Cyclodextrin-based polymers for therapeutics delivery
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-047/48
C08B-037/16
C08F-224/00
C08G-063/91
출원번호
US-0769076
(2013-02-15)
등록번호
US-8603454
(2013-12-10)
발명자
/ 주소
Cheng, Jianjun
Davis, Mark E.
Khin, Kay T.
출원인 / 주소
Cerulean Pharma Inc.
대리인 / 주소
Lando & Anastasi LLP
인용정보
피인용 횟수 :
0인용 특허 :
123
초록▼
The present invention relates to novel compositions of therapeutic cyclodextrin containing polymeric compounds designed as a carrier for small molecule therapeutics delivery and pharmaceutical compositions thereof. These cyclodextrin-containing polymers improve drug stability and solubility, and red
The present invention relates to novel compositions of therapeutic cyclodextrin containing polymeric compounds designed as a carrier for small molecule therapeutics delivery and pharmaceutical compositions thereof. These cyclodextrin-containing polymers improve drug stability and solubility, and reduce toxicity of the small molecule therapeutic when used in vivo. Furthermore, by selecting from a variety of linker groups and targeting ligands the polymers present methods for controlled delivery of the therapeutic agents. The invention also relates to methods of treating subjects with the therapeutic compositions described herein. The invention further relates to methods for conducting pharmaceutical business comprising manufacturing, licensing, or distributing kits containing or relating to the polymeric compounds described herein.
대표청구항▼
1. A pharmaceutical composition comprising a sugar and a water soluble linear polymer conjugate, wherein the water soluble linear polymer conjugate comprises: a linear polymer comprising cyclodextrin moieties and comonomers which do not contain cyclodextrin moieties (comonomers); andtherapeutic agen
1. A pharmaceutical composition comprising a sugar and a water soluble linear polymer conjugate, wherein the water soluble linear polymer conjugate comprises: a linear polymer comprising cyclodextrin moieties and comonomers which do not contain cyclodextrin moieties (comonomers); andtherapeutic agents covalently linked to the linear polymer, wherein the therapeutic agents are cleaved from the water soluble linear polymer conjugate under biological conditions to release the therapeutic agents;wherein the water soluble linear polymer conjugate comprises at least four cyclodextrin moieties and at least four comonomers. 2. The pharmaceutical composition of claim 1, wherein each of the at least four cyclodextrin moieties and each of the at least four comonomers alternate in the water soluble linear polymer conjugate. 3. The pharmaceutical composition of claim 1, wherein the therapeutic agents are attached via linkers. 4. The pharmaceutical composition of claim 1, wherein the comonomer comprises residues of at least two functional groups through which reaction and linkage of the cyclodextrin moieties was achieved. 5. The pharmaceutical composition of claim 4, wherein the at least two functional groups, which may be the same or different, or terminal or internal, of each comonomer comprise an amino acid, imidazole, hydroxyl, thio, acyl halide, —HC═CH—, —C≡C— group, or derivative thereof. 6. The pharmaceutical composition of claim 1, wherein the cyclodextrin moiety comprises an alpha, beta, or gamma cyclodextrin moiety. 7. The pharmaceutical composition of claim 1, wherein the therapeutic agents are at least 5% by weight of the water soluble linear polymer conjugate. 8. The pharmaceutical composition of claim 1, wherein the comonomer comprises a polyethylene glycol and the cyclodextrin moiety comprises beta-cyclodextrin. 9. The pharmaceutical composition of claim 1, wherein the therapeutic agent is an anti-neoplastic agent. 10. The pharmaceutical composition of claim 1, wherein the therapeutic agent is a topoisomerase I inhibitor. 11. The pharmaceutical composition of claim 1, wherein the therapeutic agent is a camptothecin analog. 12. The pharmaceutical composition of claim 11, wherein the camptothecin analog is topotecan. 13. The pharmaceutical composition of claim 11, wherein the camptothecin analog is irinotecan. 14. The pharmaceutical composition of claim 1, wherein the therapeutic agent is a peptide. 15. The pharmaceutical composition of claim 1, wherein the therapeutic agent is an anti-inflammatory agent. 16. The pharmaceutical composition of claim 1, wherein administration of the composition to a patient results in release of the therapeutic agent over a period of at least 6 hours. 17. The pharmaceutical composition of claim 1, wherein administration of the composition to a patient results in release of the therapeutic agent over a period of 6 hours to a month. 