WO1996022270A1 - Biopolymeres derives de matieres grasses diacides hydrolysables - Google Patents

Biopolymeres derives de matieres grasses diacides hydrolysables Download PDF

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Publication number
WO1996022270A1
WO1996022270A1 PCT/IB1995/000007 IB9500007W WO9622270A1 WO 1996022270 A1 WO1996022270 A1 WO 1996022270A1 IB 9500007 W IB9500007 W IB 9500007W WO 9622270 A1 WO9622270 A1 WO 9622270A1
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Prior art keywords
degradable bond
derivative
hydrolytically
acid
diacid
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PCT/IB1995/000007
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English (en)
Inventor
Abraham Jacob Domb
Raphael Nudelman
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Yissum Research Development Co. Of The Hebrew University Of Jerusalem
Kohn, Kenneth, I.
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Application filed by Yissum Research Development Co. Of The Hebrew University Of Jerusalem, Kohn, Kenneth, I. filed Critical Yissum Research Development Co. Of The Hebrew University Of Jerusalem
Priority to PCT/IB1995/000007 priority Critical patent/WO1996022270A1/fr
Priority to AU18209/95A priority patent/AU1820995A/en
Publication of WO1996022270A1 publication Critical patent/WO1996022270A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/347—Saturated compounds containing more than one carboxyl group containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/12—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from polycarboxylic acids and polyhydroxy compounds
    • C08G63/46—Polyesters chemically modified by esterification
    • C08G63/48—Polyesters chemically modified by esterification by unsaturated higher fatty oils or their acids; by resin acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G67/00—Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
    • C08G67/04—Polyanhydrides

Definitions

  • This invention relates to the area of organic synthesis and, in particular, the synthesis of biocompatible polymers.
  • biodegradable polymers Over the last 20 years, many classes of biodegradable polymers have been under development for a wide variety of biomedical applications. 1
  • the most actively pursued biomaterials include: the lactide/glycolide copolymers, polyorthoesters, polycaprolactones, polyphosphazenes and polyanhydrides. 1,2,3
  • polyanhydrides 1,2,3
  • polyanhydrides are a unique class of polymers because some of them demonstrate a near zero order drug release and a relatively rapid biodegradation in vivo .
  • Some of the desired physico-chemical and mechanical properties in a single polymer that could be used in an implantable or injectable drug delivery system are: a. hydrophobic enough so that the drug is released in a predictable and controlled way;
  • suitable physical properties for device fabrication properties low melting point, usually below 100°C, and soluble in common organic solvents
  • poly(carboxyphenoxy propane) [P(CPP)] displays near zero order erosion and release kinetics. 4
  • this polymer displays an extremely slow degradation rate, and it is estimated that a drug delivery device prepared from P(CPP) would take almost three years to completely degrade in vivo.
  • the FAD and related oligomers of fatty acids are the coupling products of two or more unsaturated fatty acids in which the original fatty acids are connected via a chemically stable C-C bond (non-hydrolyzable). Because the oligomerized fatty acids contain a non-natural structure (C-C branching points), they may not be eliminated at the same rate and capacity as natural fatty acids, which are readily eliminated from the body by a ⁇ -oxidation process.
  • a monomeric diacid derivative comprising at least two fatty acids coupled by a hydrolytically or enzymatically degradable bond is formed.
  • the bond degrades forming naturally occurring fatty acid products thereby allowing elimination.
  • the monomeric diacid derivative has the structure
  • R, R 1 and R 2 are aliphatic organic residues with 0 to 20 carbon atoms and can be the same or different
  • X is an enzymatically or hydrolytically degradable bond selected from the group consisting of ester, amide, urethane, acetal, urea, and carbonate bonds can be formed.
  • the absence of stable C-C nonhydroyzable branching bonds allows these monomers to be first hydrolyzed to the respective natural acids and then rapidly eliminated since naturally occurring fatty acids are formed and are readily eliminated from the body via ⁇ -oxidation.
