MXPA97001689A

MXPA97001689A - Absorbib polioxaesters

Info

Publication number: MXPA97001689A
Application number: MXPA/A/1997/001689A
Authority: MX
Inventors: S Bezwada Rao; D Jamiolkowski Dennis
Original assignee: Johnson & Johnson
Priority date: 1997-03-05
Filing date: 1997-03-05
Publication date: 1998-04-01

Abstract

The present invention discloses a novel aliphatic polyoxyester which is bioabsorbable and which can be used to produce surgical devices such as sutures, sutures with added needles, and molded devices, and the like, the invention also contemplates a process for producing these polyesters, the aliphatic polyoxaesters of The present invention has a first bivalve repeat unit of the formula: [OC (O) -C (R1) (R2) -O- (R3) -OC (R1) (R2) -C (O) -] and a second repeating unit selected from the group of formulas consisting of: II [-O-R4-] A, III [-O-R5-C (O) -] B and XI ([-O-R5-C ( O)] PO) LG and combinations of the same

Description

ABSORBABLE POLIOXAESTERES FIELD OF THE INVENTION The present invention is a continuation in part of the serial number 08 / 554,011, filed on November 6, 1955, which is a continuation in part of the number of εeppe 08 / 366,308, filed on January 6, 1995, now a U.S. patent. No. 5,464,929 all assigned to Ethicon, Inc. (and all incorporated herein by reference). The present invention relates to a bioabsorbable polymeric material and more particularly to surgical products made from said polymers.

BACKGROUND OF THE INVENTION Since the first work of Carothers in the 20's and 30's, aromatic polyesterers particularly > Polyethylene terephthalate has become the most important commercial polyether ether. The utility of these polymers is intimately linked to the hardening action of the p-phenylene group in the polymer chain. The presence of the p-phenylene group in the base structure of the polymer chain leads to high melting points and good mechanical properties especially for fibers, films and some molded products. In fact, polyethylene terephthalate has become the polymer of choice for many common consumer products, such as one or two two-liter soda containers. Different related polyester resins have been described in the patents of E.U.A. 4,440,922, 4,552,948 and 4,963,641 that seek to improve the properties of polyethylene terephthalate by replacing terephthalic acid with other related dicarboxylic acids containing femlene groups. These polymers are generally designed to reduce the gas permeability of aromatic polyesters. Other aromatic polyesters have also been developed for special applications such as stable bioabsorbable radiation materials. U.S. Patent Nos. 4,510,295, 4,546,152 and 4,689,424 disclose sterilizable aromatic radiation polyesters that can be used to make sutures and the like. These polymers, polyethylene terephthalate, have femlene groups in the base structure of the polymers. However, less research has been recorded in poliesteree aliphatic. After Carotherß's first work on polyesters, aliphatic polyesters were generally ignored because it was believed that these materials had low melting points and high solubilities. The only aliphatic polyesterers that have been extensively studied are polylactones such as polylactide, polyglycolide, poly (p-dioxanone) and p-olicaprolactone. These polilactonaß alifaticaß They have been used mainly for bioabsorbable surgical sutures and surgical devices such as staples. Although polylactones have proven useful in many applications, they do not meet all the needs of the medical community. For example, polylactone films do not transmit water vapor, therefore, they are not ideally suited for use as bandages in which the transmission of water vapor should be desired. Only recently, the interest in aliphatic polyesters without lactone has been renewed. The Patent of E.U.A. 5,349,028 discloses the formation of very simple aliphatic polyesters based on the reaction of a diol with a dicarboxylic acid to form prepolymer chains that deßpueß ßon coupled β. These polyesters have been promoted for use in fibers and molded articles since these polyesters are biodegradable after they are buried as well as on land. However, these materials do not describe how to be suitable for use in surgical devices. Thus, an object of the present invention is to provide a new class of aliphatic polyesterers and mixtures thereof which can be used in surgical devices such as sutures, molded devices, drug assortment matrices, coatings, lubricants and the like.

BRIEF DESCRIPTION OF THE INVENTION A new class of synthetic polymeric materials which are bioabsorbable and which can be used to produce surgical devices such as sutures, sutures with added needles, molded devices, drug assortment matrices, coatings, lubricants and the like have been discovered. The invention also contemplates a process for producing bioabsorbable polymers and copolymers. The polyoxatestereß ali aticoe of the present invention are polyesters comprising a first divalent repeating unit of the formula I: C? -C (O) -C? R?) (R2) -0- (R3) -0-C (R?) (R2) -C (0) -] T and a second repeating unit selected from the group of formulas consisting of: C-0-R5-C (0) -] B III (C-0-RS-C (0)] P-0) LG XI and combinations thereof, wherein Ri and 2 are independently hydrogen or an alkyl group containing from 1 to 8 carbon atoms; R3 is an alkylene unit containing from 2 to 12 carbon atoms or is an oxyalkylene group of the following formula: -? CH2) C -O- 1D - (CH2) E - IV where C is an integer on the scale of 2 to about 5, D is an integer on the scale of about 0 to about 2,000, and E is an integer on the scale of about 2 to about 5, except when D is zero, in which case E will be an integer from 0 to approximately 12; R is an alkyl ene unit containing from 2 to 8 carbon atoms; A is independently an integer on the scale of 1 to about 2,000; Rs is selected from the group consisting of -CÍRßHR? -, - (CH2) 3-0 ~, -CH2-CH2-0-CH2-, CRßH-CH2-, - (CH2U-, - (CH2) F -0-C (0) ~ and - (CH2) FC (0) -CH2-; R6 and R7 ßon independently hydrogen or an alkyl containing from 1 to 8 carbon atornoß; Re eß hydrogen or methyl; F eß? N enter-o in the scale from 2 to 6, B is an integer in the scale of 1 an so that the average molecular weight of formula III is less than about 200,000, preferably less than about 100,000, and most preferred less than about 40,000; P is an integer in the scale from 1 to rn so that the average molecular weight of formula XI is less than about 1,000,000, preferably less than about 200,000 and most preferred less than about 40,000; G represents the residue minus 1 to L hydrogen atoms of the hydroxyl group of an alcohol which previously contains from 1 to about 200 hydroxyl groups; and L is an integer from 1 to about 200.

