Non-Pegylated Long-Circulating Liposomes

• US 20080279927A1
• Filed: 07/17/2008
• Published: 11/13/2008
• Est. Priority Date: 12/31/2002
• Status: Active Grant

• Current Assignee: Bharat Serums and Vaccines Limited
• Original Assignee: Bharat Serums and Vaccines Limited
• Inventors: Pai, Srikanth Annappa, Rivankar, Sangeeta Hanurmesh, DAFTARY, Gautam Vinod
• Granted Patent: US 9,005,655 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention provides a long circulating non-pegylated liposomal doxorubicin hydrochloride composition for parenteral administration and a process for its preparation. The circulation time in Swiss albino mice is at least 25 times longer than conventional non-liposomal formulations. The non-pegylated liposomes are stable, exhibit low toxicity and have been found to be efficacious in different tumor models.

Claims

1-22. -22. (canceled)

23. A long circulating non-pegylated liposomal doxorubicin composition for parenteral administration comprising, doxorubicin hydrochloride non-pegylated liposomes, histidine hydrochloride, and sucrose;

wherein the doxorubicin non-pegylated liposomes comprise distearoylphosphatidyl choline (DSPC), cholesterol, sucrose;

wherein the liposomes have an average size 0.06 μ

m to 0.16 μ

m; and

wherein the non-pegylated doxorubicin liposomes have a circulation time in blood at least 25 times longer than that of ADRIAMYCIN when tested in Swiss albino mice at equivalent doses.

24. The composition of claim 23, wherein the doxorubicin concentration encapsulated in the liposomes is from 1 mM to 10 mM expressed as doxorubicin hydrochloride.

25. The composition of claim 24, wherein the doxorubicin hydrochloride concentration is from 3 mM to 7 mM.

26. The composition of claim 25, wherein the doxorubicin hydrochloride concentration is about 3.45 mM.

27. The composition of claim 25, wherein the doxorubicin hydrochloride concentration is about 6.9 mM.

28. The composition of claim 23, wherein the molar ratio of distearoylphosphatidyl choline to cholesterol is from 1:

0.6 to 1;

0.8.

29. The composition of claim 28, wherein the molar ratio of distearoylphosphatidyl choline to cholesterol is about 1:

0.7.

30. The composition of claim 23, wherein the molar ratio of doxorubicin hydrochloride to distearoylphosphatidyl choline is from 1:

2 to 1;

15.

31. The composition of claim 30, wherein the molar ratio of doxorubicin hydrochloride to distearoylphosphatidyl choline is about 1:

3.5.

32. The composition of claim 23, wherein the sucrose concentration is from 0.1M to 0.5M.

33. The composition of claim 32, wherein the sucrose concentration is about 0.29M.

34. The composition of claim 23, wherein the concentration of histidine hydrochloride is from 1 mM to 100 mM.

35. The composition of claim 34, wherein the concentration of histidine hydrochloride is from 8 mM to 12 mM.

36. The composition of claim 35, wherein the concentration of histidine hydrochloride is about 10 mM.

37. The composition of claim 23, wherein the average size of the liposomes is from 0.08 μ

m to 0.12 μ

m.

38. The composition of claim 23, wherein the doxorubicin hydrochloride is present at 2 mg/ml;

and

wherein the molar ratio doxorubicin to DSPC is 1;

3.5; and

wherein the ratio of DSPC to cholesterol is 1;

0.7.

39. The composition of claim 23, wherein the doxorubicin hydrochloride is present at 4 mg/ml;

and

wherein the molar ration of doxorubicin DSPC is 1;

3.5; and

wherein the ration DSPC to cholesterol is 1;

0.7.

40. The composition of claim 23, wherein the circulation time (t_1/2) in blood is at least 40 times longer than that obtained with ADRIAMYCIN when tested in Swiss albino mice at equivalent doses.

41. A method for reducing tumor growth comprising administering the composition of claim 23.

42. A method for reducing tumor growth comprising administering the composition of claim 38.

43-60. -60. (canceled)