2~92~46 203-396 (1?69) nIOA13SORI~BI,E l~LENDS Ol; A ~IOAl~SORBA13Ll:
COPOLYMER AND A rOLY(O~YYALl~YLEl~E) I;IE:LD Oli TIIE INVr,NT~ON
This invention relates generally to novel bioabsorbable compositions.
More particularly, this invention relates to new bioabsorbable polymer blends useful for coating medical devices.
~J~CKGROIJN~ O~ TIII~ INYI;,NTION
Bioabsorbable coa~ings are applied to a wide range of medical devices for a variety of reasons. The natllre of the medical device used as the substrate for the coating wilt normally determine which particular characteristics are desired in the coating. For example, implantable porous prostheses for use as bone or other hard tissue replacements are usually formecl from polymeric beads or parlic]es having a biologically compatible, hydropllilic coating. The hydrophilic coating on the particles facilitates infllsioll of body fluids into the pores of the implant, ~hereby faci1itating the ingrowth of tissue into the pores of the implant. Such prostheses are described in U.S. Patent Nos. 4,728,570; 4,535,485; 4,547,327; and 4,536,158.
As another example, synthetic vascular grafts made from tubes of fabric rnay be manufactured from yarns coated with a hydrophilic coating. In addition, a surface of the fabric may be coated with an absorbable coating to temporarily render the olllerwise porous fabric impervious to blood and~or other body fluids. It is desirable that ~he fluids-occlllcling coa~ing exhibit sufrlcient elasticity to accommodate the alternate elongation ancl contraction which llle tubular fabric prothesis llndergoes when implanted in the body. Such tubular fabric protheses are described in U.S. Palelll No. 4,990,158.
2092~6 In certain applications, a medical device may advantageously include a hydrophobic coating. ~Iydropl~obic coatings provi~le desirable handling characteristics, allowing easy and accurate positioning of the device, better holding of knots, and decreased slipping in the gloved hands of surgeons. Additional1y, medicat devices with hydrophobic coatings may provide improved tissue retaining properties, for example, where it is desired to hold tissue together.
Copolymers of glycolide and trimethylene carbonate (also referred to as 1,3-dioxan-2-one) have been used to fabricate bioabsorbable medical devices or surgical articles. See for example, U.S. Patent Nos. 4,243,775; ~,300,565;
4,429,030; 4,633,873; and 4,719,917. ~dditionally, glycolide-trimethylene carbonate (GTMC) polymers have been applied to sutures and other surgical articles as a bioabsorbable coating. Sce U.S. Patent Nos. 4,705,820 and 4,7~8,979. GTMC
polymers have also been formed into filaments and braided witll non-absorbable components (see U.S. Patent No. 4,792,336) and used to coat or encapsulate a woven mesh or other textile structllres formed by filaments of non~absorbable polymers (see Europem Patent ~pplication No. 0334046).
U.S. Patent No. 4,452,973 describes poly(glycolic acid)/poly(oxyalkylene) AB~ triblock copolymers useflll as absorbable sutures.
SUMMAR~ OF T~TE INVENTTON
It has now been found tllat blends of poly(oxyalkylene) with a bioabsorbable copolymer having soft segments are llseful as bioabsorbable compositions, sucll as, for example bioabsorbable coatings for medical drvices.
Tllese blends provide coatings wllicl- have good elastic, durability and llydropllilic and/or hydrophobic properties as required ror a particular end use. The soft segments of the copolymer may be forrned by incorporating into tlle copolymer a monomer ; . -, , .
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selected from the group consisting of trimethylene carbonate, dioxanone, caprolactone, a]ky]ene oxalates, hytiroxybutyrates, esteramides, hydroxyva]erates, urcthanes, hexamethy]ene carbonate and mixtllres thereof. The blend optiona]]y 5 includes a medico-surgica]ly usefill substance, such as, for examp]e, an antithrombogenic substance.
DESCRIPrlON Oli' PRr,lir,RRr,D r,MnODIMr,NTS
The compositions of the present invention comprise polymer blends containing or physical mixtures Or: (a) a bioabsorbable copolymer having soft segments; and (b) poly(oxyalkylene).
