FORMULATION OF INSOLUBLE SMALL MOLECULE THERAPEUTICS IN LIPID-BASED CARRIERS

• US 20090291129A1
• Filed: 12/01/2006
• Published: 11/26/2009
• Est. Priority Date: 12/06/2005
• Status: Active Grant

• Current Assignee: Rigel Pharmaceuticals, Inc.
• Original Assignee: Rigel Pharmaceuticals, Inc.
• Inventors: Parmar, Manjeet M.
• Granted Patent: US 8,246,984 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis

Abstract

The present invention provides formulations containing at least one unsaturated amphiphilic lipid and an amphipathic or hydrophobic drug and methods of making these formulations. In particular, the present invention provides formulations of at least one unsaturated phospholipid and an amphipathic or hydrophobic pyrimidine drug, methods of making these formulations and the use of such formulations in a variety of contexts, including, for example, the treatment of proliferative disorders, such as tumors and cancers.

Claims

1. A formulation comprising at least one unsaturated amphiphilic lipid and an amphipathic or hydrophobic drug or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof wherein the drug and the lipid are present in a ratio ranging from between about 0.015 and about 0.15 on a mole/mole basis.

2. The formulation of claim 1 further comprising a pharmaceutically acceptable vehicle.

3. The formulation of claim 1 in which the drug is lidocaine, doxorubicin, vinorelbine, sodium thiopental, cholesterol, testosterone, alpha tocopherol, phenyl butazone, diphenyl hydramine, pyriamine or desloratidine.

4. The formulation of claim 1 in which the drug is a pyrimidine derivative.

5. The formulation of claim 1 in which the drug is a 2,4-pyrimidinediamine derivative.

6. The formulation of claim 5 in which the 2,4-pyrimidinediamine derivative is selected from compounds 1, 2, 3, 4 and 5, illustrated below:

7. The formulation of claim 6 in which the pyrimidine derivative is

8. The formulation of any one of claim 1 in which the drug has a log P greater than equal to about 3 and less than or equal to about 5.

9. The formulation of claim 1 in which the lipid has a transition temperature below about 30°

C. or below about 20°

C.

10. The formulation of claim 1 in which the lipid includes one or more unsaturated acyl moieties.

11. The formulation of claim 1 in which the lipid is a phospholipid.

12. The formulation of claim 11 in which the phospholipid includes one or more unsaturated acyl moieties.

13. The formulation of any one of claim 10 in which the unsaturated acyl moiety is C₁₂-C₂₄ alkenyl.

14. The formulation of any one of claim 10 in which the unsaturated acyl moiety is C₁₆-C₂₀ alkenyl.

15. The formulation of claim 13 in which the unsaturated acyl moiety is cis n-alkenyl.

16. The formulation of claim 14 in which the unsaturated acyl moiety is cis n-alkenyl.

17. The formulation of claim 12 in which the unsaturated acyl moiety is selected from the group consisting of oleoyl, elaidoyl, myristoleoyl, palmitoleoyl, arachidonyl, linoleoyl, linolenyl, petroselinyl and erucyl.

18. The formulation of claim 12 in which the phospholipid is a phosphatidylglycerol, a phosphatidylserine, a phosphatidylethanolamine or a phosphatidic acid.

19. The formulation of claim 12 in which the phospholipid is a phosphatidylcholine.

20. The formulation of any one of claim 18 in which the unsaturated acyl moiety is selected from the group consisting of petroselinyl, erucyl, oleoyl, claidoyl, palmitoleoyl, myristoleoyl, arachidonyl, linoleoyl, linolenyl and combinations thereof.

21. The formulation of claim 19 in which the phosphatidylcholine is dioleoylphosphatidylcholine, dielaidoylphosphatidylcholine, dipetroselinylphosphatidylcholine, dierucylphosphatidylcholine, dipalmitoleoylphosphatidylcholine, dimyristoleoylphosphatidylcholine, diarchidonylphosphatidylcholine, dilinoleoylphosphatidylcholine, dilinolenylphosphatidylcholinc, or combinations thereof.

22. The formulation of claim 19 in which the phosphatidylcholine is dioleoylphosphatidylcholine.

23. The formulation of claim 1 in which the drug and the lipid are present in a ratio ranging from between about 0.05 and about 0.12 on a mole/mole basis.

24. The formulation of claim 1 in which the ratio of the drug and the lipid is about 0.10 on a mole to mole basis.

25. The formulation of claim 1 in which the lipid forms a bilayer, liposome, a micelle, a vesicle, a suspension, a microsphere, an emulsion or combinations thereof.

26. The formulation of claim 1 in which the lipid forms a bilayer.

27. The formulation of claim 26 in which the liposome is a small unimellar liposome, a large unilimellar liposome, a multimellar liposome or combinations thereof.