  • FIGURE 1 is a graph showing hydrolytic degradation of polymers based on ricinoleic acid as determined by weight loss and conversion of anhydride to acid groups, degradation being determined in 0.1M phosphate buffer pH 7.4 at 37oC;
  • FIGURE 2 is a graph showing in vitro release of ciprofloxacin from ricinoleic acid maleate-based polymeric devices, drug release being determined in 0.1M phosphate buffer pH 7.4 at 37°C;
  • FIGURE 3 is a graph showing in vitro release of ciprofloxacin from ricinoleic acid maleate-sebacic acid copolymer based polymeric devices, drug release being determined in 0.1M phosphate buffer pH 7.4 at 37oC. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
  • the present invention relates to biodegradable polymers containing novel hydrolyzable diacid fats which provide hydrophobicity and improved physical and mechanical properties to the polymers as compared to biopolymers that do not contain these monomeric units, and yet are completely degradable to natural products when exposed to biological environments.
  • the diacids were synthesized from fatty acids containing a hydroxyl or amine side group and aliphatic diacid derivatives.
  • the general structure of these monomers is:
  • R, R 1 and R 2 are aliphatic organic residues with 0 to 20 carbon atoms and can be the same or different
  • X is an enzymatically or hydrolytically degradable bond selected from the group consisting of ester, amide, urethane, acetal, urea, or carbonate bonds can be formed.
  • Examples of other useful monomers are diacid derivatives of tartaric acid and glycerylmonostearate.
  • These monomers are synthesized, for example, from natural hydroxy fatty acids which are reacted with dicarboxylic acid derivatives, such as cyclic anhydrides, to provide diacid monomers suitable for anhydride and ester polymerization.
  • the reaction is conducted in an organic solvent where the hydroxy acid is reacted under reflux with the cyclic anhydride, when other reactive acids are used, the reaction conditions should be adjusted.
  • the natural molecules are therefore linked by an hydrolyzable bond which include: ester, amide, imide, orthoester, carbonate, urethane, urea or phosphate ester.
  • These diacid fats can be polymerized or copolymerized into a polyanhydride or polyester and form polymers that are, in general, of a low melting point (below 100°C), soluble in common organic solvents, and pliable materials.
  • This invention is demonstrated by the synthesis and characterization of polymers based on ricinoleic acid. Natural hydroxy fatty acids, such as 12-hydroxy stearic acid and ricinoleic acid were reacted with cyclic anhydrides such as succinic or maleic anhydride, to provide diacid monomers suitable for anhydride and ester polymerization. These monomers are expected to degrade in vivo into their fatty acid and succinic acid counterparts since they are bound by a hydrolyzable ester bond.
  • the structures of the diacids are:
  • Diacids were synthesized based on Ricinoleic acid, 12-hydroxy oleic acid. The hydroxyl group was reacted with maleic anhydride to form ricinoleic acid maleate (I). Hydrogenolysis of this diacid forms the saturated derivative, 12-hydroxy stearic acid succinate (II). A third diacid monomer was synthesized from the reaction between 12-hydroxy stearic acid and maleic anhydride (III). These diacid monomers were incorporated into a polyanhydride or polyester and used as carriers for drugs.
  • the diacid fats used as examples in this application have the following general structures:
  • These monomers are diacid derivatives of monoglycerides, tartaric acid and fatty acids having an additional functional group with one or more natural molecules linked by an hydrolyzable bond which include; ester, amide, imide, orthoester, carbonate, urethane, urea or phosphate ester.
  • These diacid fats can be polymerized or copolymerized into a polyanhydride or polyester and form polymers that are, in general, of a low melting point (below 100°C), soluble in common organic solvents, and pliable materials that are useful in making biodegradable medical devices.
  • microspheres loaded with drugs can be prepared for the delivery of drugs in vivo and in vitro . Because these monomers hydrolyze in a biological environment to their original natural and safe counterparts, they are biocompatible and their elimination time after polymer degradation is within three months.
  • these diacid fats can be used as plasticizing components in plastics such as nylon, polyurethane as substitute for oligomerized fatty acids with the advantage of simple structure and ease of preparation.