DETAILED DESCRIPTION OF THE INVENTION The aliphatic polyoxaesters of the present invention are the reaction product of an aliphatic polyoxycarboxylic acid and at least one of the following compounds: a diol (or polydiol), a lactone (or lactone oligomer), coupling agent or combination of the same. Suitable aliphatic alpha-oxycarboxylic acids for use in the present invention generally have the following formula: H0-C (0) -C (R?) (R2) -0- (R3) -0-C (R?) (R2) -C (O) ~ 0H V wherein Ri and R2 are independently selected from the group consisting of hydrogen or an alkyl group containing from 1 to 8 carbon atoms and R3 is an alkylene containing from 2 to 12 carbon atoms or is an oxyalkylene group of the following formula: II (CH2) c-0-3-D (CH2) E IV where C is an integer on the scale of about 2 to about 5, D is an integer on the scale of about 0 to about 2,000 and preferably 0 to 12, and E is an integer on the scale of about 2 to about 5. These aliphatic alpha-hydroxyoxycarboxy acids can be formed at reacting a diol or polyol with an alpha-halocarboxylic acid such as or broacetic acid or chloroacetic acid under suitable conditions. The diols or polyidioles suitable for use in the present invention are diol or diol repeat units with up to 8 carbon atoms having the formulas: HC- (0-RA-) A-I0H, O T wherein R 4 is an alkylene unit containing from 2 to 8 units of rnetylene; A is an integer in the range from 1 to approximately 2,000 and preferably from 1 to approximately 1000. Examples of suitable diols include diols selected from the group consisting of 1,2-etaned? Oi (ethylene glycol), 1,2-propaned? ol (propylene glycol), 1,3-propaned? ol, 1,4-butaned? ol, 1,5-pentaned? ol, 1,3-cyclopentanediol, 1.6 -hexaned? ol, 1,4-c? clohexaned? ol, 1,8-octanediol and combinations thereof. Examples of preferred polyidioles include polycides selected from the group consisting of (HC-0-CH 2 -Cb-J ?OH,) of polyethylene glycol and (HC-0-CH 2 -CH-ÍCH 3) -] AOH,) polypropylene glycol.

The polymer produced by reacting the aliphatic dioxycarboxylic acid with the diols described above must provide a polymer that generally has the formula: L-0-C (0) -C (RI) (R2) -0- (R3) -0-C (R?) (R2) -C (0) - (0-R4) A-3N VII wherein Ri, R2, R3, R4 and A are as described above; and N is an integer in the scale of about 1 to about 10,000 and preferably is in the range of about 10 to about 1,000 and most preferred in the scale of about 50 to about 200. Suitable lactone monomers that can used in the present invention generally have the formula: -O-Rs-C (O) - VIII These lactone rnonomers can be polymerized to provide polymers of the following general structures: HC-0-Rs-C (0) -] B0H IX (HC-0-RS-C (0)] P-0 -) - L6 X wherein R5 is independently selected from the group consisting of -C (Rβ) (R7) -., - (CH2) 3-0-, -CH2-CH2-0-CH2 -, -CR8H-CH2-, - (CH2) «-, - (CH2) F -OC (O) - and - (CH2) F -C (O) -CH2-; e and R7 are independently hydrogen or an alkyl containing from 1 to 8 carbon atoms; Re is hydrogen or methyl; F is an integer from 2 to 6; B is an integer in the scale of l a n so that the average molecular weight number of formula IX eß is less than about 200,000, preferably less than 100,000, and most preferred less than 40,000; The entire scale is so that the molecular weight number of formula X is less than about 1,000,000, preferably less than about 200,000, and preferably less than 40,000; G represents the residue less than 1 to L hydrogen atoms of the hydroxyl groups of an alcohol that previously contains from 1 to about 200 hydroxyl groups; and L is an integer from about 1 to about 200. In a G mode the residue of a dihydroxy alcohol minus both hydroxyl groups will be and the average molecular weight number of formula X will be less than about 1,000,000, preferably less. of approximately 200,000 and I prefer less than around 40,000. In another embodiment of the present invention G may be a polymer containing pendant hydroxyl groups (including polysaccharides). Suitable repeating units derived from lactone can be generated from the following monomers including but not limited to lactone monomers selected from the group consisting of glycolide, d-lactide, 1-lactide, meso-lactide, e- caprolactone, p-dioxanone, trimethylene carbonate, 1,4-dioxepane-2-one, 1,5-dioxene-2-one, and combinations thereof.

The polymer formed by reacting the diol (or polydiol) deecpto above VI and the aliphatic polyoxycarboxylic acid V can also be copolimepzarse in a condensation polymerization with the lactone polymers IX described above to form a polymer generally of the formula: GÍ-C (O) -CÍRI) (R2) -0-R3-0-C (R?) (R2) -C (0) - (0-R4) A-0) S XII (C (0) ~ Rs-0) B JI O [(-C (O) -C (R?) (R2) -0-R3-0-C (R?) (R2) -C (0) - (0-R *) A -0) S (C-0-RS-C (0)] P-0-) LG] I XIII where ? is an integer in the scale of about 1 to about 10,000 and preferably from 1 to about 1,000 and W is an integer on the scale of about 1 to about 1,000. These polymers can be made in the form of random copolymers or block copolymers. For the diols, the aliphatic polyoxycarboxylic acids and nonordinate lactone acids described above, a coupler-selected agent can be added from the group consisting of tri-functional or tetrafunctional polyols, oxycarboxylic acids, and polybasic carboxylic acids (or acid anhydrides thereof) . Adding coupling agents causes the branching of long chains, which can impart desirable properties in the molten state of the polyester prepolymer.

