Pharmaceutical formulations employing short-chain sphingolipids and their use

• US 7,915,227 B2
• Filed: 11/11/2004
• Issued: 03/29/2011
• Est. Priority Date: 11/14/2003
• Status: Expired due to Fees

• Current Assignee: Het Nederlands Kanker Instituut
• Original Assignee: Het Nederlands Kanker Instituut
• Inventors: Verheij, Marcel, Koning, Gerben A., Van Blitterswijk, Wim J., Veldman, Robert J.
• Primary Examiner(s): Jiang; Shaojia Anna
• Assistant Examiner(s): Henry; Michael C
• Application Number:
  US10/579,230
• Publication Number:
  US 20070082855A1
• Time in Patent Office: 2,329 Days
• Field of Search: 514/25, 514/23, 514/53, 514/34, 514/78, 536/17.9, 536/4.1, 536/53
• US Class Current: 514/25
• 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 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Pharmaceutical formulations containing (i) an amphiphilic drug and (ii) a short-chain sphingolipid are described and provided herein along with methods of making and using same.

Claims

1. A pharmaceutical formulation suitable for parenteral administration comprising:

(i) an amphiphilic drug selected from the group consisting of an anthracycline and an alkaloid; and

(ii) a short-chain sphingolipid selected from compounds of the following formula;

2. A pharmaceutical formulation according to claim 1, wherein said drug is an anthracycline.

3. A pharmaceutical formulation according to claim 1, wherein said drug is selected from:

doxorubicin, idarubicin, epirubicin, aclarubicin, mitrozantrone, and daunorubicin, and salts thereof.

4. A pharmaceutical formulation according to claim 1, wherein said drug is doxorubicin or doxorubicin hydrochloride.

5. A pharmaceutical formulation according to claim 1, wherein said drug is an alkaloid.

6. A pharmaceutical formulation according to claim 1, wherein said drug is selected from:

topotecan and camptothecin.

7. A pharmaceutical formulation according to claim 1, wherein R² is linear.

8. A pharmaceutical formulation according to claim 1, wherein R² is linear;

and has from 0 to 3 carbon-carbon double bonds.

9. A pharmaceutical formulation according to claim 1, wherein R² is unsubstituted or substituted with from 1 to 3 substituents selected from C_1-4alkyl, —

OH, C_1-4alkoxy, —

C(═

O)OH, and —

C(═

O)O—

C_1-4alkyl.

10. A pharmaceutical formulation according to claim 1, wherein R² is —

(CH₂)_nCH₃, wherein n is an integer from 4 to 8.

11. A pharmaceutical formulation according to claim 1, wherein R² is —

(CH₂)_nCH₃, wherein n is an integer from 6 to 8.

12. A pharmaceutical formulation according to claim 1, wherein R² is —

(CH₂)₆CH₃.

13. A pharmaceutical formulation according to claim 1, wherein the bond marked alpha is a double bond and R⁵ is —

H.

14. A pharmaceutical formulation according to claim 1, wherein the bond marked alpha is a single bond;

and R⁵ is —

H.

15. A pharmaceutical formulation according to claim 1, wherein the bond marked alpha is a single bond;

and R⁵ is —

OH.

16. A pharmaceutical formulation according to claim 1, wherein R³ is linear.

17. A pharmaceutical formulation according to claim 1, wherein R³ is linear;

and has from 0 to 3 carbon-carbon double bonds.

18. A pharmaceutical formulation according to claim 1, wherein R³ is unsubstituted or substituted with from 1 to 3 substituents selected from C_1-4alkyl, —

OH, C_1-4alkoxy.

19. A pharmaceutical formulation according to claim 1, wherein R³ is —

(CH₂)_nCH₃, wherein n is an integer from 8 to 16.

20. A pharmaceutical formulation according to claim 1, wherein R³ is —

(CH₂)₁₂CH₃.

21. A pharmaceutical formulation according to claim 1, wherein the moiety:

22. A pharmaceutical formulation according to claim 1, wherein R⁴ is —

H, —

OH, —

OMe, —

OEt, —

O(iPr), —

O(nPr), —

O(nBu), —

O(iBu), —

O(sBu), or —

O(tBu).

23. A pharmaceutical formulation according to claim 1, wherein R⁴ is —

OH.

24. A pharmaceutical formulation according to claim 1, wherein R^N is —

H, -Me, or -Et.

