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Flowable Composition Comprising Biocompatible Oligomer-Polymer Compositions

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Flowable Composition Comprising Biocompatible Oligomer-Polymer Compositions (19) TZZ ___T (11) EP 2 291 174 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) C08L 67/04 (2006.01) 28.01.2015 Bulletin 2015/05 (86) International application number: (21) Application number: 09758745.5 PCT/US2009/003363 (22) Date of filing: 03.06.2009 (87) International publication number: WO 2009/148581 (10.12.2009 Gazette 2009/50) (54) FLOWABLE COMPOSITION COMPRISING BIOCOMPATIBLE OLIGOMER-POLYMER COMPOSITIONS FLIESSFÄHIGE ZUSAMMENSETZUNG ENTHALTEND BIOKOMPATIBLE OLIGOMER-POLYMER- ZUSAMMENSETZUNGEN COMPOSITIONS FLUIDES COMPRENANT COMPOSITIONS OLIGOMÈRES-POLYMÈRES BIOCOMPATIBLES (84) Designated Contracting States: (72) Inventor: NORTON, Richard, L. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Ft. Collins HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL CO 80524 (US) PT RO SE SI SK TR (74) Representative: Peters, Hajo et al (30) Priority: 03.06.2008 US 58458 P ZACCO GmbH Bayerstrasse 83 (43) Date of publication of application: 80335 München (DE) 09.03.2011 Bulletin 2011/10 (56) References cited: (73) Proprietor: Tolmar Therapeutics, Inc. EP-A- 1 586 309 US-A- 2 371 281 Fort Collins, CO 80526 (US) US-B1- 6 815 469 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 291 174 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 291 174 B1 Description FIELD OF THE INVENTION 5 [0001] The field of invention is biocompatible oligomer-polymer compositions for thein situ formation of implants, wherein the implants release a bioactive agent, a metabolite, or a prodrug thereof, at a controlled rate. BACKGROUND OF THE INVENTION 10 [0002] Compositions adapted for use in controlled release delivery systems, such as biodegradable and bioerodible implants, are well known. Such controlled release systems are in general advantageous as they provide for the controlled and sustained release of medications, often directly at or near the desired site of action, over the period of days, weeks or even months. [0003] Controlled release systems include polymer matrices that are known to be broken down in the body by various 15 endogenous substances such as enzymes and water, such as polyesters including poly-lactide, poly-glycolide, polyc- aprolactone, and copolymers thereof, as well as capped versions using C1 to C10 mono-alkanols and chain-extended versions using C2 to C30 diols and polyols. Especially preferred are the "PLG copolymers" prepared from glycolide (1,4- dioxan-2,5-dione, glycolic acid cyclic dimer lactone) and lactide (3,6-dimethyl-1,4-dioxan-2,5-dione, lactic acid cyclic dimer lactone) as well as the capped and chain extended versions thereof. These copolymer materials are particularly 20 favored for this application due to their facile breakdown in vivo by water or enzymes in the body to non-toxic materials, and their favorable properties in temporally controlling the release of biologically active agents ("bioactive agents") that may be contained within a mass of the polymer. [0004] These controlled release systems are typically prepared with a biocompatible polar aprotic organic liquid, injected into the body of a patient, and the biocompatible polar aprotic