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WO2009036083A2 - Compositions de polymère pour la libération contrôlable de médicaments - Google Patents

Compositions de polymère pour la libération contrôlable de médicaments Download PDF

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Publication number
WO2009036083A2
WO2009036083A2 PCT/US2008/075884 US2008075884W WO2009036083A2 WO 2009036083 A2 WO2009036083 A2 WO 2009036083A2 US 2008075884 W US2008075884 W US 2008075884W WO 2009036083 A2 WO2009036083 A2 WO 2009036083A2
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Prior art keywords
polymer
polymer composition
stent
polyol
branched
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PCT/US2008/075884
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WO2009036083A3 (fr
Inventor
Weijian Zhang
Tin Trong Tran
Soonkap Hahn
Jae Young Yang
Younjung Yuk
Kenneth D. Brown
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Curexo USA Inc
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Curexo USA Inc
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Publication of WO2009036083A2 publication Critical patent/WO2009036083A2/fr
Publication of WO2009036083A3 publication Critical patent/WO2009036083A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
    • C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
    • C08G18/6666—Compounds of group C08G18/48 or C08G18/52
    • C08G18/667—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38
    • C08G18/6674—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3203
    • C08G18/6677—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3203 having at least three hydroxy groups
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • 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
    • 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
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L75/00—Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
    • C08L75/04—Polyurethanes
    • C08L75/08—Polyurethanes from polyethers
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2270/00—Compositions for creating interpenetrating networks
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones

Definitions

  • the present application is generally related to polymer compositions, and more particularly, to polymer compositions useful for the delivery of biologically active agents in medical devices and/or drug delivery systems, including drug eluting stents.
  • Restenosis is defined as a re-narrowing or blockage of an artery as an arterial healing response after injury incurred during transluminal coronary revascularization.
  • Neointimal growth the cause of restenosis, involves dedifferentiation of vascular smooth muscle cells from a contractile state to a secretory media into the intima, and synthesis of extracellular matrix.
  • Non-erodible stent coatings mainly serve as physical support devices and carriers for bioactive molecules and guidance for tissue growth.
  • Non- erodible materials include inert coatings such as styrene-b-isobutylene-b-styrene in Taxus stent (Boston Scientific, Natick, MA), and polyethylene-co-vinyl acetate (PEVA) and poly n- butyl methacrylate (PBMA) in Cypher stent (Cordis Corp., Miami, FL), which remain permanently in body.
  • inert coatings such as styrene-b-isobutylene-b-styrene in Taxus stent (Boston Scientific, Natick, MA), and polyethylene-co-vinyl acetate (PEVA) and poly n- butyl methacrylate (PBMA) in Cypher stent (Cordis Corp., Miami, FL), which remain permanently in body.
  • Bioerodible or biodegradable polymers such as poly-L-lactide (PLLA), poly-glycolide (PGA), poly(lactide-co-glycolide) (PLGA), and poly(lactide)-co- poly(caprolactone), in the other hand, are broken down into molecules that are metabolized and removed from the body via normal metabolic pathways.
  • PLLA poly-L-lactide
  • PGA poly-glycolide
  • PLGA poly(lactide-co-glycolide)
  • caprolactone poly(lactide)-co- poly(caprolactone)
  • biodegradable polymers can be formulated with dispersion of drug within the polymeric preparation. Drug release would then occur by drug dissolution, drug diffusion and breakdown of the base polymer.
  • biodegradable polymers such as PLGA, poly(lactic acid) (PLA) and polycaprolactone (PCL) have been studied for medical- device applications, and a few have been used for stent coatings in commercial products.
  • Biodegradable polyesters of lactic acid and glycolic acid mainly PLGA and PLA, which were approved by FDA for medical use, have been widely used in medical devices in many forms, such as implants, scaffolds, microspheres, microparticles, nanoparticles, in many cases as drug carriers.
  • the major advantages of PLGA and PLA are their well -documented excellent tissue compatibility, low immunogenicity, lack of long-term adverse tissue reaction, low toxicity, and satisfactory mechanical properties over other biodegradable polymers [R.L. Dunn, in: Biomedical Applications of Syntarehetic Biodegradable polymers, J. O. Hollinger (Ed.), p.17. CRC press, Boca Raton, FL (1995)].
  • a polymer should possess suitable physical properties, in terms of flexibility, elasticity, glass transition temperature (7 1 J 3 elongation, and tensile strength.
  • Crystalline PLLA is rigid and non-elastic, which poses a difficulty for stent coating.
  • PLGA and poiy-AL-lactide (PDLLA) also have some disadvantages.
  • Mw molecular weights
  • the resulting low pH is detrimental to both the drugs which are carried in the polymer matrices and the surrounding tissues.
  • Many drugs or biological agents such as proteins are susceptible to acid hydrolysis or deactivation. Acidic polymer degradation products are known to cause tissue inflammation or necrosis. Acidic monomers or oligomers also increase polymer degradation rate by acid catalyzed hydrolysis.
  • Another important property of a stent coating is its degradation/erosion profile, measured as water uptake, polymer disintegration, molecular weight reduction, and weight gain/loss. Polymer coatings that disintegrate to particles in significantly large sizes and/or numbers as a result of erosion may cause thrombosis and other cell or tissue responses. Rapid polymer erosion may also alter drug release profiles resulting in drag release burst. In our experiment ⁇ EXAMPLE 7) PLGA film samples lost their physical integrity after soaking in buffer solutions for 3 weeks.
  • Embodiments provide a polymer composition that can be used as a biodegradable carrier for therapeutic agents, which are released in a controlled manner.
  • One aspect includes a polymer composition for use in fo ⁇ ning a polymeric coating disposed on the surface of a stent, which is designed for insertion into a blood vessel.
  • the polymer composition includes two components: (i) a crosslinked polymer derived from a branched polyethylene glycol (PEG) polyol (one embodiment of the method is described in Example 3) (ii) a randomly-formed polyester of L- lactic acid (L), glycolic acid (G) and 6-hydroxyhexanoic acid (C).
  • the weight percentage of the branched PEG polyol in the composition is in the range of 0-40% (w/w).
  • the weight percentage of the first component in the composition is tailored to provide appropriate physical characteristics for stent coating, microspheres, or polymer implant, in terms of glass transition temperature (T ⁇ ), tensile strength, elongation, water absorption, and drug release properties for specific drugs, as well as polymer degradation properties based on the requirements of selected applications.
  • T ⁇ glass transition temperature
  • the two-component composition is formed by (i) mixing the two components for a period of time, such as about 1-24 hours, or about 1-16 hours, or about 4 hours, and (ii) treating the mixture with an aqueous solution, such as a buffer solution, for example, an about 0.05 M borate aqueous solution with pH about 8.3 and (iii) continuing the mixing for additional about 1-24 hours, such as about 1-8 hours, or about 1—4 hours.
