Continuous release pharmaceutical compositions
First Claim
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1. A pharmaceutical composition comprising (a) from 50% to 99.999% of a polylactide 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 optically active form, and such polyactide 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 about the same as the molecular weight of tetragastrin, which is not significantly hydrolized 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 matrix and is partitioned between polypeptide and polylactide to form aqueous polypeptide domains, the said domains increasing with increasing absorption of water until the continuity of the 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
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Abstract
Pharmaceutical compositions, comprising a polylactide and a pharmacologically active, acid stable polypeptide, which when placed in an aqueous physiological environment 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.
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Citations
17 Claims
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1. A pharmaceutical composition comprising (a) from 50% to 99.999% of a polylactide 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 optically active form, and such polyactide 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 about the same as the molecular weight of tetragastrin, which is not significantly hydrolized 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 matrix and is partitioned between polypeptide and polylactide to form aqueous polypeptide domains, the said domains increasing with increasing absorption of water until the continuity of the 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
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)
Specification