Examples of coupling agents poly works Les suitableß include prop > anion of tprnethylol, glycepna, pent ae itptol, rnálico acid, citric acid, tartaric acid, thimeric acid, tricarboxylic acid of propane, anhydro tetr carboxylic acid of cyclopentane and combinations thereof. The amount of coupling agent to be added before the gel occurs depends on the type of coupling agent used and the polymerization conditions of the polyoxaester or molecular weight of the prepolymer to which it is added. Generally on the scale of about 0.1 to about LO mole percent of a functional or tetrafunctional tp coupling agent may be added based on the moles of present or anticipated aliphatic polyoxaester polymers of the βββεβε. The polymerization of the aliphatic polyoxaester is preferably carried out under molten polycondensation in the presence of an organometallic catalyst at elevated temperatures. The organometallic catalyst is preferably a brass baεe catalyst for example stannous octoate. The catalyst preferably will be present in the mixture at a molar ratio of diol, polyoxycarboxylic aliphatic acid and optionally lactone monomer to catalyst will be in the range of about 15,000 to about 80,000 / 1. The reaction is preferably carried out at a temperature which is not less than about 120 ° C or reduced pressure. Laß Higher polymerization temperatures may lead to further increases in the molecular weight of the copolymer, which may be desirable for numerous applications. The exact reaction conditions chosen will depend on numerous factors, including the properties of the desired polymer, the viscosity of the reaction mixture, and the glass transition temperature and softening temperature of the polymer. The preferred reaction conditions of temperature, time and pressure can be determined by ensuring these and other factors. Generally, the reaction mixture will be maintained at approximately 220 ° C. The polymerization reaction can be allowed to proceed at this temperature until the desired molecular weight and conversion of p-orcenta e is achieved for the copolymer, which will typically take from about 15 minutes to 24 hours. Increasing the reaction temperature generally decreases the reaction time required to achieve a particular molecular weight. In one embodiment, aliphatic polyoxyester copolymers can be prepared by forming an aliphatic polyoxaester prepolymer polymerized under molten polycondensation conditions, then adding at least one lactone monomer or lactone prepolymer. The mixture should then be subjected to the desired conditions of temperature and time to copolymerize the prepolymer with the lactone monomers. The molecular weight of the prepolymer as well as its L3 The composition can be varied depending on the desired characteristic that the pr? e? ol? rnero will impart to the copolymer. However, it is preferred that the polyoxaester aliphatic prepolymers of which the copolymer is prepared have a molecular weight that provides an inherent viscosity between about 0.2 to about 2.0 deciliters per gram (dl / g) as measured at a solution of hexafluoroisopropansl of 0.1 g / dl at 25 ° C. Those skilled in the art will note that the aliphatic polyoxae ester prepolymers described herein can also be made from mixtures of more than one diol and dioxycarboxylic acid. One of the beneficial properties of the aliphatic polyoxaester made by the process of this invention is that the ester umonees are hydrolytically unstable, and therefore the polymer is bioabsorbable because it divides into small segment to the exposed tissue wet body In this respect, while it is seen that the reactable co-matepales can be incorporated into the reaction mixture of the aliphatic dioxycarboxylic acid and the diol for the formation of the aliphatic polyoxyester prepolymer, it is preferable that the reaction mixture does not include a concentration of any reactable co-matepal that the non-absorbable prepared polymer can give. Preferably, the reaction mixture is substantially free of any reactable co-matepal if the resulting polymer is not brazed. The polymers of this invention can be melted by different methods to prepare a wide array of useful devices. These polymers can be injection or compression molded to make medical and surgical implant devices, especially devices for closing wounds. The devices for closing preferred wounds are fasteners, staples and surgical sutures. Alternatively, the aliphatic polyoxaesters can be squeezed to prepare fibers. The filaments thus produced can be fabricated in sutures or ligatures, added to surgical needles, packaged, and sterilized by known techniques. The polymers of the present invention can be spun as a multi-filament yarn and woven or spun to form sponges or gauze, (or non-woven sheets can be prepared) or used together with other compression structures as prosthetic devices within a human body or animal where it is desirable for the structure to have high tensile stress and desirable levels of docility and / or ductility. Useful modalities include tubes, which include branched tubes, for artery, vein, or intestinal repair, nerve joint, tendon joint, sheets to classify and support damaged surface abrasions, particularly major abrasions, or areas where the skin and tissues are critical. They are damaged or surgically removed. Additionally, the polymers can be molded to form films which, when sterilized, are useful as adhesion prevention barriers. Another alternative technique Processor for the polymer blends of this invention includes solvent molding, particularly for those applications wherein a drug assortment matrix is desired. In more detail, the surgical and medical uses of the filaments, films, and molded articles of the present invention include, but are not necessarily limited to: spun, woven or non-woven products, and molded products including: a. bandage for burns b. hernia patches c. prescription bandages d. facial substitutes e. gauze, cloth, sheet, felt or sponge for liver hernosestasis f. gauze bandages g. arterial graft or substitutes h. bandages for skin surfaces. i. suture knot bra j. pins, fasteners, screws and orthopedic plates k. clips (for example, for vena cava) 1. staples rn. hooks, buttons, and fasteners n. bone substitutes (for example, jaw prostheses) or. intrauterine devices (for example, spernicidal devices) p. Drainage or test tubes or capillaries q. surgical instruments r. implants or vascular supports s. vertebral discs t. external tube for kidney and heart-lung machines? . artificial skin and others v. frames for a couple of cells in weaving engineering applications. In another embodiment, the aliphatic polyoxaester is used to coat a surface of a surgical article to improve the lubricity of the coated surface. The polymer blends can be applied as a coating using conventional techniques. For example, the polymer blends can be solubilized in a dilute solution of a volatile organic solvent, for example, acetone, methanol, ethyl acetate or toluene, and then the article can be immersed in the solution to coat its surface. Once the surface is coated, the surgical article can be removed from the solution where it can be placed at a high temperature until the solvent and any residual reactable material are removed. For use in coating applications aliphatic polyoxaesters must exhibit a viscosity inherent, as measured in 0.1 gram per deciliter (g / dl) of hexafluoroisopropanol (HFTP), between about 0.5 to about 2.0 dl / g, preferably from about 0.10 to about 0.80 dl / g. If the inherent viscosity is less than about 0.05 dl / g, then the polymer can not have the integrity needed for the preparation of films or coatings for the surfaces of various surgical and medical articles. On the other hand, although it is possible to use polymers with an inherent viscosity greater than about 2.0 dl / g, it can be extremely difficult to do so. Although it is contemplated that numerous surgical articles (including but not limited to endoscopic instruments) can be coated with the polymer of this invention to improve the surface properties of the article, the preferred surgical articles are sutures and surgical needles. The preferred surgical article rnáß is a suture, very preferred added to a needle. Preferably, the suture is a synthetic absorbable suture. These sutures are derived, for example, from homopolymers and copolymers of lactone monomers such as glycolide, lactide, e ~ caprolactone, 1,4-dioxanone, and tri ethylene carbonate. The preferred suture is an interlaced multi-filament suture composed of polyglycolide or p-oli (glycolide-co-lactide). The amount of coating polymer that will be applied on the surface of an interlaced suture can determined impirically, and will depend on the particular copolymer and suture chosen. Ideally, the amount of coating copolymer applied to the surface of the suture may vary from about 0.5 to about 30 percent of the weight of the coated suture, most preferably from about 1.0 to about 20 weight percent, most preferred of 1 about 5 weight percent. If the amount of coating on the suture is greater than about 30 weight percent, then the risk of the coating flaking when the suture piazes through the tissue may increase. The sutures coated with the polymers of this invention are desirable since they have a slippery feeling, thus making it easier for the surgeon to slip a knot under the suture to the site of surgical trauma. In addition, the suture can pass through the body tissue more easily, thus reducing tissue trauma. These advantages are exhibited in comparison with sutures that do not have their surfaces coated with the polymer blends of this invention. In another embodiment of the present invention, when the article is a surgical needle, the amount of coating applied to the surface of the article is an amount that creates a layer with a thickness that preferably ranges from about 2 to about 20 microns on the needle , preferably from about 4 to about 8 microns. If the The amount of coating on the needle was such that the thickness of the coating layer was greater than about 20 microns, or if the thickness was less than about 2 microns, then the desired performance of the needle while passing through the tissue was not can achieve. In another embodiment of the present invention, the aliphatic polyoxester can be used as a pharmaceutical carrier in a drug assortment matrix. To form this matrix the polioxaesteree ße would mix with a therapeutic agent to form the matrix. The variety of different therapeutic agents that can be used together with the aliphatic polyoxaesters of the invention is broad. In general, therapeutic agents that can be administered by means of the pharmaceutical compositions of the invention include, without limitation: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; anthelmintics; antiart ptj coß; antiaesthetic agents; anticomvulsants; antidepressants; antidiuretic agents; antidiarrhea; antiistarninae; antiinflammatory agents; antimigraphic preparations; antinausea; antineoplastic; antiparkinsonißmo drugs; antipruritics; antipsychotics; antipyretics; antießpasrnodi coß; anticholinergic; sympathomimetics; xanthe derivatives; cardiovascular preparations that include calcium channel blocker and beta-blockers such as pmdolol and antiarptmica; antihypertensive; diuretics; vaßodilatadoreß which include coronary general, fetal and cerebral pep; stimulants of the central nervous system; preparations for toe and flu, which include descongeßtionadoreß; horrnonaß taleß corno estradiol and other eteroids, which include corticosteroid; hypnotics; inrnunosupresivoe; muscle relaxants; parasitic parasitic; psycho-stimulant; ßedanteß; and reassuring; and naturally derived or genetically formulated proteins, polysaccharides, glycoproteins or li op otemaß. The drug ßupid matrix can be administered in any suitable dosage form such as orally, parenterally, subcutaneously as an implant, vammally or as ßupoßitone. Matrix formulations containing the aliphatic polyoxester can be formulated by mixing one or more therapeutic agents with the polyoxaester. The therapeutic agent may be present as a liquid, a finely divided solid, or any other appropriate physical form. Typically, p > optionally, the matrix will include one or more additives, for example, non-toxic auxiliary substances, such as diluents, vehicles, excipients, stabilizers or the like. Other suitable additives can be formulated with the mixture of polymer and pharmaceutically active agent or compound, however, if the water is to be used it must be added immediately before administration. The amount of therapeutic agent will depend on the particular drug used and medical condition that will be treated. Typically, the amount of drug represents about 0.001% to about 70%, typically from about 0.001% to about 50%, very typical of about 0.001% to about 20% by weight of the matrix. The amount and type of polyoxester incorporated in the parenteral type will vary depending on the desired release and the amount of drug employed. The product may contain mixtures of polymers having different molecular weights to provide the desired release profile or consistency of a given formulation. The polyoxaester, upon contact with body fluids including blood or the like, undergoes gradual degradation (primarily through hydrolysis) with concomitant release of the dispersed drug over an extended or sustained period (as compared to the release of na? isotonic saline solution). This can result in prolonged assortment (eg, for 1 to 2,000 hours, preferably 2 to 800 hours) of effective amounts (eg, 0.0001 rng / kg / hour to 10 rng / kg / hour) of the drug. This dosage form can be administered as necessary depending on the subject to be treated, the severity of the affliction, the judgment of the prescribing physician, and ßimilareß. Individual formulations of drugs and polyoxaester can be tested in appropriate models in vitro and in vivo to achieve the desired drug release profiles. For example, a drug can be formulated with a poiioxaester and 0 0 orally administered to an animal. The drug release profile can then be controlled p > or appropriate means such as by taking blood samples at specific times and testing the samples for drug concentration. After this procedure or the like, those skilled in the art will be able to formulate a variety of formulations. The polymers, copolymers and rnezclae of the present invention can be entangled to affect the mechanical properties. Interlacing can be achieved by adding interlaced and / or irradiating enhancers (such as garna-irradiation). In particular, the interleaving can be used to control the agitation of the water of said invention. In a further embodiment of the present invention, the polymers and mixtures of these polymers can be used in tissue engineering applications as supports for cells. Suitable tissue framework structures are known in the art such as the articular-prostatic cartilage described in the US patent. 5,306,311, the porous biodegradable scaffold described in UO 94/25079, and the prevascularized implants described in UO 93/08850 (all incorporated herein by reference). Methods for seeding and / or culturing cells in tissue frames are also known in the art as those methods described in EPO 422 209 Bl, WO 88/03785, UO 90/12604 and UO 95/33821 (all incorporated herein by reference. ). The examples set out below are for purposes of illustration, and are not intended to limit the scope of said invention in any way. Numerous additional embodiments within the scope and spirit of the invention will be apparent to those skilled in the art.