  • aqueous solution such as a buffer solution, for example, an about 0.05 M borate aqueous solution with pH about 8.3
  • about 1-5% (v/v) of an aqueous solution in an organic solvent or a mixture of organic solvents is used.
  • the polymer composition is a randomly- formed polyester of i-lactic acid (L), glycolic acid (G), and 6-hydroxyhexanoic acid (C).
  • the molar ratio of the monomers for the polymerization is tailored to provide the appropriate physical characteristics for stent coating, microspheres, or polymer implant, in terms of glass transition temperature (T e ), tensile strength, elongation, water absorption, and drug release profiles for specific drugs, as well as polymer degradation profiles based on the requirements of selected applications.
  • T e glass transition temperature
  • the molar ratio of L/G/C of the polyester products is about 80- ⁇ 40/50—10/30-5.
  • the molar ratio of L/G/C of the polyester products may be (80-50/49-0/30-1); in another embodiment about 80-50/40-10/20- 10; in yet another embodimentabout 70-60/30-10/20-10.
  • Another embodiment provides a method for producing biodegradable polyesters from i-lactide, glycolide and ⁇ -caprolactone via a random polymerization reaction.
  • the composition of the polyesters is composed of randomly arranged ester units of L-lactic acid, glycolic acid and 6-hydroxyhexanoic acid.
  • the composition may include one or more additives, which is/are a hydrophih ' c and/or water soluble polymer(s) including, but not limited to, polyethylene glycol, polyvinylpyrrolidone (PVP), polyacrylic acid or polyvinyl alcohol.
  • additives which is/are a hydrophih ' c and/or water soluble polymer(s) including, but not limited to, polyethylene glycol, polyvinylpyrrolidone (PVP), polyacrylic acid or polyvinyl alcohol.
  • the biodegradable polymer composition has the appropriate physical properties, such as elongation capacity, tensile strength, glass transition temperature (T g ), and adhesion that are necessary for coating the surface of a stent and resisting coating delamination during stent crimping and expansion.
  • the biodegradable polymer compositions in this invention are a carrier of bioactive agents and have suitable physicochemical properties such as hydrophilicity and drag permeability, and b ⁇ ocompatibility such as tissue compatibility, and hemocompatibility in a biological environment such as human artery.
  • the Mw of the polyester in the composition for stent coating is about 20 to 120 kilo DaIt ons and the thickness of the coating is about 5-20 ⁇ m, and the total coating weight is about 50-500 ⁇ g which completely degrades and disintegrates in an artery within a few weeks to a few months.
  • the polymer composition for stent coating includes at least one therapeutic agent.
  • the stent coating may include multiple layers, and each layer may have the same or different polymer compositions, and the same or different bioactive agents.
  • the stent coating may have a top coating or outer layer for providing b ⁇ ocompatibility and/or controlling drug release profiles.
  • Another aspect provides a method for disposing the composition on the surface of a stent.
  • the coating has adequate adhesion to the surface of a stent and elasticity to avoid dislocation, cracking and delamination during stent crimping, expansion and deployment to a desired location such as a human artery.
  • the coating procedure includes spraying an adequate polymer solution, for example, about 0.5-5 % w/v of the polymer in an organic solvent, such as acetone or acetonitrile onto a surface of a stent made from materials such as polymers or metal.
  • the coating equipment used in the procedure includes an ultrasonic nozzle which produces a very thin and uniform spray pattern.
  • coated stents are placed in an oven at a preset temperature, for example at about 30-60° C, such as about 37° C for a period of time of about 8-32 hours, such as about 16 hours to yield a coated stent with a coating weight of about 100 to 500 ⁇ g.
  • the thickness of the stent coating is between about 5-20 ⁇ m or about 5-10 ⁇ m.
  • the coating weight is about 50-500 ⁇ g, such as about 150 ⁇ g for a stent with an outside diameter of 2-4 mm and a length of 8-12 mm.
  • the polymer composition comprise a copolymer of at least two of l-lactide, £>,Z-lactide, glycolide, and ⁇ -caprolactone.
  • At least a portion of the polymer composition is bioerodible, biodegradable, or a combination thereof. In some embodiments, at least a portion of the branched PEG polymer and the polyester are interpenetrating or semi-interpenetrating.
  • the branched PEG polymer in the composition has a weight average molecular weight of at least about 6,000 Daltons.
  • the polyester has a weight average molecular weight in the range of from about 20,000 to about 200,000 Daltons. In some embodiments, the polyester has a weight average molecular weight in the range of from about 40,000 to about 80,000 Daltons. In some embodiments, the polyester has a weight average molecular weight in the range of from about 100,000 to about 200,000 Daltons. In some embodiments, the polyester has a T g in the range of from about 0° C to about 40° C.
  • Some embodiments further comprise one or more non-reactive additives.
  • Some embodiments further comprise a biologically active agent.
  • the biologically active agent has a controllable release kinetics.
  • the implantable medical device is a stent.
  • the polymer composition further comprises at least one of an anti-proliferative, an anti-inflammatory, an an ti -thrombotic, or an anti-restenotic agent.
  • the method for the preparation of the polymer composition comprises contacting the branched PEG polymer and the polyester, hi some embodiments, the contacting is performed in a solution phase. In some embodiments, the contacting is performed in a solution phase comprising 1-5% (v/v) of an aqueous solution in an organic solvent. Some embodiments further comprise removing a solvent.
  • Some embodiments further comprise contacting the branched PEG polymer and the polyester with one or more additives. Some embodiments further comprise contacting the branched PEG polymer and the polyester with a biologically active agent,
  • the polymer composition comprises a polymer or a copolymer made from monomers selected from a group consisting of Z-lactide, D,Z.-lactide, glycolide, and f-caprolactone.
  • Some embodiments further comprise synthesizing the branched PEG polymer by a method comprising: contacting a branched PEG polyol with a polyisocyanate and a crosslinker at an elevated temperature, such as about 50-180° C or about 80-150° C, for example, about 120° C.
  • the crosslinker comprises trimethylolpropane .
  • Some embodiments further comprise synthesizing the polyester by a method comprising ring-opening copolymerization of lactide, glycolide, and e-caprolactone.
  • the lactide is i-lactide.
  • interpenetrating polymer network composition and a method for synthesizing the interpenetrating polymer network composition.
  • Said interpenetrating polymer network composition comprises a covalently crosslinked polymer formed by the reaction of a branched PEG polyol with a polyisocyanate and one or more additional crosslinkable molecules, and a biodegradable aliphatic polyester.
  • the additional crosslinkable molecule is a branched small molecule polyol.
  • the branched small molecule polyol is an afkane or arene substituted with two or more hydroxy] groups.
  • the branched small molecule polyol is glycerin.