Bioabsorbable copolymers suitable for preparing the blends of this invention contain onc or more comonomer which provide soft segments. ~or example, soft segments may be incorporated into polymers of glycolide, lactide or glycolide lactide copolymers by incorporatillg trimethylene carbonate as a comonomer during polymerization. Other comonomers suitable for generating soft segments include dioxanone, caprolactone, alkylene oxalates, hydroxyblltyrates, esteramides, 20 hydroxyvalerates, llrethanes, hexamethylene carbonate and mixtures thereof.
Trimethylene carbonate, dioxanone and caprolactone are the preferred comonomers.These comonomers may be present in an amount up to 75 mole percent, and preferably between abollt 65 mole percent.
The bioabsorbable copolymer used in the present invention may be formed by copolymerizing one or morc Or Ihe aforementioned sof~ segment comonomers with one or more monomers known to produce a bioabsorbable polymer, such as, for example, glycolide or lactide. ~referred bioabsorbable copolymer include copolymers of glycolide and trimethylene carbonate.
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Glycolide-trimethylene carbonate copolymers employed in particularly usefl11 ernbodiments of the present invenlion may contain up to about 50 mole percent glycolide and llp to abollt 75 mole percent trimethylene carbonate. A preferred 5 copolymer is glycolide/trimethylene carbonate (GTMC) copolymer containing about 35 mole percent glycolide and about 65 mole percent trimethylene carbonate.
Polyoxyalkylenes usefill in this invention incl~lde those which are hydrophilic in nature, such as, for example, polyethylene oxide, poly(oxyethylene- !
l O oxypropylene) copolymers and block copolymers of polyoxyethylene and polyoxypropylene commercially available under the tradename Pluronic.
Hydrophobic polyethers may also be used in the present blends. Sllitable hydrophobic polyethers include polypropylene oxide, polypentylene oxide and poly-1,4-butane diol.
Polyelhylene oxide tPEO) polymers suitable for llse in this invention are commercially available in a wide variety of molecular weights. Preferred polyethylene oxide polymers are those having a molecular weight from about 400 to about 20,000. Most preferred is a polyetllylene oxide with a molecular weight of8000. Generally, as the amolmt of polyethylene oxide in the blend is increased, the 20 hydrophylicity of the blend will increase. The polymer blends may include poly(oxyalkylene) in an amount up to about 50 percent based on the total weight of the blend. Preferably, the blend will contain between abollt 10 and 20 percent polyalkylene oxide based on the total weight of the blend.
The compositions of the present invention may be formulated to possess a desired set of characteristics depending on the application in which tl~e compositions are to be used. I~or example, the hydrophobic or hydropllilic natllre of the composition may be adjusted by the choice of polyalkylene oxide or mixture of polyalkylene oxides. ~ balancc of hydropllilic and hydropllobic characteristics are achievable by thc compositions Or tl~e present inventiom ~s another examplc, the rate .
at which the composition bioabsorbs may be adjllsted by varying the amounts of glycolide and trimethylene carbonate in the copolymer.
Otller components may be included in the compositions of this 5 invention sucll that tlle coating compositions are employed as a carrier for one or more medico-surgically usefill subs~ances, e.g., those which accelerate or otherwise beneficially modify the healing process ~vhen applied to a wound or surgical siie. In general, any biologically active material which is sol~lble in and otherwise compatible 10 with the selected coating composition can be incorporated therein in therapeutically useful annollnts. I~or example, a therape~ltic agent may be chosen for its antimicrobial properties, capability for promoting wound repair and/or tissue growth or for specific indica~ions sucll as thrombolysis. Antimicrobial agents such as broad spectmm antibio~ics (gentamycin sulpllate, erytllromycin or derivatized glycopeptides) which are slowly released in~o the ~issue can be applied in tl-is manner to aid in combating clinical and sub-clinical infections in a surgical or trauma wound site. To promote wound repair and/or tiss~le growth, one or several growtll promoting factors can be added to the coating, e.g., fibroblast growth ractor, bone growth factor, epidermal 20 growth factor, plalelet derived growtll factor, macrophage derived growth factor, alveolar derived growth factor, monocy~e derived growth factor, magainin, and soforth. Some therapeutic indications are: gTycerol with tissue or kidney plasminogen activator to cause tllrombolysis, s~lperoxide dismlltase to scavenge tissue damaging 25 free radicals, tumor necrosis factor for cancer therapy or colony stimulating factor and interferon, interlellkin-2 or otl1er Iymphokine to enhance the immune system.
