WO2009036083A2 - Polymer compositions for controllable drug delivery - Google Patents

Abstract

A polymer composition comprising an IPN polymer network of a branched polyether and a biodegradable aliphatic polyester, or a biodegradable aliphatic polyester exhibits useful physical and drug release characteristics. Accordingly, the polymer composition is useful in drag delivery systems and medical devices, for example, drug eluting stents, and the treatment of mammals therewith. Also provided are methods for synthesizing and characterizing the polymer composition.

Description

CUREX.OOIVPC PATENT

POLYMER COMPOSITIONS FOR CONTROLLABLE DRUG DELIVERY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US provisional application numbers 60/971,822 and 60/991,567, filed September 12, 2007 and November 30, 2007 respectively, both of which are incorporated herein by reference in there entirety.

BACKGROUND

Technical Field

|0002] 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.

Discussion of Related Art

[0003] Over the past decade, the use of endoluminal metallic stents has become a standard procedure during percutaneous coronary intervention (PCl) for coronary artery blockage.

(0004] Although stents significantly reduce restenosis when compared with balloon angioplasty, restenosis rates in patients are still 20 % to 40 % at 6 months. With the increase in incidence of coronary stenting and frequency of the stent use for off-label lesions, stent restenosis is expected to remain as a principal drawback of coronary stent.

[0005] 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.

[0006] Attempts to attenuate restenosis after angioplasty and stenting using systemic therapies have resulted in frustration. Drug eluting stent, a metallic stent coated with a polymeric carrier of active agent, represents a significant advance in the coronary stenting, which delivers a high concentration of anti-restenosis agent to the injured artery tissue over a sustained period of time. [0007) Polymer stent coatings can be grouped into two categories: non-erodible polymers and bioerodible polymers. 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. 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.

[0008] Such 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. Several 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.

[0009] 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)].

[0010] Nevertheless, to be used as stent coatings a polymer should possess suitable physical properties, in terms of flexibility, elasticity, glass transition temperature (7¹J₃ 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. First, because of their high 7j,s they are rigid matrices at body temperature, and have limited diffusion of drugs, especially those with high molecular weights (Mw) such as proteins. Second, acidic degradation products generated in the polymer matrix of PLGA or PDLLA are accumulated due to the slow diffusion character of the polymer glassy state. 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.

[0011] Accordingly, there is a need in the art for a biodegradable polymer composition designed to have a desirable combination of physical, drug release and degradation properties as a controllable drug delivery systems. Specifically, there is a need for a polymer composition as a stent coating which overcomes above and other shortcomings.

SUMMARY OF THE INVENTION

[0012] Embodiments provide a polymer composition that can be used as a biodegradable carrier for therapeutic agents, which are released in a controlled manner.

[0013] One aspect includes a polymer composition for use in foπning a polymeric coating disposed on the surface of a stent, which is designed for insertion into a blood vessel.

[0014] In one embodiment, 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.

|0015] In one embodiment, 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. In one embodiment, about 1-5% (v/v) of an aqueous solution in an organic solvent or a mixture of organic solvents is used.

[0016) In one embodiment, 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. In one embodiment, the molar ratio of L/G/C of the polyester products is about 80-^40/50—10/30-5. In another embodiment, 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.

[0017] Another embodiment provides a method for producing biodegradable polyesters from i-lactide, glycolide and ε-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.

[0018] In another embodiment, 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.

[0019] In another embodiment, 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.

[0020] In another embodiment, 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 bϊocompatibility such as tissue compatibility, and hemocompatibility in a biological environment such as human artery.

[0021] In another embodiment, 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 μm, and the total coating weight is about 50-500 μg which completely degrades and disintegrates in an artery within a few weeks to a few months.

[0022] hi another embodiment, the polymer composition for stent coating includes at least one therapeutic agent. In some embodiments 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. In some embodiments the stent coating may have a top coating or outer layer for providing bϊocompatibility and/or controlling drug release profiles.

[0023] 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.