EXAMPLE 1 PREPARATION OF DERMETHYL ESTER OF 3, 6-DIOXAOCTANEDIOIC ACID Triethylene glycol 3,6-Dioxaoctanedioic Acid Dimethyl ester of 3,6-dioxaoctanedioic acid The diacid, 3,6-dioxaoctanedioic acid, was synthesized by means of oxidation of triethylene glycol. Oxidation was carried out in a 500-milliliter three-neck flask with a thermometer, an additional funnel, a gas absorption tube and a spinning magnetic bar. The reaction bottle was immersed in an oil bath that rests on a magnetic stirrer. For the reaction bottle were added L57.3 ml of a 60% nitric acid solution; 37.0 g of tolpene glycol was added to the additional funnel. The contents of the bottle were heated to 78-80 ° C. A test tube containing 0.5 g of glycol and 1 ml of concentrated nitric acid was heated in a water bath until brown gases appeared to appear. The contents were then added to the reaction bottle. The mixture was stirred for a few minutes; the glycol was then added carefully. The rate of adhesion had to be controlled with extreme care to keep the reaction under control. The adhesion rate was sufficiently low so that the heat of the exothermic reaction mixture was maintained at 78-82 ° C. After the ester had finished adding (80 min.), The temperature of the reaction mixture was maintained at 78-80 ° C for an additional hour. By continuing to maintain this temperature scale, the excess of nitric acid and water was then distilled under reduced pressure (water suction). The syrup-like residue was cooled; some ßonidoß appeared. The reaction product had the expected IR and NMR spectrum for the dicarboxylic acid; the crude product was used as such for esterification. The preparation of the crude 3,6-d-oxo-octane-dioxide acid was achieved in the following manner: For the reaction bottle containing 36 g of the crude diacid, 110 rnl of methanol was added. This was stirred for 3 days at room temperature then 15 g of sodium bicarbonate were added and they waved during the night. The mixture was filtered to revert solidβ. For the liquid, an additional 10 g of sodium bicarbonate was added; This mixture was stirred during the night. The mixture was filtered once more; the liquid was fractionally distilled. The NMR analysis of the product was ticado showed a mixture of dimethylic triglycolate (78.4 mol%) and monornetyl triglycolate (.21.6 mol%). No significant condensation of diacid was observed.

