants (e.g., cemented orthopedic prostheses).
  • vascular grafts ophthalmologic implants e.g., multino (multeno) implants and
  • a stent such as a stent comprising a generally tubular structure.
  • a stent is commonly used as a tubular structure disposed inside the lumen of a duct to relieve an obstruction.
  • stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ.
  • a typical method of expansion occurs through the use of a catheter- mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • An exemplary stent is a stent for treating narrowing or obstruction of a body passageway in a human or animal in need thereof.
  • Body passageway refers to any of number of passageways, tubes, pipes, tracts, canals, sinuses or conduits which have an inner lumen and allow the flow of materials within the body.
  • body passageways include arteries and veins, lacrimal ducts, the trachea, bronchi, bronchiole, nasal passages (including the sinuses) and other airways, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina and other passageways of the female reproductive tract, the vasdeferens and other passageways of the male reproductive tract, and the ventricular system (cerebrospinal fluid) of the brain and the spinal cord.
  • Exemplary devices of the invention are for these above-mentioned body passageways, such as stents, e.g., vascular stents.
  • vascular stents e.g., vascular stents.
  • vascular stents There is a multiplicity of different vascular stents known in the art that may be utilized following percutaneous transluminal coronary angioplasty.
  • Any number of stents may be utilized in accordance with the present invention and the invention is not limited to the specific stents that are described in exemplary embodiments of the present invention. The skilled artisan will recognize that any number of stents may be utilized in connection with the present invention.
  • other medical devices may be utilized, such as e.g., orthopedic implants.
  • the stent can be made of various materials including stainless steel, CoCr, titanium, titanium alloys, NiTi, and polymers typically used for implantable medical devices.
  • Exemplary polymers include polyurethanes, polyacrylate esters, polyacrylic acid, polyvinyl acetate, silicones, styrene-isobutylene-styrene block copolymers such as styrene- isobutylene-styrene tert-block copolymers (SIBS); polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone; polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinyl ethers; polyvinyl aromatics; polyethylene oxides; polyesters including polyethylene terephthalate; polyamides; polyacrylamides; polyethers including polyether sulfone; polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene; polycarbonates, silox
  • the nonbiodegradable polymer is selected from poly(n-butyl methacrylate)/poly(ethene vinyl acetate), polyacrylate, poly(lactide-co-E- caprolactone), PTFE, paralyene C, polyethylene-co-vinyl acetate, poly n- butyl methacrylate, poly(styrene-b-isobutylene-b-styrene) (a tri-block copolymer of styrene and isobutylene subunits built on 1 ,3-di(2-methoxy-2-propyl)-5-tert- butylbenzene, TranseluteTM).
  • the implantable devices disclosed herein are implanted in a subject in need thereof to achieve a therapeutic effect, e.g., therapeutic treatment and/or prophylactic/preventative measures.
  • a therapeutic effect e.g., therapeutic treatment and/or prophylactic/preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disease as well as those at risk for the disease (e.g., those who are likely to ultimately acquire the disorder).
  • a therapeutic method can also result in the prevention or amelioration of symptoms, or an otherwise desired biological outcome, and may be evaluated by improved clinical signs, delayed onset of disease, reduced/elevated levels of lymphocytes and/or antibodies.
  • the method comprises inserting an implantable medical device in the form of vascular stent into a blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with a composition as described above, such that the vascular obstruction is eliminated.
  • stents may be placed in a wide array of blood vessels, both arteries and veins, to prevent recurrent stenosis (restenosis) at, e.g., a site of (failed) angioplasties, to treat narrowings that would likely fail if treated with angioplasty, and to treat post surgical narrowings (e.g., dialysis graft stenosis).
  • This Example demonstrates the preparation of coatings for Drug Eluting Stents (DES) comprising cholesterol and an additional solid lipid.
  • Two lipid coating compositions were prepared. A first coating containing 30 wt% cholesterol (CHO) and 70 wt% hydrogenated castor oil (HCO) was prepared by dissolving the CHO in methylene chloride (dichloromethane, DCM) to form a 0.2% CHO-containing solution. HCO was separately dissolved in tetrahydrofuran (THF) to form a 0.2% HCO-containing solution. Both solutions were then mixed in proportion to form the resulting 30%CHO-70%HCO composite coating. A second coating was prepared with 50% CHO and 50% HCO in a similar manner as explained above. The drug N-benzoyl staurosporine (PKC 412, Novartis) was added and completely dissolved in the mixture of the two solutions in the amounts listed in Table 1.
  • PPC 412 The drug N-benzoyl staurosporine
  • Stents with 22-mm made of stainless steel were coated by dipping the stents into the respective drug-containing solutions, and slowly pulled out at a speed of approximately 4 mm/sec. The coated stents were dried in the ambient environment for 4 hours. For each composition two dosage levels of drug (low dose and high dose) were prepared. Control samples were prepared with the coating compositions described above without the addition of the drug. Detailed amount of the final samples are listed in Table 1. Drugs other than PKC 412 can be used by this method to prepare the DES.
  • HCASMC Human Coronary Artery Smooth Muscle Cells
  • DES 5x104 HCASMC were plated into 12-well cluster plates (Corning Inc.) and cultured in complete smooth muscle growth medium overnight. After 24 hours of incubation, both the DES and control stents (lipid coated, but without drug) were gently added to each well, and other cells in separate wells were grown without any stents (medium control).
  • Paclitaxel (PTX) a drug with known cardiovascular application, added at a dose of 0.1 ⁇ g/mL into separate well served as a positive control.
  • FIG. 1 is a bar graph showing the cell growth inhibition for each sample of Table 1 , as well as a sample containing culture medium only and a sample of paclitaxel added to another well at a concentration of 0.1 ⁇ g/mL.
  • the inhibitory effect of PKC412 DES was expressed as a percentage of cell growth inhibition as compared to the medium control.
  • each lipid coating-containing drug reduced substantially the cell numbers after 7 days of culture as compared to control coating with no drug or to the culture with medium only. This growth inhibition was comparable to the inhibitory effect of paclitaxel added to another well at a concentration of 0.1 ⁇ g/mL.
  • compositions can be beneficial to practical clinical needs in the situation a dual-drug eluting profile is needed with the demand of different eluting profiles, from fast to slow.
  • the results of this Example suggest that (1 ) the lipid matrix is biocompatible with human coronary artery smooth muscle cells, (2) the coating matrix may provide protection to stabilize the N-benzoyl staurosporine from environmental degradation such as light exposure, increased temperatures (from ambient to 50-60 0 C during ETO sterilization) and (3) based on the in vitro observation in which the film released an effective dose over a period of at least 7 days, a slow-release of the N-benzoyl staurosporine from both lipid compositions may be expected in vivo.
  • N-benzoyl staurosporine (PKC 412, Novartis) is known to be vulnerable under exposure of light (as that of sirolimus), where the color of PKC 412 will change due to ring-rupture.
  • This light sensitivity is especially pronounced when the Drug is present in molecular form, e.g., dissolved in solution or in some a liquid or solid matrix material.
  • This Example demonstrates the ability of the cholesterol containing film to protect a light-sensitive pharmaceutically active agent from excessive degradation.
  • the PKC 412 was dissolved in CHO-HCO-containing solutions prepared in the manner described in Example 1 , with a CHO concentration ranging from 25%, 30%, 50%, and 75% and PKC 412 maintained at 10%, in terms of solid weight of the HCO and CHO in the solution.
  • the drug-containing solutions were placed under direct (fluorescence) light exposure at a distance of 50 cm and an intensity of 6OW for 24 hours.
  • the appearance of the solution turned from clear, transparent to yellow-greenish (or somewhat yellowish color) for the solutions containing CHO at less than 50% by weight of solids in the solution.
  • the CHO offered a stabilizing effect PKC 412.
  • Degradation of PKC 412 or sirolimus is primarily caused by light and oxidation, resulting in ring rupture.
  • cholesterol may (a) prevent oxidation of staurosporine by being oxidized itself instead, and/or (2) absorb effectively the harmful (radiation) wavelengths of the fluorescent light, thereby shielding the drug molecules.
  • a drug-containing coating was coated onto 22- mm stainless steel stents, with 5% N-benzoyl staurosporine in the lipid matrix.
  • Two lipid matrix solutions were prepared by dissolving a composition of 75% cholesterol/25% hydrogenated castor oil into tetrahydrofuran (THF) and dichrolomethane (DCM), respectively, to form a solution. Addition of the N- benzoyl staurosporine into each solution lipid-containing solution (dissolved in THF and DCM, respectively) formed the drug-containing solution.
  • THF tetrahydrofuran
  • DCM dichrolomethane
  • a spray coating was employed.