[0024] In one embodiment of the aspect, 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. In one embodiment, the coating equipment used in the procedure includes an ultrasonic nozzle which produces a very thin and uniform spray pattern. By carefully controlling the coating parameters such as polymer solution concentration and injection rate, nozzle air/gas flow, nozzle power, and stent rotation speed a very precise, reproducible, controllable coating in terms of coating pattern, microstructure and coating weight can be produced. Ln one embodiment, the coating is substantially on the abluminal surface of a stent. The 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 μg.

|0025) In another embodiment of the aspect, the thickness of the stent coating is between about 5-20 μm or about 5-10 μm. The coating weight is about 50-500 μg, such as about 150 μg for a stent with an outside diameter of 2-4 mm and a length of 8-12 mm.

[0026] Some embodiments provide a polymer composition, an implantable medical device comprising the polymer composition and a method of treating a mammal therewith, and/or a method for synthesizing the polymer composition, a polymer composition comprising a polymer mixture, wherein the polymer mixture comprises: a branched PEG polymer comprising a -(CH₂J₂O- subunϊt, and a urethane subunit; and a polyester comprising a -(CHR),,,Cθ₂- subunit, wherein R = H or CH₃, m = 1 or 5, independently for each subunit.

[00271 Some embodiments provide a polymer composition comprising a polyester, which comprises a -(CHR)_7nCO₂- subunit, wherein R = H or CH₃, m = 1 or 5, independently for each subunit. In some embodiments the polymer composition comprise a copolymer of at least two of l-lactide, £>,Z-lactide, glycolide, and ^-caprolactone.

[0028] In some embodiments, 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.

[0029] In some embodiments, the branched PEG polymer in the composition has a weight average molecular weight of at least about 6,000 Daltons.

[0030] In some embodiments, 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.

[0031] Some embodiments further comprise one or more non-reactive additives.

[0032] Some embodiments further comprise a biologically active agent. In some embodiments, the biologically active agent has a controllable release kinetics.

[0033] In some embodiments, the implantable medical device is a stent. [0034J In some embodiments, the polymer composition further comprises at least one of an anti-proliferative, an anti-inflammatory, an an ti -thrombotic, or an anti-restenotic agent.

[0035] In some embodiments, 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.

[0036] 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,

[0037] In some embodiments 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.

|0038] 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. In some embodiments, the crosslinker comprises trimethylolpropane .

[0039] Some embodiments further comprise synthesizing the polyester by a method comprising ring-opening copolymerization of lactide, glycolide, and e-caprolactone. In some embodiments, the lactide is i-lactide.

[0040] Some embodiments provide an 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.

{0041] In some embodiments, the additional crosslinkable molecule is a branched small molecule polyol. In some embodiments, the branched small molecule polyol is an afkane or arene substituted with two or more hydroxy] groups. In some embodiments, the branched small molecule polyol is glycerin. In some embodiments, the branched small molecule polyol is trimethylolpropane.

[0042] In some embodiments, the polyisocyanate is an alkane or arene substituted with two or more isocyanate groups. In some embodiments, the polyisocyanate is isophorone diisocyanate.

[0043] In some embodiments, 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.

[0044] In some embodiments, the branched PEG polyol in the inventive composition can be represented by the following formula:

H₂C-OR₁ HC-OR₁

H₂C-OR₁ wherein Ri is given by the formula:

wherein R₂ 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 R₂ 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.

[0045] In some embodiments, 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.

[0046] Some embodiments further comprise one or more biologically active agents. [0047] In some embodiments, 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.

[0048] 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.

{0049] In some embodiments, the mixing is performed in a solution phase. In some embodiments, 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. hi some embodiments, 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 carboxylϊc acids.

[0050] 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.

|0051] 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.

[0052] hi some embodiments, the drug delivery system is suitable for releasing a biological active agent in a body in a controlled manner. [0053] In some embodiments, the biologically active agent is an antiproliferative, anti -inflammatory, anti-thrombotic or anti-restenotic agent.

[0054] 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.

[0055] 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.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] 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 μg and drug loading 5% w/w.

J 0057] 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).