EXAMPLE 2 PREPARATION OF POLIOXAESTER FROM METHYL ESTERS OF 3-6-DIOXAOCTANODIOIC ACID AND ETHYLENE GLYCOL methyl esters of 3,6-d? oxaoctanedioic acid POLI "OXA" ESTERES A 50 ml, mechanically stirred, flame-dried glass reactor, suitable for polycondensation reaction, was charged with 20.62 g (approximately 0.1 mole) of the methyl esters of 3,6-dα-oxo-octane-acetic acid from the example l, 18.62 g (0.3 moles) of distilled ethylene glycol, and 0.0606 rnl of a solution of 0.33M of ethanetanose octoate in toluene. After purging the reactor and venting with nitrogen, the temperature was gradually increased over the cure from 26 hours to 180 ° C. A temperature of 180 ° C was then maintained for another 20 hours; During all these periods of heating ba or nitrogen to an atmosphere, the methanol formed was collected. The reaction bottle was allowed to cool to room temperature; then it was heated slowly under reduced pressure (0.015-1.0 nm) over the course of approximately 32 hours at 160 ° C, during which time they collected additional distillates. A temperature of 160 ° C was maintained for 4 hours after a sample, a few grams in size, of the polymer formed took. It was found that the sample had an inherent viscosity (I.V.) of 0.28 dl / g, as determined in hexafluoroisopropanol (HFIP) at 25 ° C at a concentration of 0.1 g / dl. The continuous polymerization under reduced pressure with increasing temperature, in the course of about 16 hours, from 160 ° C to 180 ° C; a temperature of 180 ° C was maintained for an additional 8 hours, at which time a sample of polymer was taken and the thickness of the vessel having a T.V. of 0.34 of 1 / g. The reaction continuous or reduced pressure for another 8 hours at 180 ° C. The resulting polymer has an inherent viscosity of 0.40 dl / g, as determined in HFIP at 25 ° C and at a concentration of 0.1 g / dl.

EXAMPLE 3 PREPARATION OF POLIOXAESTER WITH 3,6,9-TRIOXAUNDECANODIOIC ACID AND ETHYLENE GLYCOL 3, 6-9-tr? oxaundecanod acid? POLG? XA '? STERES A 250 milliliter glass reactor, mechanically stirred, flame dried, suitable for polycondensation reaction, was charged with 44.44 g (0.2 mole) of 3,6-9-tr? Oxadecaneodonic acid, 62.07 g (1.0 mole) of distilled ethylene glycol, and 9.96 mg of dibutyltin oxide. After purging the reactor and venting with nitrogen, the contents of the reaction flask were gradually heated under Nitrogen at one atmosphere, over the course of about 32 hours, at about 180 ° C, during that time the water formed was collected. The reaction mass was allowed to cool to room temperature. The reaction mask was then heated under reduced pressure (0.015-1.0), gradually increasing the temperature to 180 ° C in about 40 hours; During this time additional distillates were collected. Polymerization continued under reduced pressure while maintaining at 180 ° C for an additional 16 hours. The resulting polymer has an inherent viscosity of 0.63 dl / g as determined in HFIP at 25 ° C and a concentration of 0.1 g / dl.