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Abstract

La présente invention concerne des revêtements en pellicule solide pour dispositifs médicaux implantables comprenant une pellicule solide recouvrant au moins une partie du dispositif. La pellicule solide comprend : au moins un lipide choisi parmi le cholestérol et des dérivés du cholestérol; au moins un lipide solide supplémentaire autre que le cholestérol et les dérivés du cholestérol; et une quantité thérapeutiquement efficace d'au moins un agent pharmaceutiquement actif. Cette invention concerne également des procédés de préparation de revêtements pelliculaires et des méthodes de traitement de maladies utilisant ces dispositifs implantables.
PCT/CA2007/002325 2006-12-22 2007-12-21 Revêtements pour dispositifs médicaux implantables comprenant du cholestérol Ceased WO2008077247A1 (fr)

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US4921757A (en) * 1985-04-26 1990-05-01 Massachusetts Institute Of Technology System for delayed and pulsed release of biologically active substances
CA2442593A1 (fr) * 2001-04-04 2002-10-17 Chienna B.V. Revetement pour dispositifs medicaux comprenant un copolymere de poly(terephtalate de polyalkyleneglycol) et d'un polyester aromatique
WO2003028622A2 (fr) * 2001-10-02 2003-04-10 Biorest Ltd Procede d'administration de medicaments a un tissu au moyen de dispositifs medicaux enrobes des medicaments
WO2006014969A2 (fr) * 2004-07-29 2006-02-09 Boston Scientific Limited Dispositif medical a couche de revetement renfermant des elements structurels et son procede de production

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