[0058] FlG. 3 illustrates erosion and degradation profiles of an embodiment of the polymer composition as described in EXAMPLE 5.

[0059] FIG. 4 illustrates release profiles of methotrexate as described in EXAMPLE 6.

[0060] FIG. 5 is a photograph of samples of the polymer compositions comprising methotrexate in the erosion study described in EXAMPLE 7.

[0061] 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.

[0062] FIG. 7 is a SEM image of an expanded coronary stent coated with an invention polymer composition, with total coating weight of 300 μg, loaded with 5% (w/w) paclitaxel, wherein no flaking, cracking, or delamination of the coating was observed.

{0063] FIG. 8 is a SEM image of an expanded coronary stent coated with an invention polymer composition, with total coating weight of 190 μg, loaded with 17% (w/w) sirolimus, wherein no flaking, cracking, or delamination of the coating was observed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

[0064] "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. "Terpolymer" refers to a copolymer made from three different monomers.

[0065] An interpenetrating polymer network (IPN) is any material containing two polymers, both in network forms, which are synthesized and/or crosslinked in the immediate presence of the other. Semi-IPN is one in which only one of the polymer systems is crossl inked

[0066] Molecular weights for polymers are weight average molecular weights in Daltons (Da) or kilo Daltons (kDa).

[0067] As used herein, the term "alkyl" includes straight- and branched-chain and cyclic monovalent substituents. Typically, the alkyl substituents contain 1-lOC (alkyl). For example, 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

[0068] "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.

[0069] 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.

[0070] "About" as used herein means +/- 10% of the value it describes. H. Polymer Compositions

[0071] Some embodiments of 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. In some embodiments, the partially crosslinked first components is thoroughly mixed with the second component and fully crosslinked in the mixture to foπn an interpenetrating network (IPN) or semi-interpenetrating (semi IPN) polymer network. The polymer composition may comprise additional components, for example, one or more additives, for example, other polymers, fillers, and/or biologically active agents.

[0072] Embodiments of the first component comprise a partially crosslinked polyol formed by the reaction of a branched PEG polyol, such as a PEGylated glycerol, of the formula CH₂RCHRCH₂R, where R is -(OCH₂CH₂)_πOH, with a small molecule substituted with two or more isocyanate groups (-N=C=O) (a polyisocyanate), in an functional group equivalent ratio of about 1 :2 (-OH in polyol: -NCO in polyisocyanate). 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.

J0073] Those skilled in the art will understand that the polyisocyanate is an aliphatic or aromatic polyisocyanate. As used herein, the term "polyisocyanate'^" refers to compounds comprising a plurality of isocyanate groups, including, diisocyanates, triisocyanates, and polyisocyanates.

[0074] The first component can be further branched by reacting with one or more crosslinkable small molecules. In one embodiment, 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.

Trim ethylolpropane

[0075] In some embodiments, 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. In one embodiment, 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). In another embodiment elongation is greater than 100%, such as greater than 200%, 300%, 400%, 500%, 600%, 700%, or 800%. For example, elongation is about 100%- 1000%, such as 300%-700%, or 400%-600%. In another embodiment, the glass transition temperature is about 0-40⁰C, such as 10-30 °C or 15-25 ⁰C.

[0076] 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. In a similar way other branched polyols such as trimethylolpropane, trimethylolethane, pentaerythritol, and sorbitol may be used to form branched PEG polyols. In other embodiments, 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.

[0077J It is believed that the presence of the polyether chains, for example, PEG, in the first component provides hydrophilicity to the polymer composition, thereby facilitating water penetration, polymer degradation, and consequently drug diffusion. Our studies indicated that during the drug release period, articles or devices made from the polymer composition maintained their overall shapes and integrity, but lost density. These results indicated the polymer composition degrades by homogenous erosion and degradation in aqueous environments. Since it is known that hydrophobic surface attracts macrophages and increases protein deposits the polymer composition containing the branched PEG polyol can be used as top coatings for stents, thus increasing the hydrophilicity and biocompatibility of the stent surfaces. It was also found that incorporating hydrophilic PEG in polymers will increase the water absorption of the polymer and drug release rate.

|0078] 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. Without being bound by theory, it is believed that 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.

