Continuous release pharmaceutical compositions formed by freeze drying acetic acid solutions of polylactide
First Claim
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1. A process for the manufacture of a pharmaceutical composition comprising (a) from 50% to 99.9% of a polyactide which is a polymer of lactic acid alone, a copolymer of lactic acid and glycolic acid wherein the ratio of glycolide to lactide units is from 0 up to 3:
- 1, a mixture of such polymers, a mixture of such copolymers, or a mixture of such polymers and copolymers, the lactic acid being either in racemic or in optionally active form, and such polylactide being either soluble in benzene and having an inherent viscosity of from 0.093 (1 g. per 100 ml. in chloroform) to 0.5 (1 g. per 100 ml. in benzene), or insoluble in benzene and having an inherent viscosity of from 0.093 (1 g. per 100 ml. in chloroform) to 4 (1 g. per 100 ml in chloroform or dioxan), and (b) from 0.001% to 50% of a pharmacologically active polypeptide which has a molecular weight at least that of tetragastrin, which is not significantly hydrolyzed under the conditions encountered within the composition during the period of use envisioned, and which contains four or more amino acid residues, said polypeptide being uniformly dispersed in said polylactide, which composition, when placed in an aqueous physiological-type environment absorbs water and exhibits two successive phases of release of polypeptide, the first phase being release by initial diffusion through aqueous polypeptide domains communicating with the exterior surface of the composition, and the second phase being release consequent upon degradation of the polylactide, characterized in that the diffusion phase and the degradation-induced phase overlap in time, said composition being further characterized by the fact that, when placed in an aqueous physiological type environment, water diffuses into the polylacide and is partitioned between polypeptide and polyactide to form aqueous polypeptide domains, said domains increasing with increasing absorption of water until the continuity of said domains reaches a sufficient level to communicate with the exterior surface of the composition, whereupon polypeptide starts to be released from said composition by diffusion through aqueous polypeptide channels formed from said domains, which second phase continues until substantially all of the remaining polypeptide is released, said process comprising;
dissolving said polylactide and said polypeptide in glacial acetic acid,freeze drying the resulting solution, andshaping the resulting freeze dried powder at an elevated temperature.
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Abstract
Pharmaceutical compositions, comprising a polylactide and a pharmacologically active, acid stable polypeptide, which when placed in an aqueous physiological equipment release the polypeptide at an approximately constant rate in an essentially monophasic manner, with a minimal, or no induction period prior to the release; polylactides suitable for use in said compositions; and a method for the manufacture of such polylactides.
106 Citations
1 Claim
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1. A process for the manufacture of a pharmaceutical composition comprising (a) from 50% to 99.9% of a polyactide which is a polymer of lactic acid alone, a copolymer of lactic acid and glycolic acid wherein the ratio of glycolide to lactide units is from 0 up to 3:
- 1, a mixture of such polymers, a mixture of such copolymers, or a mixture of such polymers and copolymers, the lactic acid being either in racemic or in optionally active form, and such polylactide being either soluble in benzene and having an inherent viscosity of from 0.093 (1 g. per 100 ml. in chloroform) to 0.5 (1 g. per 100 ml. in benzene), or insoluble in benzene and having an inherent viscosity of from 0.093 (1 g. per 100 ml. in chloroform) to 4 (1 g. per 100 ml in chloroform or dioxan), and (b) from 0.001% to 50% of a pharmacologically active polypeptide which has a molecular weight at least that of tetragastrin, which is not significantly hydrolyzed under the conditions encountered within the composition during the period of use envisioned, and which contains four or more amino acid residues, said polypeptide being uniformly dispersed in said polylactide, which composition, when placed in an aqueous physiological-type environment absorbs water and exhibits two successive phases of release of polypeptide, the first phase being release by initial diffusion through aqueous polypeptide domains communicating with the exterior surface of the composition, and the second phase being release consequent upon degradation of the polylactide, characterized in that the diffusion phase and the degradation-induced phase overlap in time, said composition being further characterized by the fact that, when placed in an aqueous physiological type environment, water diffuses into the polylacide and is partitioned between polypeptide and polyactide to form aqueous polypeptide domains, said domains increasing with increasing absorption of water until the continuity of said domains reaches a sufficient level to communicate with the exterior surface of the composition, whereupon polypeptide starts to be released from said composition by diffusion through aqueous polypeptide channels formed from said domains, which second phase continues until substantially all of the remaining polypeptide is released, said process comprising;
dissolving said polylactide and said polypeptide in glacial acetic acid, freeze drying the resulting solution, and shaping the resulting freeze dried powder at an elevated temperature.
- 1, a mixture of such polymers, a mixture of such copolymers, or a mixture of such polymers and copolymers, the lactic acid being either in racemic or in optionally active form, and such polylactide being either soluble in benzene and having an inherent viscosity of from 0.093 (1 g. per 100 ml. in chloroform) to 0.5 (1 g. per 100 ml. in benzene), or insoluble in benzene and having an inherent viscosity of from 0.093 (1 g. per 100 ml. in chloroform) to 4 (1 g. per 100 ml in chloroform or dioxan), and (b) from 0.001% to 50% of a pharmacologically active polypeptide which has a molecular weight at least that of tetragastrin, which is not significantly hydrolyzed under the conditions encountered within the composition during the period of use envisioned, and which contains four or more amino acid residues, said polypeptide being uniformly dispersed in said polylactide, which composition, when placed in an aqueous physiological-type environment absorbs water and exhibits two successive phases of release of polypeptide, the first phase being release by initial diffusion through aqueous polypeptide domains communicating with the exterior surface of the composition, and the second phase being release consequent upon degradation of the polylactide, characterized in that the diffusion phase and the degradation-induced phase overlap in time, said composition being further characterized by the fact that, when placed in an aqueous physiological type environment, water diffuses into the polylacide and is partitioned between polypeptide and polyactide to form aqueous polypeptide domains, said domains increasing with increasing absorption of water until the continuity of said domains reaches a sufficient level to communicate with the exterior surface of the composition, whereupon polypeptide starts to be released from said composition by diffusion through aqueous polypeptide channels formed from said domains, which second phase continues until substantially all of the remaining polypeptide is released, said process comprising;
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Current AssigneeAstrazeneca UK Limited (Astrazeneca PLC)
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Original AssigneeImperial Chemical Industries PLC (IMPERIAL CHEMICAL INDUSTRIES)
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InventorsHutchinson, Francis G.
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Primary Examiner(s)Page, Thurman
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Assistant Examiner(s)Kulkoski, Peter F.
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Application NumberUS06/861,839Time in Patent Office1,786 DaysField of Search424/22, 424/19, 424/423, 424/468, 424/78US Class Current514/7.6CPC Class CodesA61K 9/0024 Solid, semi-solid or solidi...A61K 9/1647 Polyesters, e.g. poly(lacti...A61K 9/204 Polyesters, e.g. poly(lacti...A61K 9/7007 Drug-containing films, memb...C07D 319/12 not condensed with other ringsC08G 63/08 Lactones or lactidesY10S 930/28 Bound to a nonpeptide drug,...
