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-0769052
(2013-02-15)
등록번호
US-8580244
(2013-11-12)
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 :
121
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); andcamptothecin moi
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); andcamptothecin moieties covalently linked to the linear polymer, wherein the camptothecin moieties are cleaved from the water soluble linear polymer conjugate under biological conditions to release the camptothecin moieties;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 the comonomers comprise polyethylene glycol. 3. The pharmaceutical composition of claim 2, wherein the polyethylene glycol has a molecular weight of 0.2 kDa to 5 kD. 4. The pharmaceutical composition of claim 1, wherein each of the at least four cyclodextrin moieties alternates with each of the at least four comonomers in the water soluble linear polymer conjugate. 5. The pharmaceutical composition of claim 1, wherein the camptothecin moieties are at least 5% by weight of the water soluble linear polymer conjugate. 6. The pharmaceutical composition of claim 1, wherein administration of the composition to a patient results in release of the camptothecin moieties over a period of at least 6 hours. 7. The pharmaceutical composition of claim 1, wherein administration of the composition to a patient results in release of the camptothecin moieties over a period of 6 hours to a month. 8. The pharmaceutical composition of claim 1, wherein, upon administration of the composition to a patient, the rate of the camptothecin moieties release is dependent primarily upon the rate of hydrolysis as opposed to enzymatic cleavage. 9. The pharmaceutical composition of claim 1, wherein the water soluble linear polymer conjugate has a molecular weight of 10,000-500,000 amu. 10. The pharmaceutical composition of claim 1, wherein the water soluble linear polymer conjugate has a molecular weight of 30,000-520,000 amu. 11. The pharmaceutical composition of claim 1, wherein the water soluble linear polymer conjugate has a molecular weight of 70,000-150,000 amu. 12. The pharmaceutical composition of claim 1, wherein the cyclodextrin moieties are at least about 10% by weight of the linear polymer. 13. The pharmaceutical composition of claim 1, wherein the cyclodextrin moieties are at least about 20% by weight of the linear polymer. 14. The pharmaceutical composition of claim 1, wherein the cyclodextrin moieties are at least about 30% by weight of the linear polymer. 15. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable carrier. 16. A pharmaceutical composition comprising a sugar and a water soluble linear polymer conjugate comprising: a linear polymer comprising cyclodextrin moieties and comonomers comprising a polyethylene glycol; andcamptothecin moieties covalently linked to the linear polymer, wherein the camptothecin moieties are cleaved from the water soluble linear polymer conjugate under biological conditions to release the camptothecin moieties;wherein the water soluble linear polymer conjugate comprises at least four cyclodextrin moieties and at least four comonomers. 17. The pharmaceutical composition of claim 16, further comprising a pharmaceutically acceptable carrier. 18. The pharmaceutical composition of claim 16, wherein the water soluble linear polymer conjugate has a molecular weight of 30,000-520,000 amu. 19. The pharmaceutical composition of claim 16, wherein the water soluble linear polymer conjugate has a molecular weight of 70,000-150,000 amu. 20. The pharmaceutical composition of claim 16, wherein the camptothecin moieties are at least 5% by weight of the water soluble linear polymer conjugate. 21. The pharmaceutical composition of claim 16, wherein administration of the composition to a patient results in release of the camptothecin moieties over a period of at least 6 hours. 22. A pharmaceutical composition comprising a sugar and a water soluble linear polymer conjugate comprising: a linear polymer comprising cyclodextrin moieties and comonomers which do not contain cyclodextrin moieties (comonomers); and camptothecin moieties covalently linked to the linear polymer, wherein the camptothecin moieties are cleaved from the water soluble linear polymer conjugate under biological conditions to release the camptothecin moieties;wherein the water soluble linear polymer conjugate comprises at least four cyclodextrin moieties and at least four comonomers and has a molecular weight of 30,000-520,000 amu. 23. The pharmaceutical composition of claim 22, further comprising a pharmaceutically acceptable carrier. 24. The pharmaceutical composition of claim 22, wherein the camptothecin moieties are at least 5% by weight of the water soluble linear polymer conjugate. 25. The pharmaceutical composition of claim 22, wherein administration of the composition to a patient results in release of the camptothecin moieties over a period of at least 6 hours. 26. The pharmaceutical composition of claim 22, wherein the water soluble linear polymer conjugate has a molecular weight of 70,000-150,000 amu. 27. The pharmaceutical composition of claim 22, wherein the comonomers comprise polyethylene glycol. 28. The pharmaceutical composition of claim 1, wherein the sugar is mannitol. 