  • the present invention allows the preparation of a drug release system which will deliver a pharmacologically effective amount of a drug.
  • the drug is held or entrapped in a polymer matrix.
  • the matrix essentially consists of repeating units of a monomeric diacid derivative comprising at least two fatty acids coupled by a hydrolytically or enzymatically degradable bond whereby said degradable bond in a biological environment degrades forming naturally occurring fatty acid products. As the bonds degrade the drug is released.
  • the bonds can be ester, amide, urethane, urea and carbonate bonds.
  • the drugs in solid form are melted or dispersed in the polymer to form a matrix, small molecules, as well as large molecules, such as peptides, proteins, and antibodies, can be delivered from the polymer matrix.
  • the duration of drug release is mostly affected by the hydrophobicity of the drug, drug loading, and polymer composition.
  • the present invention can be used as a biocompatible, biodegradable, implantable material essentially consisting of repeating units of a monomeric diacid derivative comprising at least two fatty acids coupled by a hydrolytically or enzymatically degradable bond whereby said degradable bond in a biological environment degrades forming naturally occurring fatty acid products.
  • the bonds can be ester, amide, urethane, urea and carbonate bonds.
  • the implantable material can be used to form dressings, sutures and the like that need to be implanted but not remain in the body. For example, they can be used as films for surgical adhesion prevention by placing the polymer film at the abraded area during surgery.
  • the method for synthesizing the biodegradable polymer containing hydrolyzable diacid fats requires the preparation of at least one highly pure prepolymer of monomeric diacid derivative comprising at least two fatty acids coupled by a hydrolytically or enzymatically degradable bond.
  • the prepolymer is then polymerized at a temperature and reaction time to form a polyanhydride or polyester of an appropriate molecular weight.
  • the polymerization is stopped when a molecular weight between 10,000 and 100,000 is obtained for the needed application or device.
  • a copolymer is formed from at least two highly pure prepolymers polymerized together as described above.
  • Typical and useful co-monomers are the aliphatic diacid such as adipic, subernic, dodedecane dicarboxylic acid.
  • Other co-monomers can be iso-phthalic acid, terephthalic acid, carboxphenoxypropane.
  • the copolymer of RAM with subernic acid gave a Mw of 32,000, the copolymer with iso-phthalic acid gave a Mw of 24,000.
  • the ricinoleic acid maleate of the present invention are useful as plasticizer for plastic modeling.
  • the following is the preferred method of preparing the formulation.
  • Low volatile polyester mixtures based on Ricinoleic acid maleate are useful as plasticizer for plastic modeling:
  • a mixture of adipic acid (58 grams), ricinoleic acid maleate (7 grams), propylene glycol (38 grams), and n-hexanol (13 grams) was heated at 140°C for five hours while water was distilled.
  • 0.05% of stannous octoate was added as catalyst and the reaction temperature was increased to 180°C and a vacuum of 0.1 mm Hg was applied for an additional three hours.
  • the resulting viscous polymer had a molecular weight of 700 as determined by gel permeation chromatography.
  • the resulting oligomer was mixed 30 weight percent with polyvinylchloride (PVC) to form a flexible sheet which had a loss of 0.5 weight percent in the volatility test at 105oC for three days compared to 1.2 to 2.5% with the phthalate plasticizer.
  • PVC polyvinylchloride
  • Other plasticizers were prepared similarly using hydroxy stearic acid succinate or hydroxy stearic acid maleate instead of ricinoleic acid maleate.
  • hydrophilic plasticizer Ricinoleic acid maleate was reacted with two equivalents of poly(ethylene glycol) MW ⁇ 2,000 in toluene with 1% H3PO4 (85% concentration) as catalyst. The reaction was continued for five hours at 110oC. Toluene was evaporated to dryness to form an oily material. The material was mixed in PVC to form a flexible sheet which had a loss of .6% at 105oC for three days volatility test.