[0079] After the first component is mixed with the second component, discussed in greater detail below, and treated with an aqueous buffer solution, 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.

[0080] 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. However, in another embodiment, the solvents are those which are aprotic and polar, and miscϊble 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.

[0081] 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). However, those skilled in the art will understand that numerous other crosslinking reactions may occur between nucleophiles (-OH, -NH_2, such as hydroxyls in polyols or polyesters and amino groups in hydrolyzed isocyanates) and electrophiles (-NCO) in the reaction mixture to provide a variety of different molecular species not illustrated in SCHEME 1.

[0082] In 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 R₁, reacts with one of the isocyanate groups in a polyisocyanate to form III, in which the end of the PEG chain is isocyanate- capped. In one embodiment, 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. The term "toluene diisocyanate^" refers to 2,4-toIuene diisocyanate, 2,6-toluene diisocyanate, or mixtures thereof. In some embodiments, 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. As discussed above 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.

NCO NCO

VIII

[0083] In step B, a hydroxyl group of a small molecule polyol IV, of which only one methylenehydroxy] group (-CH₂OH) is illustrated with the rest of the molecule abbreviated as R₂, reacts with a polyisocyanate [Ip(NCO)₂] to provide an isocyanate-capped polyol V. hi one embodiment, 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. In the illustrated embodiment, 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.

[0084] In step C, the other unreacted isocyanate group of the isocyanate-capped polyol V is hydrolyzed by water to give amine VI. In some embodiments, an intermediate carbamic acid is formed, which loses CO₂ to give the amine group. In one embodiment, 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.

|0085] In 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. Those skilled in the art will also understand that, any of the uncapped hydroxyl groups of other PEG chains (in R₍) in compound II and of other methylenehydroxyl groups (in R₂) in compound IV, as well as any of the unreacted amino groups (in R₂) 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.

[0086] In a simplified way, Steps A and B represent the urethane linker formation during the synthesis of the first component of the polymer composition, and 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).

SCHEME 1

VII

[0087] Embodiments of the second component comprise a polyester comprising aliphatic hydroxyacid subunits, -(CHR)_nCO₂-, wherein R = H, or CH₃, independently for each subunit, and n — 1 or 5. Some embodiments comprise a terpolymer of glycolide (R = H, n = 1), lactide (R = CH₃, n - 1), and ε-caprolactone (R = H, n = 5). A terpolymer of lactide, glycolide, and ε-caprolactone is referred to herein as "poly(lactide-co-glycolide-co- caprolactone)" or "PLGC." In some embodiments 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. R₂ may also be a moiety derived from these polyesters, when IV is a polyester such as PLGC in SCHEME 1.

I0088J The polyester of the second component is synthesized by any suitable method. In one embodiment, 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-hydroxycaproϊc 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. Those skilled in the art will understand that 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 transesterifϊcation catalyst known in the art, for example, Lewis acids, metal alkoxides, metal carboxylates, and the like. In some embodiments, 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. In some embodiments, T_g of the second component is from about -10 ⁰C to about 50 ⁰C, from about 0 °C to about 30 ⁰C, or from about 10 ⁰C to about 20 °C. In some embodiments, T_n, of the second component is from about 100 ⁰C to about 150 ⁰C, or from about 1 10 ⁰C to about 120 ⁰C. Embodiments of the polyester have average molecular weights of from about 20 kDa to about 200 kDa.

[0089] 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 L₁L- and D, D- lactides. In one embodiment, 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. To simplify the manufacturing procedure and increase the reproducibility of the product in terms of Mw and other physical properties 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. By simply changing the rotation rate (RPM) of the stirring and the stirring time, different polyester products with narrow Mw ranges indicated by polydispersity and consistent physical properties can be produced. When the rotation rate is further fixed at a suitable level for an efficient agitation the stirring time is the only parameter used to control the properties of the products.

[0090] 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. In embodiments comprising the first component, the second component is embedded in a matrix of the branched PEG polymer of the first component to form a homogenous IPN system.

