Polymeric benzyl carbonate-derivatives
View Patent ↗The present invention relates to polymeric derivatives, which can be conjugated to an amino-containing drug to improve its in vivo properties. The polymeric derivative can subsequently be released to yield the drug in its native form. Methods of preparing and using these polymeric derivatives and drug conjugates are described.
1. A method for treating a disease in a patient comprising administering to the patient a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug conjugate of Formula II:
wherein X is selected from the group consisting of O, S and NR 3 ;
n is 1 or 2:
POLYMER is a water soluble, non-peptidic polymer different from poly(alkylene glycol);
R 1 and R 2 are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) -alkyl, (C 1 -C 6 )-alkylenearyl, and aryl with the proviso that at least one of R 1 and R 2 is different from hydrogen;
R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 ) -alkylenearyl, and aryl; and
DRUG is plasma protein or blood coagulation factor, or a pharmaceutically acceptable salt, ester, or solvate thereof, and wherein the disease is a blood clotting disease.
2. The method of claim 1 , wherein the formulation is encapsulated in a microparticle.
3. The method of claim 1 , wherein DRUG is selected from the group consisting of erythropoietin, Factor H, Factor VIII, von Willebrand Factor, Factor VIIa, and Factor IX.
4. The method of claim 1 , wherein DRUG is Factor VIII.
5. The method of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and n-butyl.
6. The method of claim 5 , wherein R 1 is hydrogen and R 2 is methyl.
7. The method of claim 1 , wherein X is selected from the group consisting of O and NH.
8. The method of claim 7 , wherein X is O.
9. The method of claim 1 , wherein n is 1.
10. The method of claim 1 , wherein n is 2.
11. The method of claim 1 , wherein POLYMER is selected from the group consisting of polyvinylpyrrolidone, poloxamer, polysaccharide, polysialic acid, hydroxyethyl starch, icodextrin, chondroitin sulfate, dermatan sulfate, heparin, chitosan, hyaluronic acid, dextran, dextran sulfate, and pentosan polysulfate.
12. The method of claim 1 , wherein POLYMER is polysialic acid.
13. A method for treating a disease in a patient comprising administering to the patient a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug conjugate of Formula II:
wherein X is selected from the group consisting of O, S and NR 3 ;
n is 1 or 2;
POLYMER is a poly(alkylene) glycol;
R 1 is hydrogen;
R 2 is selected from the group consisting of (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkylenearyl, and aryl;
R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 ) -alkylenearyl, and aryl; and
DRUG is plasma protein or blood coagulation factor, or a pharmaceutically acceptable salt, ester, or solvate thereof, and wherein the disease is a blood clotting disease.
14. The method of claim 13 , wherein DRUG is selected from the group consisting of erythropoietin, Factor H, Factor VIII, von Willebrand Factor, Factor VIIa, and Factor IX.
15. The method of claim 14 , wherein DRUG is Factor VIII.
16. The method of claim 13 , wherein the formulation is encapsulated in a microparticle.
17. The method of claim 13 , wherein X is O.
18. The method of claim 13 , wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl.
19. The method of claim 18 , wherein R 2 is methyl.
20. The method of claim 13 , wherein n is 1.
21. The method of claim 13 , wherein n is 2.
22. The method of claim 13 , wherein the poly(alkylene glycol) comprises poly(ethylene glycol) (PEG).
23. The method of claim 22 , wherein the PEG has a molecular weight of about 200 to about 500,000.