  • the branched small molecule polyol is trimethylolpropane.
  • the polyisocyanate is an alkane or arene substituted with two or more isocyanate groups. In some embodiments, the polyisocyanate is isophorone diisocyanate.
  • the branched PEG polyol is prepared by the reaction of a branched small molecule diol or polyol with ethylene oxide. In some embodiments, the branched PEG polyol has a weight average molecular weight of at least about 2,000 Daltons.
  • the branched PEG polyol in the inventive composition can be represented by the following formula:
  • R 2 is a branched alkyl substituted with one or more hydroxyl groups, said hydroxy! groups may be isocyanate-capped by a diisocyanate or polyisocyanate such as isophorone diisocyanate, or R 2 is a moiety derived from a polyethylene glycol, a polypropylene glycol, a polyol or a polyester, which is linked to the PEG polyol chain via a urethane bond; P is an alkyl or aryl group with two covalent bonds connecting two nitrogen atoms adjacent in the chain; n is 10 to 1000, and m is 1 to 100.
  • the weight percentage of the covalently crosslinked PEG polymer is in the range of about 0% to about 40% and the weight percentage of the polyester is in the range of about 100% to about 60% compared with the total weight of the composition.
  • the method for forming the covalently crosslinked PEG polymer comprises: mixing (1) said branched PEG polyol, (2) said diisocyanates or a polyisocyanate. In some embodiments, said method for forming the covalently crosslinked PEG polymer further comprises mixing one or more additional crosslinkable molecules.
  • Some embodiments comprise mixing said covalently crosslinked PEG polymer, said biodegradable aliphatic polyester and a small amount of aqueous solution in an organic solvent or a mixture of organic solvents.
  • the mixing is performed in a solution phase.
  • the organic solvent or the mixture of organic solvents is/are selected from the group consisting of acetone, acetonitrile, 1,2-dimethoxy-ethane, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, 1,4-dioxane, and tetrahydrofuran.
  • the aqueous solution is a buffer with a pH of about 7 or higher and is made from chemicals selected from the group consisting of sodium borate, sodium phosphate, sodium dihydrogen phosphate, disodium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium phosphate, potassium carbonate, potassium hydrogen carbonate, and hydrates thereof, and sodium or potassium salts of carboxyl ⁇ c acids.
  • Some embodiments further comprise mixing the polymer mixture with one or more additives. Some embodiments further comprise mixing the polymer mixture with one or more biologically active agents.
  • Some embodiments provide a drug delivery system suitable for implanting in or injection into a body, comprising the polymer composition in the invention, which can be in any suitable form, such as microcapsules, microparticles, microspheres, nanoparticles, implants, stent coating, drug- encapsulating matrix or membrane.
  • the systems can be made as devices including buccal and oral devices, ocular devices, vaginal and intrauterine devices of cylindrical, bullet, elliptical, circular, bulbous, loop or any other shapes suited for placement in the physiological environments.
  • the drug delivery system is suitable for releasing a biological active agent in a body in a controlled manner.
  • the biologically active agent is an antiproliferative, anti -inflammatory, anti-thrombotic or anti-restenotic agent.
  • Some embodiments provide a method for forming at least a portion of the medical device comprising applying the polymer composition by at least one of spray coating, electrostatic coating, plasma coating, brush coating, powder coating, extruding, molding, welding, pressing, wrapping, and fastening.
  • Some embodiments provide a method of treating a mammal in need thereof, comprising implanting an implantable medical device comprising the polymer composition in the invention.
  • FIG. 1 illustrates paclitaxel in vitro percentage releases from stents coated with PLGA, L/G ratio 50/50 and an invention composition of PLGC, L/G/C ratio 63/25/12, with the same total coating weight of 270 ⁇ g and drug loading 5% w/w.
  • FIG. 2 illustrates sirolimus in vitro releases from stents coated with the same PLGC polymer composition as in FIG. 1 , but different total coating weights (drug loading 15% w/w).
  • FlG. 3 illustrates erosion and degradation profiles of an embodiment of the polymer composition as described in EXAMPLE 5.
  • FIG. 4 illustrates release profiles of methotrexate as described in EXAMPLE 6.
  • FIG. 5 is a photograph of samples of the polymer compositions comprising methotrexate in the erosion study described in EXAMPLE 7.
  • FlG. 6 illustrates the effect of NCO-PEG on methotrexate release profiles of PLG A-containing and PLGC-containing compositions as described in EXAMPLE 8.
  • FIG. 7 is a SEM image of an expanded coronary stent coated with an invention polymer composition, with total coating weight of 300 ⁇ g, loaded with 5% (w/w) paclitaxel, wherein no flaking, cracking, or delamination of the coating was observed.
  • FIG. 8 is a SEM image of an expanded coronary stent coated with an invention polymer composition, with total coating weight of 190 ⁇ g, loaded with 17% (w/w) sirolimus, wherein no flaking, cracking, or delamination of the coating was observed.
  • Polymer as used herein refers to homopolymers and copolymers, including random, alternating and block copolymers.
  • Copolymer refers to a polymer formed through the inter-polymerization of two (or more) chemically different monomers with each other.
  • Tepolymer refers to a copolymer made from three different monomers.
  • IPN interpenetrating polymer network
  • Semi-IPN is one in which only one of the polymer systems is crossl inked
  • Molecular weights for polymers are weight average molecular weights in Daltons (Da) or kilo Daltons (kDa).
  • alkyl includes straight- and branched-chain and cyclic monovalent substituents.
  • the alkyl substituents typically contain 1-lOC (alkyl).
  • they contain lower alkyl such as 1-6C (alkyl) or I-3C (alkyl). Examples include methyl, ethyl, isobutyl, isopropyl, cyclohexyl, cyclopentyl ethyl, and the like.
  • alkane refers to hydocarbons containing only single carbon-carbon bonds.
  • Arene' refers to monocyclic and polycyclic aromatic hydrocarbons
  • Aryl refers to a monocyclic or fused bicyclic moiety, for example, containing 5-12C, such as phenyl or naphthyl and includes "heteroaryl” that is, monocyclic or fused bicyclic ring systems containing, for example, one or more heteroatoms selected from O, S and N. Any monocyclic or fused bicyclic ring system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. Typically, the ring systems contain 5-12 ring member atoms.
  • a moiety that is ''derived from " a polyethylene glycol, a polypropylene glycol, a polyol or a polyester means that the backbone or main chain of the moiety is a polyethylene glycol, a polypropylene glycol, a polyol or a polyester.
  • the main chain in a moiety can be a straight or a branched chain, or crosslinked with other chains in the polymer.
  • the polymer composition comprise at least two components: a first component comprising a branched PEG polymer and a second component comprising a biodegradable polyester. Other embodiments comprise at least the second component.