EXAMPLE 4 PREPARATION OF POLYOXESTER WITH POLYGLYCOL AND GLYCOLIC DIODE OF ETHYLENE Polyglycol diacid. (n = l0-12) POLI "OXA" ESTERES A 500-milliliter, mechanically stirred, flame-dried glass reactor (suitable for polycondensation reaction) was charged with 123.8 g (0.2 moles) of polyglycol di-acid (molecular weight of about 619), 62.07 g (1.0 mol) ) of distilled ethylene glycol, and 9.96 mg of dibutiitin oxide. After purging the reactor and purging with nitrogen, the contents of the reaction flask were heated under nitrogen to an atmosphere, gradually increasing the temperature to 2Q0 ° C for about 32 hours; during this time the water formed was collected. The reaction flask was gradually heated under reduced pressure (0.015-1.0 ml) from room temperature to 140 ° C for approximately 24 hours, during which time additional distillates were collected. A polymer sample of about 10 g was taken at this stage, and it was discovered that it had an I.V. of 0.14 dl / g in HFIP at 25 ° C, 0.1 g / dl. Polymerization continued under reduced pressure when heating from 140 ° C to 180 ° C for about 8 hours, and then maintained at 180 ° C for an additional 8 hours. A polymer sample was taken once more and it was discovered that it had an I.V. of 0.17 dl / g. The reaction temperature was then increased to 190 ° C and maintained under reduced pressure for an additional 8 hours. The resulting polymer has an inherent viscosity of 0.70 dl / g as determined in HFIP at 25 ° C and at a concentration of 0.1 g / dl.

EXAMPLE 5 COPOLYMER OF POLIOXAESTER / CAPROLACTON® / TRIMETHYLENE CARBONATE AT 5/5/5 BY WEIGHT A 50 milliliter, single-neck, round neck flask was charged with 5 grams of the polyoxaester aliquot of Example 4 having an I.V. of 0.14 dl / g, 5.0 grams (0.0438 moles) of £ -caprolactone, 5.0 grams and 0.049 moles) of tri ethylene carbonate, and 0.0094 ml of a 0.33 molar solution of stannous toluene octoate. The bottle was adjusted with a magnetic stirring bar. The reactor was purged with nitrogen three times before venting with nitrogen. The reaction mixture was heated to 160 ° C and maintained at this temperature for 6 hours. The copolymer was dried under vacuum (0.1 mm Hg) at 80 ° C for about 16 hours to remove any unreacted ononero. The copolymer has an inherent viscosity of 0.34 dl / g as determined in HFIP at 25 ° C and at a concentration of 0.1 g / 1. The copolymer is a viscous liquid at room temperature. The molar ratio of polyoxaester / PCL / PTMC was found by NMR analysis of 47.83 / 23.73 / 28.45.

EXAMPLE 6 COPOLYMER OF POLIOXAESTER / CAPROLACTONE / GLYCOLIDE TO 6 / 8.1 / 0 / 0.9 IN WEIGHT A single-neck flask, round at the bottom, 25 ml, flame-dried, was loaded with 6 grams of the polyoxyester ester of Example 4 having an I.V. of 0.17 dl / g., 8.1 grams (0.0731 moles) of e-caprolactoma, 0.9 grams (0.008) moles of glycolide and 0.0080 ml of a solution of stannous octoate 0.33 in toluene. The bottle was adjusted with a magnetic stirring bar. The reactor was purged with nitrogen three times before venting with nitrogen. The reaction mixture was heated to 160 ° C and maintained at this temperature for about 18 hours. Copolymer Fi has an inherent viscosity of 0.26 dl / g in HFTP at 25 ° C and a concentration of 0.1 g / dl. The copolymer is solid at room temperature. The molar ratio of polyoxaester / PCL / PGA / caproiactane was found by NMR analysis to be 56.54 / 37.73 / 3.79 / 1.94.

EXAMPLE 7 IN VITRO HYDROLYSIS The polyoxaester of Example 3 was tested for in vitro hydrolysis at 50 ° C and at reflux temperature. A sample of 100 mg of the polyoxyester, placed in 100 ml of a Phosphate buffer solution (0.2 m in phosphate, pH 7.27), was completely hydrolyzed for about 7 days at 50 ° C, where at reflux it was completely hydrolyzed for about 16 hours.

EXAMPLE 8 IN VITRO HYDROLYSIS The polyoxaester of Example 2 was tested for in vitro hydrolysis at 50 ° C and at reflux temperature. A 100 mg sample of the polyoxaester, placed in a buffer solution of 100 ml (pH of 7.27), was completely hydrolyzed for about 25 days at 50 ° C, where at reflux it was completely hydrolyzed for about 16 hours.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - An aliphatic polyoxester comprising a first bivalent repeating unit in formula I: CO-C (0) -C (R?) (R2) -0- (R3) -0-C (R?) (R2) -C (0) -] I and a second repeating unit selected from the group of formulas con coniuting from: [-0-R4-IA, II C-0-RS-C (0) -] B and TU (C-0-RS-C (0)] P-0) LG XI and combinations of the members, wherein Ri and R2 are independently hydrogen or an alkyl group containing from 1 to 8 carbon atom; R3 is an alkylene unit containing from 2 to 12 carbon atoms or is an oxyalkylene group of the following formula: - [(CH2) c-0-] D- (CH2) E- IV where C is an integer in the scale from 2 to about 5, D is an integer on the scale of about 0 to about 2,000, and E is an integer on the scale of about 2 to about 5, except when D is zero, in which case E ßer an integer from 0 to about 12; R 4 is an alkylene unit containing from 2 to 8 carbon atoms; A is independently independent in the scale from 1 to approximately 2,000; R5 is selected from the group which consists of -CÍFfeHR?) -, - (CH2? 3-0-, -CH2 -CH2 -0-CH2-, CR.sub.H-CH2-, - (CH2) ü-, - (CH2) F-0-C ( 0) - and - (CH2) F ~ C (0) -CH2-; R1 and R are independently hydrogen or an alkyl containing from 1 to 8 carbon atoms, Re is hydrogen or methyl, and is an integer in the the scale from 2 to 6, B is integer in the scale of 1 an so that the molecular weight of the average number of formula III is less than about 200,000, preferably less than about LOO, 000 and very preferred less than about 40,000; P is an integer in the 1 am scale so that the average molecular weight of formula XI is less than about 1,000,000, preferably less than about 200,000 and most preferred less than about 40,000; G represents the residue minus 1 to L hydrogen atoms of the hydroxyl group of an alcohol which previously contains about 200 hydroxyl groups, and L is an integer from 1 to about 200. 2.- The aliphatic polyoxaesters according to claim 1, further characterized in that the polymer has the formula: [0-C (0) -C (R? ) (R2) -0- (R3) -0-C (R?) (R