  • ricinoleic acid Kerat 91% pure
  • maleic anhydride BDH, 99.5%
  • Sebacic acid Aldrich 99%
  • acetic anhydride toluene (dried by azeotropic distillation before use)
  • EtOH Abs.
  • CH 2 Cl 2 CH 2 Cl 2
  • CHCl 3 all Frutarom analytical grade
  • Kontron® Instruments Uvikon spectrophotometer model 930 Melting points were determined on an Electrothermal melting point apparatus. Melt transition temperatures and degree of crystallinity were determined by a Perkin Elmer DSC 7 differential scanning calorimeter, calibrated with zinc and indium standards. The heating rate was 20°C/min for all the polymers, under nitrogen atmosphere.
  • Molecular weights of the polymers and prepolymers were estimated on a GPC system composed of a spectra Physics P1000 pump, Applied Biosystems 759A Absorbance UV detector at 254 nm, Spectra Physics Data Jet injector, and a WINner/286 data analysis computer system. Samples were eluted in dichloromethane through a linear Styroget, 10 4 ⁇ pore size, at a flow rate of 1 ml/min and monitored at 254 nm. Molecular weight of polymers were determined relative to polystyrene standards (Polysciences, PA), with a molecular weight range of 400 to 1,500,000 using Maxima 840 computer program (Waters, MA).
  • Ricinoleic acid maleate A solution of ricinoleic acid (144 g, 0.48 mol) and maleic anhydride (61 g, 0.61 mol) in toluene (350 ml) was stirred at 80-90°C overnight. The excess of maleic anhydride which precipitated was removed by filtration. The solution was washed four times with distilled water, dried over MgSO 4 and evaporated to dryness to give 140.92 g (73%) of product as a dark orange oil.
  • prepolymers were prepared as previously described. 6 Briefly, sebacic acid prepolymer was prepared from the purified diacid monomer by refluxing it in excess acetic anhydride for 30 minutes and evaporating it to dryness. The hot clear viscous residue was dissolved in dichloromethane and the prepolymer was precipitated in a mixture of hexane/isopropyl ether (1:1). The solid was collected by filtration and dried by vacuum at room temperature.
  • SA sebacic acid
  • Prepolymers of the fatty acid ester based monomers were prepared as follows: Solutions of each monomer dissolved in acetic anhydride (120°C, 1:5 w/v) were stirred under reflux for 20 min.
  • the HSAS prepolymer gave a semisolid off-white product. Mw-1788 Mn-1382; IR 2900, 2850 1820, 1730 cm -1 ; 1 H-NMR 4.88 (quintet, 1H, methine), 2.77 (t, 2H, COOCO-CH 2 -CH 2 -COO-CH), 2.65 (t, 2H, COOCO-CH 2 -CH 2 -COO-CH), 2.44 (t, 2H, CH 2 -COOCO), 1.65 (m, 4H, CH 2 -CH-OCO-CH 2 ), 1.55 (quintet, 2H, CH 2 - CH 2 -COOCO) 1.25 (m, 22H, aliphatic methylenes), 0.85 (t, 3H, CH 2 -CH 3 ).
  • the prepolymers underwent melt polycondensation.
  • RAM prepolymer (10 g, 33 mmol) was placed in a KIMAX® glass tube with a side arm or a round bottomed flask and polymerized at 180°C under reduced pressure (0.1-0.5 mm Hg) .
  • the polymerization was complete after 90 minutes.
  • the by-products, acetic anhydride and acetic acid, were trapped in a liquid N 2 trap.
  • the homopolymers were viscous yellow oils.
  • Copolymers were prepared similarly by polymerizing a mixture of prepolymers at 180°C under reduced pressure.
  • RAM prepolymer (5 g, 17 mmol) was mixed with sebacic acid prepolymer (SA-diAc) (5 g, 21 mmol) and polymerized at 180oC under reduced pressure for 60-90 minutes depending on the amount being polymerized.
  • SA-diAc sebacic acid prepolymer
  • the crude polymers were dissolved in CH 2 Cl 2 (1.5 w/v) and filtered into stirring di-isopropyl ether (100-200 ml). The precipitate was separated by filtration, washed with di-isopropyl ether, and dried in the Rotavapor.