Other examples Or materia]s whicll may be addetl to the blends of tllis invention inclllde antitllroml)ogellic agents (sllch as heparin, hirlldin and prostaglandins), 30 pharmaco10gically iac~ive agents, anti-coagulants, osteogenic factors, anti-filngals, imm~mosuppressive agcnts, anti-inrlamlllatory agents, preservatives, saccharides, .: ~
diagnostic agents, antihistamines, hormones, enzymes, peptides ancltor steroids. The amount of each additional component added ~ill depend on the particlllar nature of the component and the purpose for aclding the component. Typically, however, thes amount of each optiona1 component will be below about 10% by weight of the toka weight of the blend.
The phrase "total weight Or the blend" is intende(l to include ~he weight of GTMC and poly(oxyalkylene) and any additional ingredients included in the blend, 10 but is intended to exclude the weight of the solvent, if any, employed in mixing or applying the blend.
The preparation and application of the polymer blends of the present invention may be accomplished by any suitable melhod which provides a substantially homogenous mixture of the two principal polymer components (i.e., GTMC and poly(oxyalkylene)). For example, tlle bioabsorbable copolymer and poly(oxyalkylene) may be melt blended. Preferably, the components of the blends are dissolved in asolvent and mixed to providc a substantially homogenolls solution. Tlle solution is applied to a substrate such as a medical device, and the solvent is removed, such as 20 for example, by evaporation.
More particul~rly, in forming the solution it is preferred to first dissolve the GTMC polymer in just enougll solvent to dissolve the polymer with stirring. Then the poly(oxyalkylene) is slowly added with continlled stirring. If 2~; necessary, adclitional amounts of solvent may be added to efrectuate complete dissolving of the poly(oxyalkylene).
The compositions of this invention form absorbable rllms having good durability, elastic and hydrophilic or hydropl1obic properties. They may be used for 30 surface coating and/or encapsul;lting and may act to r~ll voids or interstices in medical dcvices, sucll as, ror example, vascnlar grart ma~crials or beacls used to form .
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orthopedic or dental implants. The coating composi~ions may be applied to absorbable or non-absorbable substrates.
Corolvmcr rlcparation A copolymer of glycolide and trimetl)ylene carbonate was prepared by melt phase ring opening copolymerization of 28.42 grams (35 mole percent) glycolide O and 46.41 grams (65 mole percent) trimelhylene carbonate in the presence of stannous octoate (1.9 cc of .2 gms Or stannous octoate ~lissolved in 25 cc of ether) in an appropriate reaction vessel at 1600C for 12 hollrs. After polymerization the vessel was allowed to cool to room temperature. The polymer was then removed from the vessel, dried in vacuum and kept dry until used.
I'olvmcr l~lcnd Prc~ar:ltio 22.5 grams of dried poly (glycolide-co-trimethylene carbonate) was placed into a round bottom flask and dissolved in about 200 ml of methylene chloride.
20 Polyethylene oxide (2.5 gms; molecular weigllt 8000) was slowly adlled to this solution wllile stirring. After complete addition of polyethylene oxide, stirring of the mixture was conlinued for 16 hours. Arter tl-orougll mixing, the solution mixture was poured into a dish and lhe excess solvent was evaporated. The thick film formed was 5 dried well under vacullm (24 hours at room temperature) and stored dry. The resulting material contained 90% GTMC copolymer and 10% PEO.
Coatin~ Onto Yn.sclllar Grnrt Tul)cs A polymcr blend was prepared as described above containing 20 percent polyethylene oxide based on tl-c total weight of lhe blend. A 5% sollltion of . ~ . . .
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tlle blend in methylene chloridc was applied to a Iengtll of a vascular graft tube having a diameter of 2-3 mm by dipping the tube into the solution and evaporating off the solvent. The vascular graft tube was woven from filaments of both absorbable5 and non-absorbable materials; namely, filaments of poly(glycolide/lactide) andfilaments of Hytrel 5556 (an elastomer commercially available from E. I. duPont de Nemours ~ Co., Delaware). Irt vitro tesling suggests that the blend of this Example would begin to absorb in about 2-3 hollrs after implantation into a mammalian body.
It is not intended to limit the present invention to the specific embodiments described above. It is recognized that changes may be made in the coating compositions specifically described herein without departing from the scope and teaching of the instant invention, and it is intended to encompass all other embodiments, alternatives an(l modifilcalions consistent with the invention.
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