METHODS OF INCREASING THE BIOAVAILABILITY AND/OR CELLULAR UPDATE OF DRUGS

• US 20110150984A1
• Filed: 03/02/2011
• Published: 06/23/2011
• Est. Priority Date: 11/14/2003
• Status: Abandoned Application

• Current Assignee: Het Nederlands Kanker Instituut
• Original Assignee: Het Nederlands Kanker Instituut
• Inventors: VELDMAN, Robert J., VAN BLITTERSWIJK, Wim J., KONING, Gerben A., VERHEIJ, Marcel
• Application Number:
  US13/038,655
• Publication Number:
  US 20110150984A1
• 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 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

This invention pertains to methods of increasing the bioavailability and/or cellular uptake of an amphiphilic drug when administered parenterally, which method comprises the step of parenterally co-administering the drug with a short-chain sphingolipid as described herein.

Claims

1. A method of increasing the bioavailability and/or cellular uptake of an amphiphilic drug when administered parenterally, which method comprises the step of parenterally co-administering the drug with a short-chain sphingolipid of the following formula:

2. A method according to claim 1, wherein R¹ is independently an O-linked mono-saccharide group, an O-linked di-saccharide group, or an O-linked tri-saccharide group.

3. A method according to claim 2, wherein R¹ comprises one or more 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 deoxy, di-deoxy, di-deoxy-di-dehydro, methoxy, acetoxy, carboxylic acid, sulfuric acid, amino-deoxy, N-acetyl-amino-deoxy, and N-sulfo-amino-deoxy derivatives thereof.

4. A method according to claim 1, wherein R¹ is an O-linked polyhydric alcohol group.

5. A method according to claim 4, wherein R¹ comprises one or more groups selected from:

ethanediol, propanediol, butanediol, glycerol, and erythritol.

6. A method according to claim 1, wherein R¹ is:

7. A method according to claim 1, wherein R¹ is:

8. A method according to claim 7, wherein Q comprises one or more groups selected from:

ethanediol, propanediol, butanediol, glycerol, and erythritol.

9. A method according to claim 1, wherein R² is —

(CH₂)_nCH₃, wherein n is an integer from 2 to 8.

10. A method according to claim 1, wherein R³ is —

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

11. A method according to claim 1, wherein R⁴ is independently —

H, —

OH, or —

OMe.

12. A method according to claim 1, wherein the bond marked alpha is a double bond and R⁵ is —

H.

13. A method according to claim 1, wherein the bond marked alpha is a single bond and R⁵ is independently —

H or —

OH.

14. A method according to claim 1, wherein R^N is independently —

H, -Me, or -Et.

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

16. A method according to claim 1, wherein the short-chain sphingolipid has the following formula:

17. A method according to claim 1, wherein the short-chain sphingolipid has the following formula:

18. A method according to claim 1, wherein the short-chain sphingolipid has the following formula:

19. A method according to claim 1, wherein the short-chain sphingolipid has the following formula:

20. A method according to claim 1, wherein the drug is an anthracycline or an alkaloid.

21. A method according to claim 1, wherein the drug is selected from:

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

22. A method according to claim 1, wherein the drug is doxorubicin or doxorubicin hydrochloride.

23. A method according to claim 1, wherein the drug and the short-chain sphingolipid are co-administered as components of a liposomal pharmaceutical formulation.