organic liquid dissipates to produce a solid or gel 25 biodegradable implant. However, some biocompatible polar aprotic organic liquids may have unfavorable toxicological properties and/or cause irritation to the patient. [0005] US 6,815,469 discloses biocompatible endcapped oligomeric liquids possessing free carboxyl and free hydroxyl groups. EP 1 586 309 is directed to flowable delivery formulations. [0006] There is a continuing need to develop liquids, which have favorable toxicological properties and do not cause 30 irritation to the patient, for the in situ formation of implants. SUMMARY OF THE INVENTION [0007] The present invention provides biocompatible oligomer-polymer compositions for the in situ formation of im- 35 plants, wherein the implants release a bioactive agent, a metabolite, or a prodrug thereof, at a controlled rate. These compositions include biocompatible end-capped oligomeric liquids that are useful for forming implants in situ because they have very good biocompatibility and low toxicity. These biocompatible end-capped oligomeric liquids are effective for dissolving a specific polymer, have some degree of water solubility, and can be custom tailored to dissolve a particular active pharmaceutical ingredient. By being end-capped oligomers of, for example, lactide, glycolide, lactic acid, and/or 40 glycolic acid, these biocompatible oligomeric liquids are readily degraded by the body through hydrolysis to yield com- pounds with known and acceptable toxicological characteristics. [0008] The biocompatible end-capped oligomeric liquids prepared herein may be used to prepare two syringe ATRIGEL® formulations and are especially advantageous in preparing single syringe ATRIGEL ® formulations because they are not reactive with the polymer and/or the drug and will inhibit water from entering the ATRIGEL® formulation. 45 The biocompatible end-capped oligomeric liquids have similar chemical structures as the implant polymer and will react with any water that may be present in the formulation and thereby increase the storage life of the ATRIGEL® product. Further, unlike the biocompatible end-capped oligomeric liquids disclosed by Voelkel et al. in U.S. Patent No. 6,815,469, which possess free carboxyl and free hydroxyl groups that may react with the implant polymer, the biocompatible end- capped oligomeric liquids described herein are more hydrophobic and offer better solubility and stability for the implant 50 polymer. [0009] In the invention, a flowable composition is provided including: (a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid; (b) a biocompatible end-capped oligomeric liquid; and (c) a bioactive agent, a metabolite, or a prodrug thereof. The biocompatible end-capped oligomeric liquid is of the formula I, II, III, IV, or V: 55 2 EP 2 291 174 B1 5 10 15 20 25 30 35 40 45 50 55 3 EP 2 291 174 B1 5 10 15 20 wherein: each R1 is independently (C1-C12)alkyl, or (C1-C12)alkylenecarboxylic(C1-C12)alkylester; each R2 is independently (C1-C12)alkyl, carbonyl(C1-C12)alkyl, or carboxylic(C1-C12)alkylester; 25 each R3 is independently (C1-C12)alkylene; R4 is (C1-C12)alkylene, carbonyl(C1-C12)alkylcarbonyl, or (C3-C12)cycloalkadiyl; R5 is (C1-C12)alkatriyl or (C3-C12)cycloalkatriyl; R6 is (C1-C12)alkylene, (C1-C12)alkyne, (C3-C12)cycloalkadiyl, (C1-C12)alkatriyl, or (C3-C12)cycloalkatriyl; R7 is (C1-C12)alkylene or (C1-C12)alkatriyl, 30 X is absent or oxygen; W is absent, carbonyl, or carbonyloxy; and any alkyl or alkylene of R 1, R2, R3, R4, R5, R6 and R7 can optionally be substituted on carbon with one or more oxo, hydroxy, halogen, nitro, cyano, (C1-C12)alkyl, (C1-C6)alkoxy, trifluoromethyl, and optionally interrupted on carbon with one or more oxy, imino, or thio, and is optionally partially unsaturated; and 35 each a, b, c, and d is independently 0, 1, 2, 3, 4, or 5. [0010] The biocompatible end-capped oligomeric liquid is a liquid at ambient temperature. Accordingly, any particular species set out by the foregoing formulas that is not a liquid at or near ambient temperature is excluded. It is believed that all species set out by the foregoing formulas are liquids at ambient temperature or near ambient temperature. 40 [0011] In one embodiment, each1 Ris independently -(CH2)mCH3, -CH2CH2(OCH2CH2)mO(CH2)nCH3, -CH2CH2(OCH2CH2)mOCOCH3, 2-CHCOOY, -CH(CH3)COOY, -CH2CH2COOY, -CH2CH2CH2COOY, -CH2CH2CH2CH2COOY, -CH2CH2CH2CH2CH2COOY,-CH2CH(CH3)Y, or -(cycloC6H11), wherein each m and n is in- dependently 0, 1, 2, 3, 4, 5, 6, or 7; each R2 is independently , -CH 3, -CH2CH3, -(CH2)oCH3, -CH2CH2(OCH2CH2)oOCH3, -CH2CH2(OCH2CH2)oOCH2CH3, 45 -CH2CH2(OCH2CH2)oOCOCH3, -COCH3, -CO(CH2)oCH3,-COO(CH2)oCH3, or -CO(OCH2CH2)oCH3, wherein o is 0, 1, 2, 3, 4, 5, 6, or 7; each R3 is independently -(CH2)p-, -CH(CH3)-,-(CH2CH2O)pCH2-, -(CH(CH3)CH2)-, or -(CH(CH2CH3)CH2)-, wherein p is 0, 1, 2, 3, 4, 5, 6, or 7, R4 is 2-(CH)q-, -CO(CH2)qCO-, -(CH2CH2O)qCH2CH2-,- CH2CH2CH2CH2CH2CH2-, -(CH2)qCH(CH3)-, 50 -((CH2)qO)q,-CH2CH(Y)CH2-, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl or cyclohexane-1,4-diyl, wherein q is 1, 2, 3, 4, 5, 6, or 7; R5 is (-CH2)2CH-, (-CH2)3CCH3, (-CH2)3CCH2CH3, or 1,2,6-hexanetriyl; R6 is -CH=CH-, -(CH2)r-, -O(CH2CH2O)r- wherein r is 1, 2, 3, 4, 5, 6, or 7; R7 is (-CH2)2CH-, (-CH2)2COH-, (-CH2)(-CHOH)CH-, (-CH2)(-CO)CH-, or (-CH2)(-CH=)C-; 55 X is absent or oxygen; W is absent, -CO-, or -COO-; and Y is -CH3, -C2H5, -C3H7, or -C4H9. [0012] In one embodiment, each 1 Ris independently -CH3, -CH2CH3,-(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, 4 EP 2 291 174 B1 -(CH2)5CH3, -(CH2)6CH3,-(CH2)7CH3, -CH2CH2(OCH2CH2)2OCH3, -CH2CH2(OCH2CH2)2OCH2CH3, or -CH2CH2(OCH2CH2)2OCOCH3; each R2 is independently -CH 3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -CH2CH2(OCH2CH2)2OCH3, -CH2CH2(OCH2CH2)2OCH2CH3, or -CH2CH2(OCH2CH2)2OCOCH3; 5 each R3 is independently -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-,-(CH2)5-, -(CH2)6-, -(CH2)7-, -CH(CH3)-, -(CH(CH3)CH2)-, -(CH(CH2CH3)CH2)-, -(CH2CH2OCH2)-; R4 is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -COCH2CO-,-CO(CH2)2CO-, -CO(CH2)3CO-, -CO(CH2)4CO-, -CO(CH2)5CO-,-CO(CH2)6CO-, -CO(CH2)7CO-, -CO(CH2)8CO-, -(CH2CH2O)2CH2CH2-, -(CH2CH2O)3CH2CH2- -(CH2CH2O)4CH2CH2- -(CH2CH2O)5CH2CH2-, -(CH2CH2O)6CH2CH2-, or -CH2CH2CH2CH2CH2CH2-; 10 R5 is (-CH2)2CH-; R6 is -CH=CH-, -(CH2)-, -(CH2)2-, -(CH2)3-, -(-CH2)4-, -(CH2)5-,-(CH2)6-, -(CH2)7-, -(CH2)8-, -O(CH2CH2O)-, -O(CH2CH2O)2-,-O(CH2CH2O)3-, -O(CH2CH2O)4-, -O(CH2CH2O)5-, or -O(CH2CH2O)6-; R7 is (-CH2)2CH-, (-CH2)2COH-, (-CH2)(-CHOH)CH-, (-CH2)(-CO)CH-, or (-CH2)(-CH=)C-; X is absent or oxygen; 15 W is absent, -CO-, or -COO-; and each a, b, c, and d is independently 0, 1, 2, 3, or 4.
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