  • the partially crosslinked first components is thoroughly mixed with the second component and fully crosslinked in the mixture to fo ⁇ n an interpenetrating network (IPN) or semi-interpenetrating (semi IPN) polymer network.
  • IPN interpenetrating network
  • si IPN semi-interpenetrating
  • the polymer composition may comprise additional components, for example, one or more additives, for example, other polymers, fillers, and/or biologically active agents.
  • a branched PEG polyol such as a PEGylated glycerol, of the formula CH 2 RCHRCH 2 R, where R is -(OCH 2 CH 2 ) ⁇ OH
  • a partial crosslinking reaction occurs when the hydroxyl groups of a branched PEG polyol reacts with the isocyanate group of a polyisocyanate molecule, thereby forming an adduct in which the two molecules are crosslinked through a urethane bond (-NHCOr-). Because the isocyanate groups are present in excess, unreacted isocyanate functional groups in the adduct molecules are available for further crosslinking reactions, either through urethane bonds with hydroxy] groups or through urea bonds (-NHCONH-) with amino groups.
  • polyisocyanate is an aliphatic or aromatic polyisocyanate.
  • polyisocyanate' refers to compounds comprising a plurality of isocyanate groups, including, diisocyanates, triisocyanates, and polyisocyanates.
  • the first component can be further branched by reacting with one or more crosslinkable small molecules.
  • the small molecule is a polyol, in another embodiment, the small molecule is a branched polyol. Ln yet another embodiment, the small molecule is trimethylolpropane.
  • the branching of the polymer chains of the first component provides the network structure of the IPN in some embodiments of the polymer composition.
  • the polymer composition is prepared according to the procedure set forth in EXAMPLE 4, in which an IPN polymer is formed.
  • the presence of the IPN confers to the polymer composition significant improvements in its physical properties, including glass transition temperature, tensile strength, elasticity, and elongation, as well as degradation properties and drug release properties.
  • Tensile strength and elongation are measured in accordance with ASTM D-882, using the average measurement based on 5 samples, 0.1 mm thickness, crosshead speed 4 in/min.
  • tensile strength is the least about 725 psi (or at least about 5 mPa), such as 725-5000 psi ⁇ 5-34.5 mPA, or about 1500-2000 psi).
  • elongation is greater than 100%, such as greater than 200%, 300%, 400%, 500%, 600%, 700%, or 800%.
  • elongation is about 100%- 1000%, such as 300%-700%, or 400%-600%.
  • the glass transition temperature is about 0-40 0 C, such as 10-30 °C or 15-25 0 C.
  • the branched PEG polyol is generally prepared by reacting a small molecule polyol, such as glycerol, with ethylene oxide.
  • the thus-formed polyol has one free hydroxyl group at the end of each PEG chain, which is available for crosslinking.
  • other branched polyols such as trimethylolpropane, trimethylolethane, pentaerythritol, and sorbitol may be used to form branched PEG polyols.
  • a branched polyol can react with propylene oxide to form branched PPG-based polyols, or react with a mixture of ethylene oxide and propylene oxide to form branched PEG-PPG copolymer based polyols, which are used in the synthesis of other embodiments of the branched polymer.
  • the branched PEG polyol used for the preparation of the first component has an average molecular weight (Mw) of at least about 2 kilodalton (kDa), such as about 4— 30 kDa, for example about 6 kDa.
  • Mw average molecular weight
  • kDa kilodalton
  • the molecular weight of the branched PEG polyol and the lengths of PEG chains in the polyol are important for the desired degree of entanglement and/or the formation of the IPN of the first and the second component of the polymer composition.
  • the Mw of the first component increased by about 5—10 times, compared with the Mw of the initial branched PEG polyol, indicating a crosslinking of about 5-10 branched PEG polyols during the formation of the polymer composition.
  • an important feature of the composition is that the two individual components and the final composition are soluble in an organic solvent or a mixture of organic solvents, for example, an aprotic solvent such as dichloromethane (DCM), chloroform, acetone, acetonitrile, dimethylacetamide (DMA), dimethyl formamide (DMF), tetrahydroforan (THF), 1,4-dioxane, iV-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), combinations thereof, and the like.
  • the solvents are those which are aprotic and polar, and misc ⁇ ble with a small amount of aqueous solution. According to the procedure set forth in EXAMPLE 4, the two components of the polymer composition are dissolved and mixed in acetonitrile and subsequently treated with an aqueous buffer.
  • SCHEME 1 is a simplified and exemplary illustration of crossfinking reactions that may occur during the formation of the first component (Steps A and B), and hydrolysis and further crosslinking reactions that may occur during the formation of the final polymer composition (Steps C and D).
  • nucleophiles -OH, -NH 2, such as hydroxyls in polyols or polyesters and amino groups in hydrolyzed isocyanates
  • electrophiles -NCO
  • step A a hydroxyl group (-OH) of a polyethylene glycol (PEG) chain in a branched PEG polyol II, of which only one PEG chain with a terminal hydroxyl group is illustrated, with the rest of the molecule abbreviated as R 1 , reacts with one of the isocyanate groups in a polyisocyanate to form III, in which the end of the PEG chain is isocyanate- capped.
  • the polyisocyanate is isophorone diisocyanate VHI, abbreviated as "Ip(NCO)2" in SCHEME 1.
  • the non-isocyanate portion of isophorone diisocyanate is abbreviated as "Ip" herein.
  • any suitable polyisocyanate may be used, for example, toluene diisocyanate (TDI), 4,4'-diphenylmethane diisocyanate (MDI), and the like.
  • TDI toluene diisocyanate
  • MDI 4,4'-diphenylmethane diisocyanate
  • toluene diisocyanate refers to 2,4-toIuene diisocyanate, 2,6-toluene diisocyanate, or mixtures thereof.
  • the polyisocyanate for example an aliphatic polyisocyanate., is selected to provide improved biocompatibility of the polymer composition.
  • Other hydroxyl group terminated PEG chains in the branched PEG polyol may undergo the same crosslinking reaction and provide further branching.
  • branched PEG polyols and polyisocyanates may have different structures. Those skilled in the art will understand that other branched PEG polyols and polyisocyanates may be subject to the same crosslinking reactions as shown in SCHEME 1 for the preparation of the first component.
  • step B a hydroxyl group of a small molecule polyol IV, of which only one methylenehydroxy] group (-CH 2 OH) is illustrated with the rest of the molecule abbreviated as R 2 , reacts with a polyisocyanate [Ip(NCO) 2 ] to provide an isocyanate-capped polyol V.
  • the branched polyol is trimethylolpropane (2,2- dihydroxymethyl-1-butanol).
  • Other embodiments use other suitable polyols, for example, glycerol, trimethylolethane (2,2-dihydroxymethyI-l-propanol), pentaerythritol, triethanolamine, and the like.