[0091] In some embodiments, 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. In one embodiment, the molar ratio of L/G/C is about 80-40/50-10/30-5. In another embodiment, 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. [0092) Some embodiments of the polymer composition comprise a plurality of different first component species, for example, with different molecular weights, stoichiometrics, and/or compositions. In some embodiments second component comprises a plurality of polyester species, for example, with different molecular weights, stoichiometrics and/or compositions.

[0093] 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.

[0094] Other 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.

[0095] 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.

III. Bioactive agents

[0096] The terms "biologically active agent/' ^L'drug,^" "pharmaceutical" or "bioactive agent" 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. Various forms of the medicaments or biologically active materials can be used which are capable of being released from the solid matrix of the polymer composition into adjacent tissues or fluids. 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.

[0097] 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, hyperglycemic agents, hypnotics, hypoglycemic agents, immunomodulating agents, ion exchange resins, laxatives, mineral supplements, mucolytic agents, neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives, stimulants, thyroid and anti-thyroid agents, tissue growth agents, uterine relaxants, vitamins, and antigenic materials.

[0098] More particularly, 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, guaifenesin, aluminum hydroxide, magnesium hydroxide, peptides, polypeptides, proteins, amino acids, hormones, interferons, cytokines, and vaccines. 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 a substance capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like.

J0099J 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. Examples of 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. 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.

[0100] 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.

[0101] 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. For example, 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.

J0102] To promote bone growth, 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. Further, 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.

[0103] In some embodiments, according to the procedure for the preparation of the polymer composition, upon mixing and removal of the solvents, the biologically active agent becomes incorporated into the polymer matrix. After implanted in a body 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. For example, in some embodiments, 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. In some embodiments, 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. Thus, 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.

IV. Devices and Implants

[0104] 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.

[0105] 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. Examples of 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.

J0106] In some embodiments, the entire device is substantially fabricated from the polymer composition, for example, when biodegradability of the entire device is desired. In other embodiments, 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.

[0107] For example, in an embodiment of a method for fabrication of a stent comprising an overcoating of the polymer composition, a stent is dipped in and/or sprayed with a solution of the polymer composition. In some embodiments, the polymer composition is dissolved in one or more organic solvents at a concentration of from about 0.5 % to about δ % 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. In some embodiments, the solvent comprises acetone and/or acetonitrile. In other embodiments, the polymer composition is powder coated or electrostaticly coated on a stent, optionally followed by further processing.

[0108] 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. Optionally, these forms are further processed, for example, by machining, extrusion, weaving, melt processing, welding, stretching, compressing, shrinking, spinning, and the like.

[0109] For stent coating, 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. For example, 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.

[0110] 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. Embodiments of the polymer composition exhibited strong adhesion to polished metal surfaces, for example, stent surfaces.

[0111] Some embodiments of the device or implant, in particular, the stent coating comprise a plurality of polymer compositions with different characteristics. For example, 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. In some embodiments, 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.

EXAMPLES

[0112] The following examples set forth methods for preparing and characterizing embodiments of the polymer compositions, and the fabrication of coated stents. The examples are intended to be illustrative and not to limit the scope of the disclosure. EXAMPLE 1 PLGC synthesis

[0113] PLGC copolymers were synthesized by ring-opening copolymerization of glycolide, i-lactide and ε-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. ε-Caprolactone was purchased from AJdrich (Milwaukee, WI), dried with CaH₂ and distilled under vacuum. Stannous octoate was purchased from Avocado Organics (Ward Hill, MA) and used without purification.

[0114] A solution of Sn(II)Oct in hexane (35 mg/ml, 6 μl) was added into a round bottle (5 ml) dried in oven at 100° C for 16 h, Hushed with N₂ stream for 30 sec. to remove hexane, then i-lactide (1.59 g, 11 mmol), glycolide (0.51 g, 4.4 mmol) were added and mixed, followed by addition of ε-caprolactone (0.229 g, 2 mmol). The bottle was flushed with N₂, immersed in an oil bath at 160° C, stirred at 400 RPM with a magnetic stirring bar for 5 min to melt all solids, and heated at 160° C for 48 h. 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. 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.