  • polyesters containing fatty diacid monomers Biodegradable polyesters were synthesized from the reaction between lactide, ricinoleic acid maleate, and propylene glycol in the molar ratio 8:1:1 and 1% stannous octoate as polymerization catalyst. The mixture of the monomers were polymerized at 100°C under nitrogen with constant stirring. After 24 hours, the temperature was raised to 140°C, the reaction was continued for another 24 hours and then a vacuum of 0.1 mm Hg was applied and the reaction was continued for another 8 hours. The viscous melt was solidified into a pliable tan mass. Polymers containing HSAM and HSAS monomers at various ratios were prepared similarly. The data analysis of these polymers is summarized in Table 4. All polymers were soluble in dichloromethane, chloroform, and tetrahydrofuran. IR spectra of the polymers showed esters peaks at 1720 nm.
  • poly(sebacic acid) ⁇ PSA ⁇ were implanted subcutaneously in four dorsal sites of male Sprague-Dawley rats (250-300 g). Six rats were used in the study and each rat was implanted randomly with four different specimens. All animal work was done under sterile conditions. The polymer specimens were dipped in 70% alcohol prior to insertion. The animals were sacrificed after 12 and 30 days post implantation, and the implantation sites were examined macroscopically and histologically. The polymer remnants were retrieved and analyzed.
  • Histopathology examination of tissue specimens from the area confined to the tissue in direct contact with the polymer device showed mild inflammation which was rated 2 in a scale from 1 to 5 where: 1 - resembles no irritation; 2 - slight inflammation; 3 - moderate; 4 - marked; and 5 - severe inflammation. No encapsulation was found with any of the samples.
  • the rat model has been considered highly predictable of human response for toxicant elimination 7 and biocompatibility. 8
  • Ciprofloxacin (5% by weight) was incorporated in rectangular tablets (3 ⁇ 5 ⁇ 8 mm in size and 200 mg weight) of poly(RAM-SA) 1: 1, P(HSAM:SA)1:1, P(HSAS:SA)1:1, P(FAD:SA)1:1 and poly(suberic anhydride) by the melt method.
  • In vitro drug release was determined in phosphate buffer pH 7.4 at 37°C.
  • Ciprofloxacin (5% weight) was incorporated in rectangular tablets (3 ⁇ 5 ⁇ 8 mm in size and 20 mg weight) of poly(RAM-SA) of various compositions by the melt method.
  • In vitro drug release was determined in phosphate buffer pH 7.4 at 37oC.
  • Ciprofloxacin concentration was determined by UV detection at 272 nm.
  • the results are shown in Figure 3.
  • the drug release rate was increased with the increase in the sebacic acid content in the polymer; however, a small difference in the release profile was found for the polymers composed of 40 to 80% sebacic acid (SA). Similar results were reported for the FAD-SA copolymers.
  • the preparation of dimer oleic acid or dimer erucic acid contains two steps.
  • oleic acid or erucic acid undergo a coupling reaction using clay as a catalyst.
  • the product is hydrogenated to saturate the double bonds in the product.
  • many by-products are formed, including trimers and tetramers, that are difficult to remove.
  • the FAD product contains cyclic and aromatic by-products which counts to about 30% of the Priipol 1004 and 1009 products which are the most available pure FAD products (based on producer, Unicema, information).
  • the product of the present invention contains only one component, the linear diacid monomer which is synthesized in a single esterification step (condensation reaction in general) which cannot form other oligomers or cyclic materials, but the linear diacid as described herein.

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Abstract

L'invention concerne un dérivé diacide monomère comportant au moins deux acides gras couplés par une liaison dégradable par voie hydrolytique ou enzymatique. Dans un milieu biologique, la liaison se dégrade et forme des produits acides gras d'origine naturelle, permettant ainsi l'élimination.