  • Suitable polyisocyanates are the same as discussed above in connection with step A.
  • the polyisocyanate is isophorone diisocyanate VIII, which is the same as the polyisocyanate used in step A.
  • Other embodiments use different polyisocyanates in step B.
  • step C the other unreacted isocyanate group of the isocyanate-capped polyol V is hydrolyzed by water to give amine VI.
  • an intermediate carbamic acid is formed, which loses CO 2 to give the amine group.
  • step C occurs in an organic solvent system comprising an aqueous solution, which is, for example, buffered at about pH 7.
  • Suitable buffers comprise at least one of sodium borate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, potassium bicarbonate, and hydrates thereof, and sodium and/or potassium salts of carboxylic acids.
  • SCHEME 1 illustrates the hydrolysis of an isocyanate group on the isocyanate-capped polyol V, although those skilled in the art will understand that a similar hydrolysis reaction is possible for an isocyanate group on the isocyanate-capped PEG III, which will provide the same and/or similar products.
  • step D an isocyanate group of the capped PEG III (NCO-PEG) reacts with the amino group of compound VI to form a urea linkage between compounds III and VI, thereby providing compound VII.
  • any of the uncapped hydroxyl groups of other PEG chains (in R ( ) in compound II and of other methylenehydroxyl groups (in R 2 ) in compound IV, as well as any of the unreacted amino groups (in R 2 ) in compound VI may react with any of the unreacted isocyanate groups in compounds III, V, and VI.
  • the crosslinking reactions may occur randomly through urethane bonds and urea bonds, intermolecularly and intramolecularly.
  • the resulting product of the crosslinking reactions exemplified in SCHEME 1 is a randomly crosslmked polymer mixture.
  • Steps A and B represent the urethane linker formation during the synthesis of the first component of the polymer composition
  • Steps C and D represent the amino group generation and consequent urea linker formation during the final step of the preparation of the polymer composition, when the first component network further extends through urea linker formation and forms a IPN in the polymer mixture of second component (PLGC).
  • PLGC polymer mixture of second component
  • a terpolymer of lactide, glycolide, and ⁇ -caprolactone is referred to herein as "poly(lactide-co-glycolide-co- caprolactone)" or "PLGC.”
  • the polyester of the second component comprise a polymer or copolymer made from monomers selected from a group consisting of /,-lactide, Z),Z-lactide, glycolide, and £--caprolactone, such as PLGA, , PCL, PLLA, or PDLLA.
  • Embodiments of the polyester comprise any combination of random, block, and alternating copolymer domains.
  • R 2 may also be a moiety derived from these polyesters, when IV is a polyester such as PLGC in SCHEME 1.
  • the polyester of the second component is synthesized by any suitable method.
  • the second component is synthesized by ring-opening copolymerization of suitable ester precursors, for example, lactones.
  • suitable lactone precursors include lactide (dilactone of lactic acid), glycolide (dilactone of glycolic acid), and ff-caprolactone (lactone of 6-hydroxyhexanoic acid or 6-hydroxycapro ⁇ c acid).
  • lactide diilactone of lactic acid
  • glycolide diilactone of glycolic acid
  • ff-caprolactone lactone of 6-hydroxyhexanoic acid or 6-hydroxycapro ⁇ c acid
  • Other esters and/or lactones are used in other embodiments, for example, /-hydroxybutyric acid lactone, hi some embodiments, the ester precursors are mixed in the desired stoichiometry under suitable polymerization conditions.
  • each equivalent of lactide and glycolide yields two equivalents of lactic acid monomer and glycolic acid monomer, respectively, in the polyester.
  • Some embodiments use any suitable transesterif ⁇ cation catalyst known in the art, for example, Lewis acids, metal alkoxides, metal carboxylates, and the like.
  • the catalyst is a tin catalyst, for example, tin carboxylates such as Sn(II)octoate.
  • a suitable method for preparing an embodiment the second component is described by Wang et ai, J. Biomater. Sci. Polymer Edn., 77:273 (2000), the disclosure of which is incorporated by reference.
  • Reaction conditions, stoichiometry, reagents, catalysts, and like are adjusted to provide a second component with the desired properties, including biodegradation or bioerosion rate, biocompatibility, mechanical properties, elasticity, elongation, molecular weight, chemical properties, morphology, polymer microstructure, glass transition temperature (T g ), melting temperature (T n ,), and release profile of active agents from the resulting polymer composition, and the like.
  • T g of the second component is from about -10 0 C to about 50 0 C, from about 0 °C to about 30 0 C, or from about 10 0 C to about 20 °C.
  • T n of the second component is from about 100 0 C to about 150 0 C, or from about 1 10 0 C to about 120 0 C.
  • Embodiments of the polyester have average molecular weights of from about 20 kDa to about 200 kDa.
  • the polyesters in the compositions of this invention can be prepared from Z,l-lactide; D,D-lactide; Z),i-lactide (mesolactide); and a racemic mixture of L 1 L- and D, D- lactides.
  • the ester precursors are i-lactide, glycolide and f-caprolactone.
  • the Mw and other physical properties of the product are affected by many factors, including reaction vessel, catalyst amount, agitation mode, temperature, and reaction time.
  • the PLGC polyester in this invention can be made in a round glass vessel, agitated with a magnetic string bar or a mechanical stirring apparatus under inert gas protection, heated at 160° C for 48 hours.
  • RPM rotation rate
  • different polyester products with narrow Mw ranges indicated by polydispersity and consistent physical properties can be produced.
  • the stirring time is the only parameter used to control the properties of the products.
  • Embodiments of the polymer composition comprise from about 0 wt% to about 40 wt% of the first component and from about 60 wt% to about 100 wt% of the second component.
  • the second component is embedded in a matrix of the branched PEG polymer of the first component to form a homogenous IPN system.
  • the polymer composition comprises only the second component, which is the polyester described above.
  • the molar ratio of the monomers is modified in some embodiments to provide appropriate physical and/or chemical characteristics depending on the particular application, for example stent coating, microspheres, or polymer implant, in terms of molecular weight, glass transition temperature [T g ), tensile strength, elongation, water absorption, drug eluting profile, and the like.
  • T g glass transition temperature
  • the molar ratio of L/G/C is about 80-40/50-10/30-5.
  • the molar ratio of L/G/C is about (80-50/49-0/30-1), or about 80-50/40-10/20-10, or about 70-60/30-10/20-10.
  • polymer composition comprise a plurality of different first component species, for example, with different molecular weights, stoichiometrics, and/or compositions.
  • second component comprises a plurality of polyester species, for example, with different molecular weights, stoichiometrics and/or compositions.
  • Suitable additives include non-reactive polymer fillers.