2) C (0) - (0-R *) A-1H where N is an integer on the scale around * of Approximately 10, 000.

3. - The aliphatic polyoxyesters of confo rmity with claim 1, further characterized in that the polymer has the formula: [(-C (O) -C (R?) (R2) -0-R3 -0-C (R?) (R2) -C (0) - (O-R4) A -0) S (C (0) -R5-0) B1W where S is an integer on the scale of about 1 to 10,000 and U is an integer on the scale of L to about 1,000.

4. The aliphatic polyoxaesters according to claim 1, further characterized in that the polymer has the formula: [(-C (O) -C (R?) (R2) -0-R3-0-C (R?) (R2) -C (0) - (0-R¿) A -0) S ([-0-R5-C (0) 1P-0-) LGJW where S is integer in the scale of around- from 1 to 10,000 and U is an integer on the scale of 1. to about 1,000.

5. A device made of an aliphatic polyoxaester comprising a first bivalent repeating unit of the formula I: C0 ~ C (0) -C (R?) (R2) -0- (R3) -0-C (R ?) (R2) -C (0) -] I and a second repeating unit selected from the group of formulas consisting of: C-0-R4-] A, II C-0-RS-C (0 ) -] B, and III (C-0-R5-C (0)] P-0) LG XI and combinations thereof, wherein Ri and R2 are independently hydrogen or an alkyl group containing 1 to 8 carbon atoms; 3 is an alkylene unit containing from "2 to 12 carbon atoms or is an oxyalkylene group of the following formula: -C (CH2) c-0-] D- (CH2) E-IV wherein C is an integer on the scale of 2 to about 5, D is an integer on the scale of about 0 to about 2,000, and E is an integer on the scale of about 2 to about 5, except when D is zero, in which case E will be an integer from 0 to about 12; R-; is an alkylene unit containing from 2 to 8 carbon atoms; A eß independently an integer in the range of about 2,000; Rs is selected from the group that connects -C (Rβ) (R7> -, - (CH2? 3-O-, -CH2-CH2-0-CH2-, CR? H-CH2-, - (CH2 -, - (CH2) F-0-C (0) - and - (CH2) FC (0) -CH2-, R6 and R7 are independently hydrogen or an alkyl containing from 1 to 8 carbon atom, Re is hydrogen or methyl; F is an integer on the scale of 2 to 6; B is an integer on the scale of lan so that the average number molecular weight of formula III is less than about 200,000, preferably less than about 100,000, and preferred less than about 40,000; P is an integer on the 1 am scale so that the average molecular weight of formula XI is less than about 1,000,000, preferably less than about 200,000 and most preferred less than about 40,000; G represents the residue minus 1 to L hydrogen atoms of the hydroxyl group of an alcohol that previously contains from 1 to about 200 hydroxyl groups, and L is an integer from 1 to about 200.

6.- The device according to claim 5, further characterized in that the device is a surgical absorber device.

7. - The absorbable surgical device according to claim 6, further characterized in that the abeorbible surgical device is selected from the group consisting of bandages for burns, hernia patches, prescription bandages, facial substitutes, gauzes, fabrics, sheets, felts, sponges, gauze, arterial graft, bandages for skin surfaces, suture knot brace, pins, fasteners, screws, plates, clips, staples, hooks, buttons, fasteners, bone substitutes, intrauterine devices, tubes, surgical instruments, vascular implants, vasculareß supports, vertebral discs, and artificial skin.

8. The absorbable surgical device according to claim 6, further characterized p-orque the device is a filament.

9. The filament according to claim 8, further characterized in that the filament is added to a needle.

10. A device coated with an absorbable coating comprising an aliphatic polyoxaester having a first bivalent repeating unit of the formula I: C0-C (O) -C (R?) (R2) -0- (R3) - 0-C (R?) (R2) -C (0) -] I and a second repeating unit selected from the group of formulas consisting of: COR ^ -UA, II C-0-R5-C ( 0) -] B, and III (C-0-R5-C (0)] P-0) LG XI and combinations of the members, wherein Ri and R2 are independently hydrogen or an alkyl group containing from 1 to 8 carbon atoms; R3 is an alkylene unit containing from 2 to 12 carbon atoms or is an oxyalkylene group of the following formula: -? CH2) CO-3D- (CH2) E- IV where C is an integer in the scale from 2 to about 5, D is an integer on the scale of about 0 to about 2,000, and E is an integer on the scale of about 2 to about 5, except when D is zero, in which case E was a whole from 0 to about 12; R 4 is an alkylene unit containing from 2 to 8 carbon atoms; A is independently an integer on the scale of 1 to about 2,000; R5 is selected from the group consisting of -C (Rβ) (R7) -, - (CH2) 3-0-, -CH2-CH2 -0-CH2 -, CRßH-CH2-, - (CH2 -, - (CH 2) F-0-C (0) - and - (CH 2) F -C (0) -CH 2 -; R 6 and R 7 are independently hydrogen or an alkyl containing from 1 to 8 carbon atoms; Re is hydrogen or methyl, F is an integer on the scale of 2 to 6, B is an integer on a scale of 1 an, so that the average molecular weight of formula III is about 200,000, preferably less than about 100,000 and most preferred less than about 40,000; P ee an integer in the range of 1 to 1 that the average molecular weight of formula XI is less than about 1,000,000, preferably less than about 200,000 and I prefer less than about 40,000; G represents the residue menoe 1 to L hydrogen atoms of the hydroxyl group of an alcohol which previously contains from 1 to about 200 hydroxyl groups; and L is an integer from 1 to about 200 wherein the inherent viscosity of polyoxaether eeta in the range of about 0.5 to about 2.0 deciliters per gram (dl / g) as measured in a solution of 0.1 g / 1 hexafluoropropanol ( HFIP) at 25 ° C.