28. The formulation of claim 1 in which the drug is a pyrimidine derivative and the lipid is a phospholipid.

29. The formulation of claim 1 in which the pyrimidine derivative is a 2,4-pyrimidinediamine derivative.

30. The formulation of claim 29 in which the phospholipid is phosphatidylcholine and the 2,4-pyrimidinediamine derivative is selected from compounds 1, 2, 3, 4 and 5, illustrated below:

31. The formulation of claim 30 in which the phosphatidylcholine is dioleoylphosphatidylcholine, dielaidoylphosphatidylcholine, dipetroselinylphosphatidylcholine, dierucylphosphatidylcholine, dipalmitoleoylphosphatidylcholine, dimyristoleoylphosphatidylcholine, diarchidonylphosphatidylcholine, dilinoleoylphosphatidylcholine, dilinolenylphosphatidylcholine, or combination thereof.

32. The formulation of claim 30 in which the phosphatidylcholine is dioleoylphosphatidylcholine.

33. The formulation of claim 32 in which the pyrimidine is

34. The formulation of any one of claim 29 in which the drug and the phospholipid are present in a ratio ranging from between about 0.05 and about 0.12 on a mole/mole basis.

35. The formulation of claim 34 in which the ratio of the drug and the lipid is about 0.10 mole to mole basis.

36. The formulation of claim 1 in which the lipid has a loading capacity of drug in a range between about 2 mg/mL and about 8 mg/mL.

49. A method of inhibiting proliferation of a cell comprising contacting the cell with an amount of a formulation according any one of claim 29 effective to inhibit its proliferation.

50. The method of claim 49 in which the cell is a tumor cell.

51. The method of claim 50 in which the tumor cell is a lung, colon, breast, prostate, pancreatic, ovarian or hepatic tumor cell.

52. A method of treating a proliferative disease, comprising administering to a subject in need thereof an amount of a formulation according to any one of claim 29 effective to treat the proliferative disease.

53. The method of claim 52 in which the proliferative disease is cancer.

54. The method of claim 53 in which the cancer is a metastatic tumor.

55. The method of claim 54 in which the cancer is selected from the group consisting of breast, colon, pancreatic, lung, neural, esophageal, gastric, and melanoma.

56. The method of claim 52 in which the formulation is administered orally, intraperitoneally, intravenously, intranasally or by inhalation.

57. The method of claim 52 in which the subject is a human.

37. A formulation comprising a pyrimidine derivative or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof and an unsaturated amphiphilic lipid.

38. The formulation of claim 37 in which the pyrimidine derivative is a 2,4 pyrimidinediamine derivative and the lipid is a phospholipid.

39. A method of making a formulation, said method comprising the steps of:

mixing at least one unsaturated amphiphilic lipid, an amphipathic or hydrophobic drug or pharmaceutically acceptable salts, hydrates, solvates, or N-oxides thereof and a solvent;

removing the solvent to form a residue comprising drug and lipid; and

mixing the residue with water or an aqueous solution;

wherein the drug and the lipid are present in a ratio ranging from between about 0.015 and about 0.15 on a mole/mole basis.

40. The method of claim 39 in which the mixing steps include stirring, blending, heating, shaking, agitating, sonicating, vortexing, centrifugating or combinations thereof.

41. The method of claim 39 in which the solvent is an organic solvent, a detergent, a surfactant, or combinations thereof.

42. The method of claim 41 in which the organic solvent is selected from the group consisting of dichloromethane, chloroform, haloalkanes, ethers, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethyl formamide, alcohols, polyols, water and mixtures thereof.

43. The method of claim 41 in which the detergent is TPGS, PS 80, sodium cholate, sodium dodecylsulfate, sodium salt of N-lauroylsarcosine, lauryldimethylamine-oxide, cetyltrimethylammoniumbromide or the sodium salt of bis(2-ethylhexyl)sulfosuccinate.

44. The method of claim 39 in which the residue is a film, oil, liquid, emulsion, suspension, colloid, dispersion, aggregate, microsphere, or combinations thereof.

45. The method of claim 39 in which the residue is a film.

46. The method of claim 39 in which the removing step includes lyophilization, vacuum evaporation, reverse phase evaporation, vacuum distillation, air drying, inert gas transfer or combinations thereof.

47. The method of claim 39 in which the aqueous solution is a buffer.

48. A formulation made by a process comprising the steps of:

mixing at least one unsaturated amphiphilic lipid, an amphipathic or hydrophobic drug or pharmaceutically acceptable salts, hydrates, solvates, or N-oxides thereof and a solvent;

removing the solvent to form a residue comprising drug and lipid; and

mixing the residue with water or an aqueous solution;

wherein the drug and the lipid are present in a ratio ranging from between about 0.015 and about 0.15 on a mole/mole basis.