  • Addition of water soluble polymer additives for example, polyethylene glycol, polyvinylpyrrolidone (PVP), polyacrylic acid, polyvinyl alcohol, and combinations thereof and the like, is believed to affect the duration and profile of bioerosion and drug release from the polymer composition. For example, as discussed below, in some embodiments, bioerosion and drug release are accelerated by incorporating a water soluble polymer additive.
  • additives include one or more biologically active agents, which are discussed in greater detail below. These additives are incorporated either when combining the first and second components of the polymer composition, premixed with one of the first and second component, or after the first and second component are combined.
  • Some embodiments also include biodegradable implants and methods for producing such implants.
  • These implants are solid articles that can be made from the polymer composition by known methods in the art. Included are microcapsules, microparticles, structured articles such as sutures, staples, medical devices, stents and the like as well as monolithic implants and implant films, filamentous membranes and matrices. These implants differ in the mechanical properties, degradation and drug releasing profiles from known materials due to the presence of an interpenetrating network and the properties of the polymer compositions.
  • biologically active agent/' L 'drug refers to physiologically and/or pharmacologically active substances that act locally and/or systemically in the body.
  • Biologically active agents include substances used for the treatment, prevention, diagnosis, cure, and/or mitigation of disease states and/or illness; substances that affect the structure or function of the body; and/or pro-drugs, which become biologically active, more active, and/or differently active after they have been placed in a suitable physiological environment.
  • Biologically, physiologically, and/or pharmacologically active substances can act locally and/or systemically in the human or animal body.
  • Suitable biologically active agents include acidic, basic, or amphoteric compounds and/or salts.
  • Suitable biologically active agents include nonionic molecules, polar molecules, and/or molecular complexes capable of hydrogen bonding.
  • Embodiments of the biologically active agent may be included in the polymer compositions in the form of, for example, uncharged molecules, molecular complexes, salts, ethers, esters, amides, polymer drug conjugates, and/or other forms that provide therapeutically effective biological and/or physiological activity.
  • Combinations of one or more bioactive agents and an IPN composition provide an embodiment of a pharmaceutical composition.
  • Bioactive agents contemplated for use with the polymer composition include at least one of anabolic agents, antacids, anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents, anti-coagulants, anticonvulsants, anti-diarrheals, anti-emetics, anti- infective agents including antibacterial and antimicrobial agents, anti-inflammatory agents, anti-manic agents, antimetabolite agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti -spasmodic agents, anti-thrombotic agents, antitussive agents, anti-uricemic agents, anti-anginal agents, antihistamines, appetite suppressants, biologicals, cerebral dilators, coronary dilators, bronchodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hypergly
  • the biologically active agents for use with the polymer composition include androgen inhibitors, polysaccharides, growth factors, hormones, anti- angiogenesis factors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, chlophedianol hydrochloride, chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate morphine, mineral supplements, cholestryramine, jY-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenyl propanolamine hydrochloride, caffeine, guaifen
  • Representative drugs or bioactive materials that can be used in the polymer system or solid matrix include, but are not limited to, peptide drugs, protein drugs, desensitizing materials, antigens, anti-infective agents such as antibiotics, antimicrobial agents, antiviral, antibacterial, antiparasitic, antifungal substances and combination thereof, antiallergenics, androgenic steroids, decongestants, hypnotics, steroidal anti-inflammatory agents, anti-cholinergics, sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardioactive agents, nonsteroidal anti -inflammatory agents, antiparkinsonian agents, antihypertensive agents, / ⁇ -adrenergic blocking agents, nutritional agents, and benzophenanthridine alkaloids.
  • the agent may further be
  • the pharmaceutical composition can contain biologically active agents either singly or in combination.
  • the biologically active agents can be in a controlled release component, which is dissolved, dispersed, and/or entrained in the adjunctive polymer system.
  • the controlled release component can include microstructures, macrostructures, conjugates, complexers, low water-solubility salts, and the like.
  • Microstructures include nanoparticles, microcapsules, microspheres micelles, liposomes, and the like.
  • Macrostructures include fibers, beads, and the like.
  • suitable biologically active agents include, but are not limited to, the following: Anti-inflammatory agents such as hydrocortisone, prednisone, fludrotisone, triamcinolone, dexamethasone, betamethasone, and the like. Anti-bacterial agents such as penicillins, cephalosporins, vancomycin, bacitracin, polymycins, tetracyclines, chloramphenicol, erythromycin, streptomycin, quinolone, and the like. Antifungal agents such as nystatin, gentamicin, miconazole, tolnaftate, undecyclic acid and its salts, and the like.
  • Anti-inflammatory agents such as hydrocortisone, prednisone, fludrotisone, triamcinolone, dexamethasone, betamethasone, and the like.
  • Anti-bacterial agents such as penicillins, cephalosporins, vancomycin, bacitracin, polymycins, tetracycl
  • Analgesic agents such as salicylic acid, salicylate esters and salts, acetaminophen, ibuprofen, morphine, phenylbutazone, indomethacin, sulindac, tolmetin, zomepirac, and the like.
  • Local anesthetics such as cocaine, benzocaine, novocaine, lidocaine, and the like.
  • Some embodiments include one or more suitable bioactive agents, such as anti-restenotic, antiproliferative agents, for example, paclitaxel, rapamycin (sirolimus), everolimus, tarcrolimus, zotarolimus, pimecrolimus, dexamethasone, and anti-inflammatory, antineoplastic, antiplatelet, anticoagulant, antifibrin, antimitotic, antibiotic, and antioxidant agents.
  • suitable bioactive agents such as anti-restenotic, antiproliferative agents, for example, paclitaxel, rapamycin (sirolimus), everolimus, tarcrolimus, zotarolimus, pimecrolimus, dexamethasone, and anti-inflammatory, antineoplastic, antiplatelet, anticoagulant, antifibrin, antimitotic, antibiotic, and antioxidant agents.
  • the bioactive agent may also be a substance, or metabolic precursor thereof, which is capable of promoting growth and survival of cells and tissues, or augmenting the activity of functioning cells, as for example, blood cells, neurons, muscle, bone marrow, bone cells and tissues, and the like.
  • the bioactive agent may be a nerve growth promoting substance, for example, a ganglioside, phosphatidyl serine, a nerve growth factor, and/or brain-derived neurotrophic factor.
  • the bioactive material may also be a growth factor for soft or fibrous connective tissue as, for example, a fibroblast growth factor, an epidermal growth factor, an endothelial cell growth factor, a platelet derived growth factor, an insulin-like growth factor, a periodontal ligament cell growth factor, cementum attachment extracts, and fibronectin.
  • a growth factor for soft or fibrous connective tissue as, for example, a fibroblast growth factor, an epidermal growth factor, an endothelial cell growth factor, a platelet derived growth factor, an insulin-like growth factor, a periodontal ligament cell growth factor, cementum attachment extracts, and fibronectin.