29. The pharmaceutical composition of claim 16, wherein the sugar is mannitol. 30. The pharmaceutical composition of claim 22, wherein the sugar is mannitol. 31. The pharmaceutical composition of claim 3, wherein the sugar is mannitol. 32. The pharmaceutical composition of claim 3, wherein the sugar is lactose, glucose, sucrose or sorbitol. 33. The pharmaceutical composition of claim 1, wherein the cyclodextrin moieties are alpha, beta, or gamma cyclodextrin moieties. 34. The pharmaceutical composition of claim 1, wherein the cyclodextrin moieties are beta cyclodextrin moieties. 35. The pharmaceutical composition of claim 1, wherein the camptothecin moieties are attached via a linker. 36. The pharmaceutical composition of claim 35, wherein the camptothecin moieties are attached via a glycine linker. 37. The pharmaceutical composition of claim 1, wherein the sugar is lactose, glucose, sucrose or sorbitol. 38. The pharmaceutical composition of claim 1, wherein the linear polymer conjugate has the following formula: wherein each L is independently a linker, and each D is a camptothecin moiety, or absent; and wherein the group has a Mw of 0.2 to 5 kDa and n is at least 4, provided that the linear polymer conjugate comprises at least one camptothecin moiety. 39. The pharmaceutical composition of claim 38, wherein the sugar is lactose, glucose, sucrose or sorbitol. 40. The pharmaceutical composition of claim 38, wherein the sugar is mannitol. 41. The pharmaceutical composition of claim 1, wherein the linear polymer conjugate has the following formula: wherein each L is independently a linker or absent and each D is independently a camptothecin moiety, or —OH and wherein the group has a Mw of 0.2 to 5 kDa and n is at least 4, provided that the linear polymer conjugate comprises at least one camptothecin moiety. 42. The pharmaceutical composition of claim 41, wherein each L independently comprises an amino acid or derivative thereof. 43. The pharmaceutical composition of claim 41, wherein each L independently comprises a glycine, or a derivative thereof. 44. The pharmaceutical composition of claim 41, wherein the sugar is lactose, glucose, sucrose or sorbitol. 45. The pharmaceutical composition of claim 41, wherein the sugar is mannitol. 46. The pharmaceutical composition of claim 1, wherein the cyclodextrin is beta cyclodextrin, the camptothecin is linked to the linear polymer via a glycine linker and the sugar is lactose, glucose, sucrose or sorbitol. 47. The pharmaceutical composition of claim 16, wherein the water soluble linear polymer conjugate has a molecular weight of 10,000-500,000 amu. 48. The pharmaceutical composition of claim 16, wherein the camptothecin moieties are at least 10% by weight of the water soluble linear polymer conjugate. 49. The pharmaceutical composition of claim 16, wherein the camptothecin moieties are at least 20% by weight of the water soluble linear polymer conjugate. 50. The pharmaceutical composition of claim 16, wherein the camptothecin moieties are at least 30% by weight of the water soluble linear polymer conjugate. 51. The pharmaceutical composition of claim 16, wherein administration of the composition to a patient results in release of the camptothecin moieties over a period of 6 hours to a month. 52. The pharmaceutical composition of claim 16, wherein, upon administration of the composition to a patient, the rate of the camptothecin moieties release is dependent primarily upon the rate of hydrolysis as opposed to enzymatic cleavage. 53. The pharmaceutical composition of claim 16, wherein the cyclodextrin moieties are alpha, beta, or gamma cyclodextrin moieties. 54. The pharmaceutical composition of claim 16, wherein the cyclodextrin moieties are beta cyclodextrin moieties. 55. The pharmaceutical composition of claim 16, wherein the camptothecin moieties are attached via a linker. 56. The pharmaceutical composition of claim 55, wherein the camptothecin moieties are attached via a glycine linker. 57. The pharmaceutical composition of claim 16, wherein the sugar is lactose, glucose, sucrose or sorbitol. 58. The pharmaceutical composition of claim 22, wherein the camptothecin moieties are at least 10% by weight of the water soluble linear polymer conjugate. 59. The pharmaceutical composition of claim 22, wherein the camptothecin moieties are at least 20% by weight of the water soluble linear polymer conjugate. 60. The pharmaceutical composition of claim 22, wherein the camptothecin moieties are at least 30% by weight of the water soluble linear polymer conjugate. 61. The pharmaceutical composition of claim 22, wherein the cyclodextrin moieties are alpha, beta, or gamma cyclodextrin moieties. 62. The pharmaceutical composition of claim 22, wherein the cyclodextrin moieties are beta cyclodextrin moieties. 63. The pharmaceutical composition of claim 16, wherein each of the at least four cyclodextrin moieties alternates with each of the at least four comonomers in the water soluble linear polymer conjugate, and the sugar is mannitol. 64. The pharmaceutical composition of claim 63, wherein each of the at least four comonomers comprises polyethylene glycol having a molecular weight of 0.2 kDa to 5 kDa.
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