EXAMPLE 2 PLGC Characterization

[0115} 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. EXAMPLE 3

Synthesis Of The Partially Crosslinked branched PEG Polyol (NCO-PEG) [0116] A mixture of polytriol {a branched PEG polyol), isophorone diisocyanate and trimethyolpropane with a molar ratio of 1 :33:0.15 was heated at 120 ⁰C in a nitrogen atmosphere for 48 hours. Polytriol (Mw = ~ 6 kDa) was purchased from Chemron (Paso Robles, CA) and purified by dissolving in acetonitrile and filtering through a silica gel column and drying under vacuum at 90 ⁰C overnight. Isophorone diisocyanate was purchased from Aldrich (Milwaukee, WI) and distilled under vacuum. Trimethylolpropane was purchased from Aldrich and used without purification.

EXAMPLE 4

Synthesis of branched PEG Polymer/Polyester IPN Polymer Composition [0117] 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.

EXAMPLE 5 PLGC-PEG IPN Characterization

Elongation and tensile strength

[0118] Films from EXAMPLE 4 were used in dry form and wet form (soaked in Ix PBS solution for 1 day) for elongation and tensile strength measurement to evaluate the mechanical properties of the polymer composition using PLGC as a control. The results are summarized in TABLE 1, where sample A is made from a NCO-PEG/PLGC polymer composition (NCO-PEG:PLGC =1 :9, PLGC Mw =1 1 kDa) and sample B is a PLGC control (Mw =I l kDa). TABLE 1

Dry film Wet film

Sample Tensile strength*, mPa Elongation* % Tensile strength*, mPa Elongation* %

A 13.04 450 12.52 520 B 12.17 490 6.96 490

Average of 5 specimens, ASTM D-882, 0.1 mm thickness, crosshead speed 4 in/min

Erosion and degradation profile

|0119] The erosion and degradation profiles of a polymer sample (NCO- PEG:PLGC = 1 :9, PLGC Mw =11 kDa) were determined by measuring polymer weight loss in PBS solution at different times using the following procedure:

[0120] Twenty pieces of polymer films (0.2 mm x 10 mm x 15 mm) prepared according to EXAMPLE 4 were weighed and placed individually into 20 vials. 5 mL of Ix PBS solution was added to each vial, and the samples were incubated at 37 ⁰C. Two samples were removed from the incubator each week and the test was continued for 10 weeks. Each film removed was placed in a weighing boat. The film was gently rinsed with deionized water and stored in a refrigerator until almost dry, then further dried in an oven at 50-60 ⁰C under a low vacuum until the weight is constant. Weights of the two samples were averaged and plotted in FIG. 3.

EXAMPLE 6

Methotrexate Release Study

[0121] Drug release was studied using methotrexate (MTX), which was loaded in 3 polymer samples made from NCO-PEG/PLGA polymer compositions according to EXAMPLE 4: (1) 3.6 wt% NCO-PEG and (2) PLGA as a control. Samples were in duplicate and their compositions were provided in TABLE 2. Each polymer/drug solution was prepared in a glass vial and evaporated at 50 ⁰C under vacuum to give a polymer film at the bottom of the vial. 1 mL of Ix PBS solution was added to each vial. The samples were kept at room temperature without agitation. An aliquot of 2.5 μL was taken from each vial at 1 , 4, 8, and 12 hours, and 1, 3, 6, 9, 12, 15, 18, 20 days and the methotrexate content of each sample was determined by measuring the UV absorbance of the solution at 374 nm (NanoDrop UV Spectrophotometer, model ND-1000). [0122] Materials: PLGA (50:50, lactide/glycolide, 0.37 dL/g, molecular weight = 25,000, Durect Corporation); NCO-PEG/PLGA compositions prepared according to EXAMPLE 4 using PLGA; methotrexate (Spectrum).