  • the biologically active material may be an osteoinductive or osteoconductive substance.
  • suitable bone growth promoting agents include, for example, osteoinductive factor (OIF), bone morphogenetic protein (BMP) or protein derived therefrom, demineralized bone matrix, and releasing factors thereof.
  • the agent may be a bone growth promoting substance such as hydroxyapatite, tricalcium phosphate, a di- or polyphosphonic acid, an anti -estrogen, a sodium fluoride preparation, a substance having a phosphate to calcium ratio similar to natural bone, and the like.
  • a bone growth promoting substance may be in the form, as for example, of bone chips, bone crystals, or mineral fractions of bone and/or teeth, a synthetic hydroxyapatite, or other suitable form.
  • the agent may further be capable of treating metabolic bone disorders such as abnormal calcium and phosphate metabolism by, for example, inhibiting bone resorption, promoting bone mineralization, or inhibiting calcification.
  • the active agent may also be used to promote the growth and survival of blood cells, as for example, a colony stimulating factor, and erythropoietin.
  • the biologically active agent upon mixing and removal of the solvents, the biologically active agent becomes incorporated into the polymer matrix.
  • the bioactive agent will be released from the matrix into the adjacent tissues or fluids by diffusion, migration, dissolution, and/or by polymer erosion and degradation mechanisms. Manipulation of these mechanisms also can influence the release of the bioactive agent into the surroundings at a controlled rate.
  • the polymer composition can be formulated to degrade substantially while and or after an effective and/or substantial amount of the bioactive agent is released from the matrix.
  • an bioactive agent when an bioactive agent has a low solubility in water and the diffusion is slow, for example in a case of a peptide or protein, the degradation of a substantial part of the polymer matrix is typically required, thereby exposing the bioactive agent directly to the surrounding tissue fluids.
  • the release of the biologically active agent from the matrix can be affected by, for example, the solubility of the bioactive agent in water, the diffusion rate of the bioactive agent within the matrix, or the size, shape, porosity, solubility, and/or biodegradability of the polymer matrix, among other factors, in some embodiments, the release of the biologically active agent from the matrix is controlled by varying the polymer composition, polymer molecular weight, and by adding a rate modifying agent to provide a desired release profile.
  • Some embodiments provide medical devices and/or implants comprising the polymer composition. Some embodiments are permanently implanted into a patient. Other embodiments are temporary, for example, being biodegraded in the body and/or removed after implantation. Implantation by any suitable methods, for example, surgical, through a catheter, percutaneous, injection, arthroscopic, and the like are possible. In some embodiments, a device is delivered orally or as a suppository.
  • the device is in any forms, of which partial or total biodegradability is desired, with the option of including the capability of delivery, such as sustained release delivery, of one or more biologically active agents.
  • suitable devices and/or implants include stents, graft implants, filters, annulopjasty rings, heart valves, endovascular coils, septal occluders, left atrial appendage occlusion devices, gastric balloons, gastric bands, sutures, staples, anchors, dressings, orthopedic implants, artificial joints, artificial tendons, artificial ligaments, bone screws, bone implants, artificial discs, dental implants, shunts, cochlear implants, ocular implants, cosmetic implants, microcapsules, microparticles, monolithic implants, implant films, filamentous membranes and matrices, beads, granules, and the like.
  • the entire device is substantially fabricated from the polymer composition, for example, when biodegradability of the entire device is desired.
  • subassemblies and/or subcomponents of the device including coatings, sleeves and/or fillers for cavities, holes, openings, and/or voids are fabricated from the polymer composition.
  • a stent is dipped in and/or sprayed with a solution of the polymer composition.
  • the polymer composition is dissolved in one or more organic solvents at a concentration of from about 0.5 % to about ⁇ % w/v, such as from about 1 % to about 5 % w/v.
  • Suitable solvents include acetone, acetonitrile, DMA, DMF, DMSO, dichloromethane (DCM), and combinations thereof.
  • the solvent comprises acetone and/or acetonitrile.
  • the polymer composition is powder coated or electrostaticly coated on a stent, optionally followed by further processing.
  • the polymer composition are also useful in fabricating other forms of the polymer composition, for example, films, fibers, filaments, tubes, and other solvent extrudable or castable forms.
  • these forms are further processed, for example, by machining, extrusion, weaving, melt processing, welding, stretching, compressing, shrinking, spinning, and the like.
  • the polymer composition can be modified to provide different materials with different physical properties, such as hydrophobicity, elasticity and elongation, degradation properties, and drug release properties.
  • the monomer ratio of L, G, C and the Mw of the polyester according to the procedure in Example 1 can be adjusted, to produce desired materials as coating for different layers in the stent coating, and for different drug, release profiles, and degradation rates, in some embodiments, the polyester has a weight average molecular weight in the range of from about 20,000 to about 120,000 Daltons. In some embodiments, the polyester has a weight average molecular weight in the range of from about 30,000 to about 60,000 Daltons. In some embodiments, the polyester has a weight average molecular weight in the range of from about 50,000 to about 80,000 Daltons.
  • the stent is of any suitable type known in the art, for example, tubular, coil, ring, mesh, multi-design, and the like; and comprises any suitable material, for example, metal, metal alloy, stainless steel, nitinol, polymer resins, fluorinated polymers, polytetrafluoroethylene, silicone, biopolymers, composites, biodegradable polymers and the like.
  • suitable material for example, metal, metal alloy, stainless steel, nitinol, polymer resins, fluorinated polymers, polytetrafluoroethylene, silicone, biopolymers, composites, biodegradable polymers and the like.
  • Embodiments of the polymer composition exhibited strong adhesion to polished metal surfaces, for example, stent surfaces.
  • the stent coating comprise a plurality of polymer compositions with different characteristics.
  • some embodiments comprise at least two polymer compositions with different drug release profiles, each of which may comprise the same or different biologically active agents.
  • Some embodiments comprise at least two polymer compositions with similar release profiles, each comprising different biologically active agents.
  • a first polymer composition is physically embedded in or disposed over a second polymer composition, each exhibiting different physical and chemical characteristics, with or without comprising biologically active agents.
  • PLGC copolymers were synthesized by ring-opening copolymerization of glycolide, i-lactide and ⁇ -caprolactone in a molar ratio of 63:25:12 and using 0.009 wt% stannous octoate as a catalyst.
  • Glycolide and L-lactide were purchased from Boehringer lngelheim (Petersburg, VA) and used without purification.
  • ⁇ -Caprolactone was purchased from AJdrich (Milwaukee, WI), dried with CaH 2 and distilled under vacuum.
  • Stannous octoate was purchased from Avocado Organics (Ward Hill, MA) and used without purification.
  • the bottle was cooled to room temperature and washed with EtOH and dried on a rotavapor, filled with DCM (1-3 ml), shaken or rotated for 30 min.
