Prodrugs of pharmaceuticals with improved bioavailability

• US 7,517,858 B1
• Filed: 06/07/1995
• Issued: 04/14/2009
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Kini, Ganesh D., Beadle, James R., Hostetler, Karl Y.
• Primary Examiner(s): Mullis; Jeffrey C
• Application Number:
  US08/487,081
• Time in Patent Office: 5,060 Days
• Field of Search: 514/23, 514/75, 514/80, 514/103
• US Class Current: 514/23
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07F 9/098 Esters of polyphosphoric acids or anhydrides
• CPC Class Codes: C07F 9/10 Phosphatides, e.g. lecithin
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4065 Esters of acids containing the structure -C(=X)-P(=X)(XR)2, (X = O, S, Se)

Abstract

Lipid prodrugs of pharmaceutical agents and their analogs that have increased anticancer, anti-viral, anti-inflammatory, anti-proliferative activity over the parent drug, and methods for making lipid prodrugs. Compositions comprising lipid prodrugs for treating disease and methods for treating disease which involve using the compositions.

Claims

1. A method for enhancing oral bioavailability of a drug, comprising linking the drug to a compound having the structure (I):

2. A method for increasing target tissue uptake of a drug, comprising linking the drug to a compound having the structure (I):

3. A method of enhancing the bioavailability of a molecule, wherein the molecule is unavailable or poorly available in a mammal through oral, intravenous, intramuscular, subcutaneous, parenteral or topical route of administration, wherein the method comprises covalently linking said molecule to a phospholipid species either directly through the phosphate group of the lipid species or indirectly through a bifunctional linking group to form a compound having the structure (I):

4. The method of claim 3, wherein D is a molecule having an —

OH, —

SH, carboxyl, or amino functional group through which it is directly linked to the phosphate group of structure (I) or indirectly linked to the phosphate group of structure (I) if L is present.

5. The method of claim 3 further comprising incorporating the pharmaceutical agent into a therapeutic formulation suitable for oral, intravenous, subcutaneous, parenteral or topical administration.

7. The compound of claim 5, wherein the nucleoside analogue has an acyclic hydroxylated fragment of ribose.

8. The compound of claim 7, wherein the acyclic hydroxylated fragment of ribose is hydroxylated 2-propoxymethyl.

9. The compound of claim 7, wherein the acyclic hydroxylated fragment of ribose is hydroxylated ethoxymethyl.

6. A compound having the structure (II):

10. The compound of claim 6, wherein the nucleoside has a ribose.

11. The compound of claim 6, wherein the nucleoside analogue is ganciclovir or acyclovir.

12. The compound of claim 6, wherein substituted purine is phosphonomethoxydiaminopurine.

13. The compound of claim 6, wherein the substituted purine is phosphonomethoxyethyl deoxydiaminopurine.

14. The compound of claim 6, wherein the substituted purine is 9-(2-phosphonylmethoxyethyl)adenine.

15. The compound of claim 6, wherein the substituted purine is 9-(4′

-hydroxy-1′

,2′

-butadienyl) adenine.

16. The compound of claim 6, wherein the substituted pyrimidine is 9-(4′

-hydroxy-1′

,2′

-butadienyl) cytosine.

17. The compound of claim 6, wherein the substituted pyrimidine is 3-(4′

-hydroxy-1′

,2′

-butadienyl) cytosine.

18. The compound of claim 6, wherein the purine or pyrimidine is selected from the group consisting of adenine, guanine, cytosine, and thymine.

19. The compound of claim 18, wherein the pyrimidine is cytosine.

20. The compound of claim 18, wherein the purine is adenine.

21. The compound of claim 18, wherein the pyrimidine is thymine.

22. The compound of claim 18, wherein the purine is guanine.

23. The compound of claim 6, wherein the nucleoside or nucleoside analogue has a 2,6-diaminopurine.

24. A pharmaceutical composition comprising an anti-virally effective amount of a compound of any one of claims 6-10, 11 or 12-23 and a physiologically acceptable carrier.

25. The pharmaceutical composition of claim 24, wherein the physiologically acceptable carrier is suitable for oral delivery.

26. The pharmaceutical composition of claim 24, wherein the physiologically acceptable carrier is suitable for intravenous delivery.

27. The pharmaceutical composition of claim 24, wherein the physiologically acceptable carrier is suitable for intraperitoneal delivery.

28. The pharmaceutical composition of claim 24, wherein the physiologically acceptable carrier is suitable for intramuscular delivery.

29. The pharmaceutical composition of claim 24, wherein the physiologically acceptable carrier is suitable for subcutaneous delivery.

30. The pharmaceutical composition of claim 24, wherein the physiologically acceptable carrier is suitable for topical delivery.

31. A compound having the structure (II):

32. The compound of claim 31 wherein the nucleoside analogue is acyclovir.

33. The compound of claim 31 wherein the nucleoside analogue is ganciclovir.

34. A compound having the structure (II):

35. A pharmaceutical composition comprising an anti-virally effective amount of a compound of claim 34 and a physiologically acceptable carrier.