TABLE 2

Sample DMA PLGA NCO-PEG MTX 0.05M buffer

(mL) (mg) (mg) (mg) (μL)

PLGA 0.3 60 0 5.4 0

3.6% NCO-PEG 0.3 60 2.25 5.4 5

|0123] 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 μg released per day). Results are shown in FlG. 4.

EXAMPLE 7

[0124] 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 ⁰C. 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.

[0125] The PLGA control and the 2.3% NCO-PEG sample showed disintegration on around 24th day, while the overall shape of the 5.6% NCO-PEG sample remaining intact over the study period of 30 days. Photographs of the vials on around 24th day are shown in FIG. 5. EXAMPLE 8

Comparison ofNCO-PEG/PLGC and NCO-PEG/PLGA Compositions [0126] Four samples in duplicate were prepared as described in EXAMPLE 6 with the compositions shown in TABLE 3, using NCO-PEG/PLGA compositions (PLGA Mw = -25 kDa) or NCO-PEG/PLGC compositions (PLGC Mw = -25 kDa), both prepared according to EXAMPLE 4. 2 mL of Ix M PBS solution was added to each vial, which were incubated at 37 ⁰C. MTX release was monitored by measuring the UV absorbance at 374 ran.

TABLE 3

Sample PLGA % PLGC % NCO-PEG % MTX %

1 90 0 0 10

2 82.5 0 7.5 10

3 0 90 0 10

4 0 82.5 7.5 10

[0127] 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 ⁰C) compared to that of PLGA {about 50⁰C), as evidenced by the rubbery property of PLGC at 37 ⁰C.

Claims

WHAT IS CLAIMED IS:

1. An interpenetrating polymer network composition comprising: a covalently crosslinked polymer with the following formula:

H₂C-OR₁

HC-ORi

H₂C-OR₁ wherein R) is given by the formula:

H H

._o^O^R_p.N_ViOR₂

O O

wherein a) R₂ is a branched alkyl substituted with one or more hydroxyl groups or, isocyanate-capped hydroxyl groups, or R₂ is a moiety derived from polyethylene glycol, polypropylene glycol, apolyol or a polyester; b) P is an alkyl or aryl group; c) n is 10 to 1000; d) m is l to 100; and a biodegradable aliphatic polyester.

2. The polymer composition of claim 1 , wherein P is:

and R₂ is:

wherein R₃ is H or R₄NH(C=O)- independently, wherein R₄ is a substituted alkyl group.

3. The polymer composition of claim 1, wherein the covalently crosslinked polymer is foπned by the reaction of a branched PEG polyol with a diisocyanate or polyisocyanate.

4. The polymer composition of claim 3 wherein the covalently crosslinked polymer is formed by the reaction of a branched PEG polyol with a diisocyanate or polyisocyanate and one or more additional crosslinkable molecules.

5. The polymer composition of claim 4, wherein the additional crosslinkable molecule is a branched small molecule polyol, which is an alkane or arene substituted with two or more hydroxyl groups.

6. The polymer composition of claim 4, wherein the branched PEG polyol is prepared by the reaction of a branched small molecule diol or polyol with ethylene oxide.

7. The polymer composition of claim 6, wherein the branched small molecule polyol is glycerin.

8. The polymer composition of claim 4, wherein the branched PEG polyol has a weight average molecular weight of at least about 2,000 Daltons.

9. The polymer composition of claim 4, wherein the polyisocyanate is an alkane or arene substituted with two or more isocyanate groups.

10. The polymer composition of claim 1, wherein the biodegradable aliphatic polyester comprises the subunit in the formula Of-(CHR)_nCO₂- , wherein R = H or CH₃ and n = 1 or 5.

11. The polymer composition of claim 1 , wherein the polymer composition is bioerodible, biodegradable, biocompatible, or a combination thereof.

12. The polymer composition of claim 1, wherein the biodegradable aliphatic polyester has a weight average molecular weight in the range of from about 20,000 to about 200,000 Daltons.