11. The device according to claim 10, further characterized in that the device is a suture.

12. The device according to claim 11, further characterized in that the suture is added to a needle.

13.- A drug assortment matrix containing a drug and an aliphatic polyoxaester having a first divalent repeating unit of the formula I: C0-C (0) -C (R?) (R2) -0- (R3 ) -0-C (R?) (R2) -C (0) -] I and a second repeating unit selected from the group of formulas consisting of: [-0-R4 - .A, II C -0-Rs-C (0) -] B, and III (C-0-R5-C (0)] P-0) LG XI and combinations of the terms, where Ri and R2 are independently hydrogen or a group alkyl containing 1 to 8 carbon atoms; R3 is an alkylene unit that contains from 2 to 12 carbon atoms or is an oxyalkylene group of the following formula: -II (CH2) c-0-3D- (CH2) E-IV where C is an integer in the scale from 2 to approximately 5, D is an integer on the scale of about 0 to about 2,000, and E is an integer on the scale of about 2 to about 5, except when D eß zero, in which case E ß was an integer of 0 at about 12; R is an alkyl ene unit containing from 2 to 8 carbon atoms; A is independently an integer in the scale of l to about 2,000; Rs is selected from the group consisting of -CÍRßHR? -, - (CH2) 3-0-, -CH2-CH2-0-CH2 -, CRßH-CH2-, - (CH2U-, - (CH2) F -0-C (0) - and - (CH2) FC (0) -CH2 -; R6 and 7 ßon independently hydrogen or an alkyl containing the carbon atom, Re is hydrogen or methyl, F is an integer in the scale from 2 to 6; B is an integer on the scale of lan so that the average molecular weight of formula III is about 200,000, preferably less than about 100,000, and most preferred less than about 40,000; P is an integer on the scale of 1 am so that the average molecular weight of formula XI is less than about 1,000,000, preferably less than about 200,000, and most preferred less than about 40,000; G represents the residue minus 1 to L hydrogen atoms of the hydroxyl group of an alcohol that previously contains from 1 to about 200 hydroxyl groups, and L eβ an integer from 1 to about

200.

14. The device according to claim 5, further characterized in that the polyoxaeyesterases aliphatic have the formula: C-0-CIO) -C (R?) (R2) -0- (R3) -0-C (R? ) (R2) -CÍO) - (O-R4) A-1N where N is an integer on the scale of about 1 to about 10,000.

15. The device according to claim 5, further characterized in that the aliphatic polyoxanetereß have the formula: [(-C (O) -C (R?) (R2) -0-R3-0-C (R?) (R2) -0 (0) - (0 ~ R «) A -0) S (C (0) -Rs-0) B3w where S is an integer in the scale of around- from 1 to 10,000 y) is an integer on the scale of 1 to approximately 1,000.

16. The device according to claim 5, further characterized in that the aliphatic polyoxaesters have the formula: [(-C (O) -C (R?) (R2) -0- (R3) ~ 0-C (R ?) (R2) -CÍO) - (O-R4) A -0) s (C-0-Rs-C (0) -] p-0-) LG3W where S is an integer on the scale around 1 to 10,000 and U is an integer on the scale of 1 to about 1,000.

17. The device coated with an absorbable coating according to claim 10, further characterized in that the polyoxaestereß aliphatics have the formula: C-0-C (0) -C (R?) (R2) -0- (R3) ) -0-C (R?) (R2) C (O) - (OR *) A -] N where N is an integer on the scale of about 1 to about 10,000.

18. The device coated with an absorbable coating according to claim 10, further characterized because the polioxatetere alifaticoe have the formula: [(-C (O) -C (R?) (R2) -0-R3-0 -C (R?) (R2) -CÍO) - (0-R *) A ~ 0) S (C (0) -R5-0) Bl where S is an integer on the scale of about 1 to 10,000 and U is an integer on the scale of 1 to about 1,000.

19. The device coated with an absorbable coating according to claim 10, further characterized in that the aliphatic polyoxaeyesters have the formula: [(-C (O) -C (R?) (R2) -0-R3-0- C (R?) (R2) -C (0) - (0 -R *) A -0) S (C-0-Rs-C (0)] p-0-) G3w where S is an integer in the scale of around 1 to 10,000 and U eß an integer on the scale of 1 to about 1,000.

20. The drug assortment matrix according to claim 13, further characterized in that the aliphatic polyoxaeßter has the formula: C-0-C (0) -C (R?) (R2) -0- (R3) - 0-C (R?) (R2) C (0) - (O-R4) A -3N where N e? An integer on the scale of about-about 10,000.

21. The drug assortment matrix according to claim 13, further characterized in that the polyoxyester a1i attic has the formula: (-C (O) -C (R?) (R2) -0-R3-0-C (R?) (R2) -CÍO) - (0-R¿) A ~ 0 ) S (C (0) ~ Rs-0) Bl where S is an integer on the scale of about 1 to 10,000 and U is an integer on the scale of 1 to about 1,000.

22. The drug assortment matrix according to claim 13, further characterized in that the aliphatic polyoxyester has the formula: [(-C (O) -C (R?) R 2) -0-R3-0-C ( R?) (R2) -C (0) - (0-R *) A ~ 0) S (C-0-RS-C (0)] P-0) LG3W where S is an integer in the scale of about 1 to 10,000 and U is an integer on the scale of 1 to about 1,000.