18. The pharmaceutical composition of claim 1, wherein, upon administration of the composition to a patient the rate of therapeutic agent release is dependent primarily upon the rate of hydrolysis as opposed to enzymatic cleavage. 19. The pharmaceutical composition of claim 1, wherein the water soluble linear polymer conjugate has a molecular weight of 10,000-500,000 amu. 20. The pharmaceutical composition of claim 1, wherein the cyclodextrin moieties make up at least about 10% of the linear polymer by weight. 21. The pharmaceutical composition of claim 1, wherein the comonomers comprise a group selected from the following: an alkylene chain,polysuccinic anhydride,poly-L-glutamic acid,poly(ethyleneimine),an oligosaccharide, oran amino acid chain. 22. The pharmaceutical composition of claim 1, wherein the comonomers comprise polyethylene glycol. 23. The pharmaceutical composition of claim 1, wherein the comonomers comprise polyglycolic acid or polylactic acid chain. 24. The pharmaceutical composition of claim 1, wherein the comonomers comprise a hydrocarbylene group wherein one or more methylene groups is optionally replaced by a group Y (provided that none of the Y groups are adjacent to each other), wherein each Y, independently for each occurrence, is selected from, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or —O—, C(═X) (wherein X is NR1, O or S), —OC(O)—, —C(═O)O, —NR1—, —NR1CO—, —C(O)NR1—, —S(O)n— (wherein n is 0, 1, or 2), —OC(O)—NR1, —NR1—C(O)—NR1—, —NR11-C(NR1)—NR1—, and —B(OR1)—; and R1, independently for each occurrence, represents H or a lower alkyl. 25. A pharmaceutical preparation comprising a pharmaceutical excipient and the pharmaceutical composition of claim 1. 26. A pharmaceutical preparation comprising a pharmaceutical excipient and the pharmaceutical composition of claim 8. 27. A pharmaceutical preparation comprising a pharmaceutical excipient and the pharmaceutical composition of claim 9. 28. The pharmaceutical composition of claim 1, wherein the sugar is mannitol. 29. The pharmaceutical composition of claim 8, wherein the sugar is mannitol. 30. The pharmaceutical composition of claim 9, wherein the sugar is mannitol. 31. The pharmaceutical composition of claim 2, wherein the sugar is mannitol. 32. The pharmaceutical composition of claim 8, wherein each of the at least four cyclodextrin moieties and each of the at least four comonomers alternate in the water soluble linear polymer conjugate. 33. The pharmaceutical composition of claim 32, wherein the sugar is mannitol. 34. The pharmaceutical composition of claim 9, wherein each of the at least four cyclodextrin moieties and each of the at least four comonomers alternate in the water soluble linear polymer conjugate. 35. The pharmaceutical composition of claim 34, wherein the sugar is mannitol. 36. The pharmaceutical composition of claim 10, wherein the sugar is mannitol. 37. The pharmaceutical composition of claim 10, wherein each of the at least four cyclodextrin moieties and each of the at least four comonomers alternate in the water soluble linear polymer conjugate. 38. The pharmaceutical composition of claim 37, wherein the sugar is mannitol. 39. The pharmaceutical composition of claim 22, wherein the sugar is mannitol. 40. The pharmaceutical composition of claim 22, wherein each of the at least four cyclodextrin moieties and each of the at least four comonomers alternate in the water soluble linear polymer conjugate. 41. The pharmaceutical composition of claim 40, wherein the sugar is mannitol. 42. The pharmaceutical composition of claim 8, wherein the therapeutic agent is an anti-neoplastic agent. 43. The pharmaceutical composition of claim 32, wherein the therapeutic agent is an anti-neoplastic agent. 44. The pharmaceutical composition of claim 8, wherein the therapeutic agent is an anti-inflammatory agent. 45. The pharmaceutical composition of claim 32, wherein the therapeutic agent is an anti-inflammatory agent. 46. The pharmaceutical composition of claim 22, wherein the therapeutic agent is an anti-neoplastic agent. 47. The pharmaceutical composition of claim 40, wherein the therapeutic agent is an anti-neoplastic agent. 48. The pharmaceutical composition of claim 22, wherein the therapeutic agent is an anti-inflammatory agent. 49. The pharmaceutical composition of claim 40, wherein the therapeutic agent is an anti-inflammatory agent. 50. The pharmaceutical composition of claim 42, wherein the sugar is mannitol. 51. The pharmaceutical composition of claim 43, wherein the sugar is mannitol. 52. The pharmaceutical composition of claim 46, wherein the sugar is mannitol. 53. The pharmaceutical composition of claim 47, wherein the sugar is mannitol.
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