25. A pharmaceutical formulation according to claim 1, wherein the carbon atoms marked (*) and (**) have a configuration as shown in the following formula:

26. A pharmaceutical formulation according to claim 1, wherein R¹ is an O-linked saccharide group.

27. A pharmaceutical formulation according to claim 1, wherein R¹ is an O-linked mono-, di-, or tri-saccharide group.

28. A pharmaceutical formulation according to claim 1, wherein R¹ is comprises a group or groups selected from:

arabinose, lyxose, ribose, xylose,

allose, altrose, glucose, mannose, gulose, idose, galactose, and talose;

and derivatives thereof.

29. A pharmaceutical formulation according to claim 1, wherein R¹ is an O-linked mono-, di-, or tri-saccharide group comprising a group or groups selected from:

arabinose, lyxose, ribose, xylose,

allose, altrose, glucose, mannose, gulose, idose, galactose, talose,

sucrose, maltose, lactose, cellobiose, galabiose,

globotriaose, isoglobotriaose, mucotriaose, lactotriaose, neolactotriaose gangliotriaose, galatriaose, mollutriaose, and antrotriaose;

and derivatives thereof.

30. A pharmaceutical formulation according to claim 28, wherein said saccharide group derivatives are selected from deoxy, di-deoxy, di-deoxy-di-dehydro, methoxy, acetoxy, carboxylic acid, sulfuric acid, amino-deoxy, N-acetyl-amino-deoxy, or N-sulfo-amino-deoxy.

31. A pharmaceutical formulation according to claim 1, wherein said short-chain sphingolipid has the following formula (C₈-GlcCer):

32. A pharmaceutical formulation according to claim 1, wherein said short-chain sphingolipid has the following formula:

35. A pharmaceutical formulation according to claim 1, wherein R¹ is:

an O-linked (optionally N—

(C_1-4alkyl)-substituted amino)-C_1-6alkyl-phosphate group;

or

an O-linked (polyhydric alcohol-substituted)-C_1-6alkyl-phosphate group.

36. A pharmaceutical formulation according to claim 1, wherein R¹ is:

37. A pharmaceutical formulation according to claim 1, wherein R¹ is:

38. A pharmaceutical formulation according to claim 1, wherein R¹ is:

39. A pharmaceutical formulation according to claim 1, wherein said short-chain sphingolipid has the following formula (“

C₆—

SM”

);

40. A pharmaceutical formulation according to claim 1, wherein said short-chain sphingolipid has the following formula (“

3-O-methyl-C₈—

SM”

);

41. A pharmaceutical formulation according to claim 36, wherein Q is a polyhydric alcohol group, linked via an oxygen atom.

42. A pharmaceutical formulation according to claim 41, wherein Q comprises a group selected from:

ethanediol (glycol), propanediol, butanediol, glycerol, and erythritol.

43. A pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation is a liposomal pharmaceutical formulation.

44. A liposomal pharmaceutical formulation according to claim 43, wherein the liposomes of the liposomal pharmaceutical formulation are prepared using a mixture of lipids comprising, at least, vesicle-forming lipids and said short-chain sphingolipid.

45. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids comprises phospholipids and said short-chain sphingolipid.

46. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids comprises phospholipids, cholesterol, and said short-chain sphingolipid.

47. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids comprises phosphatidylcholines, cholesterol, and said short-chain sphingolipid.

48. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids comprises fully hydrogenated soy phosphatidylcholine (HSPC), cholesterol, and said short-chain sphingolipid.

49. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids comprises dipalmitoyl-phosphatidylcholine (DPPC), cholesterol, and said short-chain sphingolipid.

50. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids additionally comprises a vesicle-forming lipid which is derivatized with a polymer chain.

51. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids additionally comprises a phosphatidylethanolamine (PE) which is derivatized with polyethyleneglycol (PEG).

52. A liposomal pharmaceutical formulation according to claim 44, wherein said mixture of lipids additionally comprises N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG2000-DSPE).

53. A pharmaceutical formulation according to claim 1, in the form of Caelyx®

or Doxil®

liposomes post-inserted with a short-chain sphingolipid selected from compounds of the following formula;

33. A pharmaceutical formulation comprising:

(i) a drug; and

(ii) a short-chain sphingolipids selected from compounds of the following formula

34. A pharmaceutical formulation according to claim 33, wherein R¹ comprises a group selected from:

ethanediol (glycol), propanediol, butanediol, glycerol, and erythritol.

54. A pharmaceutical formulation suitable for parenteral administration comprising:

(i) a drug; and

(ii) a short-chain sphingolipid selected from compounds of the following formula;

55. A pharmaceutical formulation suitable for parenteral administration comprising:

(i) an amphiphilic drug; and

(ii) a short-chain sphingolipid having the following formula (“

3-O-methyl-C₈—

SM”

);