13. The polymer composition of claim 1, further comprising one or more additives.

14. The polymer composition of claim 5, wherein the branched small molecule polyol is trimethylolpropane.

15. The polymer composition of claim 4, wherein the diisocyanate is isophorone diisocyanate.

16. The polymer composition of claim I₃ wherein the biodegradable aliphatic polyester is a terpolymer of i-lactide, glycolide, and £--caprolactone.

17. The polymer composition of claim 1, wherein the biodegradable aliphatic polyester is a polymer or a copolymer made from monomers selected from a group consisting of i-lactide, D,l-Iactide, glycolide, and s-caprolactone.

18. The polymer composition of claim 1 , wherein the weight percentage of the covalently crosslinked polymer is in the range of about 0% to about 40% and the weight percentage of the biodegradable aliphatic polyester is in the range of about 100% to about 60% compared with the total weight of the composition.

19. The polymer composition of claim 18, further comprising one or more biologically active agents.

20. A method for forming the covalently crosslinked polymer of claim 1, comprising mixing (1) said branched PEG polyol, (2) said diisocyanate or a polyisocyanate, and (3) said one or more additional crosslinkable molecules.

21. A method for forming the polymer composition of claim 1, comprising mixing said covalently crosslinked polymer, said biodegradable aliphatic polyester and about 1 -5% (v/v) of an aqueous solution in an organic solvent or a mixture of organic solvents.

22. The method of claim 21 , wherein the mixing is performed in a solution phase.

23. The method of claim 21, wherein the organic solvent or the mixture of organic solvents is/are selected from the group consisting of acetone, acetonitrile, 1,2- dimethoxyethane, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, 1,4- dioxane, and tetrahydrofuran.

24. The method of claim 21, wherein 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 carboxylic acids.

25. The method of claim 21, further comprising mixing the polymer mixture with one or more additives.

26. The method of claim 21, further comprising mixing the polymer mixture with one or more biologically active agents.

27. A drug delivery system suitable for implanting in or injection into a body, comprising the polymer composition of claim 18, which is in a form selected from the group consisting of microcapsules, microparticles, microspheres, nanoparticles, implants, stent coating, drug-encapsulating matrix or membrane.

28. An implantable medical device comprising the polymer composition of claim 18, which is suitable for releasing a biological active agent in a body in a controlled manner.

29. An implantable medical device comprising a stent and the polymer composition of claim 19, wherein the biologically active agent is an antiproliferative, anti-inflammatory, an ti -thrombotic or anti-restenotic agent.

30. A method for forming at least a portion of the medical device of claim 29, comprising applying the polymer composition by at least one of the methods of spray coating, electrostatic coating, plasma coating, brush coating, powder coating, dip coating, extruding, molding, welding, pressing, wrapping and fastening.

31. A method of treating a mammal in need thereof, comprising implanting the implantable medical device of claim 29.

32. A stent, comprising: a tubular frame comprising an open first end and an open second end, and a longitudinal passage therebetween; a biodegradable, bioerodible, and biocompatible polymer disposed on the tubular frame, said polymer comprising a terpolymer of Z-lactide, glycolide, and ε- caprolactone.

33. The stent of claim 32, wherein the biodegradable, bioerodible, and biocompatible polymer has the following properties:

(1) a tensile strength of at least about 725 psi,

(2) an elongation of greater than 100%,

(3) a glass transition temperature (T_g) about 0-40⁰C.

34. The stent of claim 32, wherein the biodegradable, bioerodible, and biocompatible polymer has a weight average molecular weight of from about 20,000 to about 120,000 Daltons.

35. The stent of claim 32, wherein the terpolymer is made by a ring- opening copolymerization reaction, the monomers are l-lactide, glycolide and ε- caprolactone, and their molar ratio is about (80-40/50-10/30-5) in the same order.

36. The stent of claim 32, wherein the biodegradable polymer further comprises at least one biologically active agent.

37. The stent of claim 36, wherein the at least one biologically active agent exhibits controlled release under physiological conditions.

38. The stent of claim 36, wherein the biological active agent is an antiproliferative, anti -inflammatory, anti-thrombotic, or anti-restenotic agent.

39. A method of treating a mammal in need thereof, comprising implanting the stent of claim 38.