Cyclodextrin-based polymers for therapeutics delivery
View Patent ↗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.
1. A water soluble linear polymer conjugate comprising:
a linear polymer comprising beta cyclodextrin moieties and comonomers which do not contain beta cyclodextrin moieties (comonomers); and
camptothecin moieties covalently linked to the linear polymer via glycine linkers, 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 beta cyclodextrin moieties and at least four comonomers.
2. The water soluble linear polymer conjugate of claim 1 , wherein the comonomer comprises a polyethylene glycol.
3. The water soluble linear polymer conjugate of claim 2 , wherein the polyethylene glycol has a molecular weight of 0.2 kDa to 5 kD.
4. The water soluble linear polymer conjugate of claim 1 , wherein each of the at least four beta cyclodextrin moieties alternates with each of the at least four comonomers in the water soluble linear polymer conjugate.
5. The water soluble linear polymer conjugate of claim 1 , wherein the camptothecin moieties are at least 5% by weight of the water soluble linear polymer conjugate.
6. The water soluble linear polymer conjugate of claim 1 , wherein the camptothecin moieties are at least 10% by weight of the water soluble linear polymer conjugate.
7. The water soluble linear polymer conjugate of claim 1 , wherein administration of the water soluble linear polymer conjugate to a patient results in release of the camptothecin moieties over a period of at least 6 hours.
8. The water soluble linear polymer conjugate of claim 1 , wherein administration of the water soluble linear polymer conjugate to a patient results in release of the camptothecin moieties over a period of 6 hours to a month.
9. The water soluble linear polymer conjugate of claim 1 , wherein, upon administration of the water soluble linear polymer conjugate to a patient, the rate of the camptothecin moieties release is dependent primarily upon the rate of hydrolysis as opposed to enzymatic cleavage.
10. The water soluble linear polymer conjugate of claim 1 , having a molecular weight of 10,000-500,000 amu.
11. The water soluble linear polymer conjugate of claim 1 , having a molecular weight of 30,000-520,000 amu.
12. The water soluble linear polymer conjugate of claim 1 , having a molecular weight of 70,000-150,000 amu.
13. The water soluble linear polymer conjugate of claim 1 , wherein the beta cyclodextrin moieties are at least about 10% by weight of the linear polymer.
14. The water soluble linear polymer conjugate of claim 1 , wherein the beta cyclodextrin moieties are at least about 20% by weight of the linear polymer.
15. The water soluble linear polymer conjugate of claim 1 , wherein the beta cyclodextrin moieties are at least about 30% by weight of the linear polymer.
16. A pharmaceutical composition comprising the water soluble linear polymer conjugate of claim 1 , and a pharmaceutically acceptable carrier.
17. A water soluble linear polymer conjugate comprising:
a linear polymer comprising beta cyclodextrin moieties and comonomers comprising a polyethylene glycol; and
camptothecin moieties covalently linked to the linear polymer via glycine linkers, 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 beta cyclodextrin moieties and at least four comonomers.
18. A pharmaceutical composition comprising the water soluble linear polymer conjugate of claim 17 , and a pharmaceutically acceptable carrier.
19. A water soluble linear polymer conjugate comprising:
a linear polymer comprising beta cyclodextrin moieties and comonomers which do not contain beta cyclodextrin moieties (comonomers); and
camptothecin moieties covalently linked to the linear polymer via glycine linkers, 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 beta cyclodextrin moieties and at least four comonomers and has a molecular weight of 30,000- 520,000 amu.
20. A pharmaceutical composition comprising the water soluble linear polymer conjugate of claim 19 , and a pharmaceutically acceptable carrier.
21. The water soluble linear polymer conjugate of claim 17 , wherein the camptothecin moieties are at least 5% by weight of the water soluble linear polymer conjugate.
22. The water soluble linear polymer conjugate of claim 17 , wherein the camptothecin moieties are at least 10 % by weight of the water soluble linear polymer conjugate.
23. The water soluble linear polymer conjugate of claim 17 , wherein administration of the water soluble linear polymer conjugate to a patient results in release of the camptothecin moieties over a period of at least 6 hours.
24. The water soluble linear polymer conjugate of claim 17 , having a molecular weight of 30,000-520,000 amu.
25. The water soluble linear polymer conjugate of claim 17 , having a molecular weight of 70,000-150,000 amu.
26. The water soluble linear polymer conjugate of claim 19 , wherein the camptothecin moieties are at least 5% by weight of the water soluble linear polymer conjugate.
27. The water soluble linear polymer conjugate of claim 19 , wherein the camptothecin moieties are at least 10% by weight of the water soluble linear polymer conjugate.
28. The water soluble linear polymer conjugate of claim 19 , wherein administration of the water soluble linear polymer conjugate to a patient results in release of the camptothecin moieties over a period of at least 6 hours.
29. The water soluble linear polymer conjugate of claim 19 , having a molecular weight of 70,000-150,000 amu.
30. The pharmaceutical composition of claim 16 , wherein the comonomer comprises a polyethylene glycol.