  • the viscous solution was poured into a polypropylene beaker. This was repeated 3-5 time until the entire polymer in the flask was washed out.
  • the polymer solution was diluted with DCM to ⁇ 10 ml, stirred at room temperature, and to which EtOH (15 ml) was added dropwise in 1 h, when a soft polymer mass was formed.
  • EtOH (15 ml) was added dropwise in 1 h, when a soft polymer mass was formed.
  • the solvent was decanted and the polymer was washed with EtOH (2x 2 ml).
  • the polymer was dried in oven at 45° C for 16 h to give an almost colorless, transparent, rubbery polymer.
  • Molecular weight (Mw) and polydispersity (PD) of the product of EXAMPLE 1 were determined by gel permeation chromatography (GPC), using Waters 2695 HPLC, Waters 2414 Refractive Index Detector, Waters HPLC columns-Styragel HR4 and HR2, a mobile phase of tetrahydrofuran, and a flow rate of 0.25 mL/min. Molecular weight and polydispersity were calibrated with polystyrene standards.
  • GPC gel permeation chromatography
  • PLGA(L/G 50/50, Durect Corporation) and PLGC (L/G/C 45/45/10, prepared similarly to EXAMPLE 1) were dissolved individually with various amounts of NCO-PEG from EXAMPLE 3 in acetonitrile to form a 12.5% w/v polymer solution containing 2.5-10 wt% of NCO-PEG relative to the total polymer weight.
  • the mixture was agitated at room temperature for 1-4 hours until a homogenous mixture is formed.
  • the mixture was then treated with 50 mM borate buffer solution (pH 8.3) in an amount of 1 % v/v of the mixture volume and stirred at room temperature for 1 hour.
  • the resulting polymer solution was cast on a smooth surface to make films or used for stent coating.
  • Methotrexate release from each formulation was followed for 7 weeks at room temperature. There was a small initial burst (about 2.5-3.5 wt% of the total methotrexate within 12 hours) from each formulation, followed by a sustained release for an extended period of time. The control (PLGA) showed a slow release in the first three days and no significant release was observed thereafter. The experiment was continued to detect erosion burst. Near zero order release of methotrexate was observed with the 3.6 % NCO- PEG formulation over 48 days (about 10 ⁇ g released per day). Results are shown in FlG. 4.
  • Polymer erosion test was carried out using three NCO-PEG/PLGA polymer compositions: PLGA as a control, 2.3% NCO-PEG and 5.6% NCO-PEG, each loaded with 5 wt% methotrexate and incubated in Ix PBS solution at 37 0 C. Drug burst due to polymer erosion was indicated by a sudden increase in UV absorption at 374 nm due to an abrupt MTX release along with a visible disintegration of the film.
  • NCO-PEG/PLGA For both NCO-PEG/PLGA and NCO-PEG/PLGC compositions, the addition of NCO-PEG increased the release of methotrexate, as shown in FIG. 6. However, the release rate of methotrexate from the NCO-PEG/PLGC composition was much higher than that from the NCO-PEG/PLGA formulation (about 3-4 times). This may be due to lower glass transition temperature (T e ) of PLGC (about 10-20 0 C) compared to that of PLGA ⁇ about 50 0 C), as evidenced by the rubbery property of PLGC at 37 0 C.
  • T e glass transition temperature

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Abstract

L'invention concerne une composition de polymère comprenant un réseau polymère interpénétré IPN d'un polyéther ramifié et d'un polyester aliphatique biodégradable, ou un polyester aliphatique biodégradable, présentant des caractéristiques physiques et de libération de médicaments utiles. Par conséquent, la composition de polymère est utile dans des systèmes d'administration de médicaments et des dispositifs médicaux, par exemple des endoprothèses éluant des médicaments, et dans le traitement de mammifères avec ceux-ci. L'invention concerne également des procédés pour la synthèse et la caractérisation de la composition de polymère.
PCT/US2008/075884 2007-09-12 2008-09-10 Compositions de polymère pour la libération contrôlable de médicaments Ceased WO2009036083A2 (fr)

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WO2012091680A1 (fr) * 2010-12-30 2012-07-05 Nanyang Technological University Dispositif utilisable en vue de la libération contrôlée d'un agent bioactif
US20120237668A1 (en) * 2009-12-02 2012-09-20 Giesecke & Devrient Gmbh Solid particles having a silicate coating
US8661630B2 (en) 2008-05-21 2014-03-04 Abbott Cardiovascular Systems Inc. Coating comprising an amorphous primer layer and a semi-crystalline reservoir layer
US9090745B2 (en) 2007-06-29 2015-07-28 Abbott Cardiovascular Systems Inc. Biodegradable triblock copolymers for implantable devices
WO2016100520A1 (fr) * 2014-12-16 2016-06-23 Boston Scientific Scimed, Inc. Compositions de polymère bioérodable

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US9090745B2 (en) 2007-06-29 2015-07-28 Abbott Cardiovascular Systems Inc. Biodegradable triblock copolymers for implantable devices
US9468707B2 (en) 2007-06-29 2016-10-18 Abbott Cardiovascular Systems Inc. Biodegradable triblock copolymers for implantable devices
US8661630B2 (en) 2008-05-21 2014-03-04 Abbott Cardiovascular Systems Inc. Coating comprising an amorphous primer layer and a semi-crystalline reservoir layer
US9592323B2 (en) 2008-05-21 2017-03-14 Abbott Cardiovascular Systems Inc. Coating comprising an amorphous primer layer and a semi-crystalline reservoir layer
WO2010132258A3 (fr) * 2009-05-14 2011-04-07 Abbott Cardiovascular Systems Inc. Revêtement comprenant un terpolymère comprenant du caprolactone et du glycolide
EP2932988A1 (fr) * 2009-05-14 2015-10-21 Abbott Cardiovascular Systems, Inc. Revêtement comprenant un terpolymère comprenant du caprolactone et du glycolide
US20120237668A1 (en) * 2009-12-02 2012-09-20 Giesecke & Devrient Gmbh Solid particles having a silicate coating
US8871299B2 (en) * 2009-12-02 2014-10-28 Giesecke & Devrient Gmbh Solid particles having a silicate coating
WO2012091680A1 (fr) * 2010-12-30 2012-07-05 Nanyang Technological University Dispositif utilisable en vue de la libération contrôlée d'un agent bioactif
US9801831B2 (en) 2010-12-30 2017-10-31 Nanyang Technological University Device for controlled release of a bioactive agent
WO2016100520A1 (fr) * 2014-12-16 2016-06-23 Boston Scientific Scimed, Inc. Compositions de polymère bioérodable
CN107249658A (zh) * 2014-12-16 2017-10-13 波士顿科学国际有限公司 生物可蚀性聚合物组合物

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