Lactone bearing absorbable polymers
View Patent ↗The present invention pertains to biodegradable polymers comprising a non-polymerizable lactone, biodegradable compositions comprising the polymer and a therapeutic agent, the use of the compositions for the sustained release of therapeutic agents, wherein the therapeutic agent is reversibly immobilized on the polymer matrix using ionic complexation between the latent carboxylic groups present on the lactone bearing polymer matrix and a cationic group on the therapeutic agent.
1. A complex comprising a polymer bearing non-polymerizable lactone ring wherein the polymer is selected from the group consisting of polyester, polyorthoester, polyphosphoester, polycarbonates, polyanhydrides and polyphosphazenes and copolymers and blends thereof, ionically complexed with a therapeutic agent containing at least one cationic group.
2. A complex comprising a polymer bearing non-polymerizable lactone ring wherein the polymer is a polyester selected from the group consisting of 1-lactide, dl-lactide, glycolide, and polyethylene glycol and the non-polymerizable lactone ring is selected from the group consisting of hydroxybutyrolactone, erythrynolactone, isopropylidene ribonolactone, isocitric acid lactone, mannarolactone, sacharrodilactone and glucarodilactone, wherein the non-polymerizable lactone ring has been ring opened to its corresponding hydroxycarboxylic acid alkali metal salt, wherein the hydroxycarboxylic acid alkali metal salt is within the polymer chain, ionically complexed with a therapeutic agent containing at least one cationic group.
3. A complex according to claim 2 , wherein the therapeutic agent is selected from the group consisting of LHRH, somatostatin, bombesin/GRP, calcitonin, bradykinins, galanin, MSH, GRF, amylin, tachykinin, secretin, PTH, CGRP, neuromedin, pTHRP, glucagon, neurotensin, ACTH, PYY, PYY, and TSH, or an analogue or fragment thereof.
4. A complex according to claim 3 , wherein the therapeutic agent is a somatostatin analogue selected from the group consisting of H-β-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, where the two Cys are bonded by a disulfide bond, N-hydroxyethylpiperazinyl-acetyl-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2 where the two Cys are bonded by a disulfide bond or N-hydroxyethylpiperazinyl-ethylsulfonyl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 where the two Cys are bonded by a disulfide bond.
5. A complex according to claim 3 , wherein the therapeutic agent is an LHRH analogue of the formula ρ-Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH 2 .
6. A sustained release composition comprising a complex according to claim 4 wherein the composition is in the form of microparticles, microspheres or rods.
7. A sustained release composition comprising a complex according to claim 5 wherein the composition is in the form of microparticles, microspheres or rods.
8. A pharmaceutical composition comprising a sustained release composition according to claim 6 having an effective amount of the therapeutic agent and a pharmaceutically-acceptable carrier.
9. A pharmaceutical composition comprising a sustained release composition according to claim 7 having an effective amount of the therapeutic agent and a pharmaceutically-acceptable carrier.
10. A method of treating or preventing a disease or a condition, which comprises administering a pharmaceutical composition according to claim 8 to a patient in need thereof, wherein said disease or condition is a disease or condition that can be treated by the therapeutic agent in the pharmaceutical composition.
11. A method of treating or preventing a disease or a condition, which comprises administering a pharmaceutical composition according to claim 9 to a patient in need thereof, wherein said disease or condition is a disease of condition that can be treated by the therapeutic agent in the pharmaceutical composition.
12. A method of administering a pharmaceutical composition according to claim 8 to a recipient, wherein said pharmaceutical composition is administered orally, through the nasal passage, through the pulmonary passage or parenterally.
13. A method of administering a pharmaceutical composition according to claim 9 to a recipient, wherein said pharmaceutical composition is administered orally, through the nasal passage, through the pulmonary passage or parenterally.
14. A complex according to claim 1 , wherein said non-polymerizable lactone ring is a five-member lactone ring.
15. A complex according to claim 1 , wherein said non-polymerizable lactone ring is a six-member lactone ring.
16. A complex according to claim 2 , wherein said non-polymerizable lactone ring is a five-member lactone ring.
17. A complex according to claim 2 , wherein said non-polymerizable lactone ring is a six-member lactone ring.