PCT/IB1995/000007 1995-01-18 1995-01-18 Biopolymeres derives de matieres grasses diacides hydrolysables WO1996022270A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/IB1995/000007 WO1996022270A1 (fr) 1995-01-18 1995-01-18 Biopolymeres derives de matieres grasses diacides hydrolysables
AU18209/95A AU1820995A (en) 1995-01-18 1995-01-18 Biopolymers derived from hydrolyzable diacid fats

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044232A3 (fr) * 2000-11-30 2003-01-23 Efrat Biopolymers Ltd Polyanhydrides
US7749539B2 (en) 2000-11-30 2010-07-06 Efrat Biopolymers Ltd. Polymeric formulations for drug delivery
US8143368B2 (en) 2004-12-23 2012-03-27 Massachusetts Institute Of Technology Disposable medical supplies from hydrolytically biodegradable plastics
US10774176B2 (en) 2014-12-18 2020-09-15 Dexcel Pharma Technologies Ltd. Alternating and semi-alternating poly(ester-anhydride) copolymers
US11141488B2 (en) 2017-03-29 2021-10-12 Dexcel Pharma Technologies Ltd. Compositions comprising biodegradable copolymers for prolonged local release of an antibiotic
WO2022029784A1 (fr) * 2020-08-07 2022-02-10 Gentagel Lr Ltd. Traitements antibiotiques et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5836268A (ja) * 1981-08-24 1983-03-03 帝人株式会社 合成繊維処理用油剤
JPS58117289A (ja) * 1981-12-30 1983-07-12 ライオン株式会社 油脂類の酸化防止方法
WO1991003512A1 (fr) * 1989-08-29 1991-03-21 Virginia Commonwealth University Composes cytoprotecteurs a base de constituents graisseux
US5019379A (en) * 1987-07-31 1991-05-28 Massachusetts Institute Of Technology Unsaturated polyanhydrides
EP0514201A1 (fr) * 1991-05-15 1992-11-19 Philip Morris Products Inc. Procédé de séparation à l'aide d'acides organiques et nouveaux acides organiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5836268A (ja) * 1981-08-24 1983-03-03 帝人株式会社 合成繊維処理用油剤
JPS58117289A (ja) * 1981-12-30 1983-07-12 ライオン株式会社 油脂類の酸化防止方法
US5019379A (en) * 1987-07-31 1991-05-28 Massachusetts Institute Of Technology Unsaturated polyanhydrides
WO1991003512A1 (fr) * 1989-08-29 1991-03-21 Virginia Commonwealth University Composes cytoprotecteurs a base de constituents graisseux
EP0514201A1 (fr) * 1991-05-15 1992-11-19 Philip Morris Products Inc. Procédé de séparation à l'aide d'acides organiques et nouveaux acides organiques

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044232A3 (fr) * 2000-11-30 2003-01-23 Efrat Biopolymers Ltd Polyanhydrides
US7297347B2 (en) 2000-11-30 2007-11-20 Efrat Biopolymers Ltd Polyanhydrides
US7749539B2 (en) 2000-11-30 2010-07-06 Efrat Biopolymers Ltd. Polymeric formulations for drug delivery
US8143368B2 (en) 2004-12-23 2012-03-27 Massachusetts Institute Of Technology Disposable medical supplies from hydrolytically biodegradable plastics
US10774176B2 (en) 2014-12-18 2020-09-15 Dexcel Pharma Technologies Ltd. Alternating and semi-alternating poly(ester-anhydride) copolymers
US11299583B2 (en) 2014-12-18 2022-04-12 Dexcel Pharma Technologies Ltd. Alternating and semi-alternating poly(ester-anhydride) copolymers
US11141488B2 (en) 2017-03-29 2021-10-12 Dexcel Pharma Technologies Ltd. Compositions comprising biodegradable copolymers for prolonged local release of an antibiotic
WO2022029784A1 (fr) * 2020-08-07 2022-02-10 Gentagel Lr Ltd. Traitements antibiotiques et leurs utilisations
WO2022029783A1 (fr) * 2020-08-07 2022-02-10 Polygene Ltd. Polyanhydrides et leurs procédés de fabrication

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