Compositions containing lysophosphotidic acids which inhibit apoptosis and uses thereof

• US 6,495,532 B1
• Filed: 02/28/2000
• Issued: 12/17/2002
• Est. Priority Date: 03/19/1997
• Status: Expired due to Fees

• Current Assignee: Sky High, LLC
• Original Assignee: Sky High, LLC
• Inventors: Bradley, John D., Picker, Donald H., Bathurst, Ian C., Foehr, Matthew W., Umansky, Samiul R., Goddard, J. Graham
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/381,489
• Time in Patent Office: 1,023 Days
• Field of Search: 514/110, 514/120, 514/725, 514/784, 514/785, 514/2
• US Class Current: 514/110
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/07 Retinol compounds, e.g. vitamin A retinoic acids A61K31/203
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention provides therapeutic compositions containing lysophosphotidic acids, methods for making the compositions, and methods of using the compositions in the preservation and treatment of organs.

Claims

1. A composition comprising a therapeutically effective amount of an LPA selected from the group consisting of

Oleyl 1-thiophosphoryl-2-O-Methyl-rac-glycerate,

1-(3-propyl oleoate)thiophosphate,

3-O-Oleoyl-2-O-methyl-rac-glycero-1-thiophosphate,

3-O-Oleyl-2-O-methyl-rac-glycero-1-thiophosphate,

3-O-Oleyl-2-O-methyl-rac-glycero-1-phosphate,

3-O-Oleyl-rac-glycero-1-phosphate,

3-O-Oleyloxypropyl-1-phosphate and

1-(3-propyl oleoate)phosphate

and a potentiating component in an amount sufficient to potentiate the therapeutic effectiveness of the LPA.

2. The composition of claim 1, wherein said component is a polyethylene glycol.

3. The composition of claim 1, wherein said component is a protein.

4. The composition of claim 1, wherein said component is a lipid membrane structure.

5. The composition according to claim 1, wherein the composition is a solution and the LPA is present in an amount of from about 0.00001% to about 10% (weight/volume).

6. The composition according to claim 1, wherein the composition is a solid and the LPA is present in an amount of from about 0.00001% to 50% (weight/weight).

7. The composition according to claim 4, wherein the lipid membrane structure comprises at least one compound selected from the group consisting of lipids, phospholipids and surfactants.

8. The composition according to claim 7, wherein the lipid is selected from the group consisting of semi-synthetic or synthetic mono- or di-glycerophospholipids, haloalkyl derivatives thereof, amphipathic steroids, and bolaamphiles.

9. The composition according to claim 8, wherein the surfactant is nonionic and is selected from the group consisting of polyoxyethylene derivatives of fatty alcohols, fatty acid esters of fatty alcohols and glyceryl esters wherein the polyoxyethylene group is coupled via an ether linkage to an alcohol group.

10. The composition according to claim 7 wherein the phospholipid is selected from the group consisting of monoacyl glyceryl phosphates and diacylglyceryl phosphates.

11. The composition according to claim 7, wherein the lipid membrane structure further comprises a tissue targeting compound.

12. The composition according to claim 11, wherein the tissue targeting compound is selected from the group consisting of:

an antibody, a cell surface receptor, a ligand for a cell surface receptor, a polysaccharide, a drug, a hormone, a hapten, a special lipid and a nucleic acid.

13. The composition according to claim 7, wherein the composition further comprises a component selected from the group consisting of polypeptides, modified polypeptides and polymers.

14. The composition according to claim 13, wherein the polypeptide is selected from the group consisting of fatty acid binding proteins.

15. The composition according to claim 13, wherein the modified polypeptide contains a modification selected from the group consisting of glycosylation, phosphorylation, myristylation, sulfation and hydroxylation.

16. The composition according to claim 13, wherein the polymer is a naturally occurring polymer and is selected from the group consisting of dextrans, hydroxyethyl starch, and polysaccharides.

17. The composition according to claim 16, wherein the polysaccharide is selected from the group consisting of trehalose, glucose, maltose, lactose, maltulose, iso-maltulose, lactulose, mono-reducing glycosides of polyhydroxy compounds selected from sugar alcohols, other straight chain polyalcohols, raffinose, stachyose, melezitose, dextran, sucrose and sugar alcohols thereof, maltitol, lactitol, iso-maltulose, palatinit, 2-D-glucopyranosyl-1f6-mannitol and their individual sugar alcohols.

18. The composition according to claim 13, wherein the polymer is synthetic and is selected from the group consisting of polyalkyl glycols, polyoxyethylated polyols, polyvinylpyrrolidone, polyhydroxyethyl methacrylate, polyvinyl alcohols, polyurethane, polytrimethylene glycol, polypropylene glycol, polyacrylic acid, polyethyloxazoline, polyacrylamide, polyphosphazene, poly(lactic acid), poly(glycolic acid), polyamino acids and polymeric mixtures thereof.

19. The composition according to claim 3, wherein the protein comprises at least one compound selected from the group consisting of:

a lipid binding protein and a lipid carrier protein.

20. The composition according to claim 3, wherein the protein is selected from the group consisting of:

albumin, soy and plant protein, cytochrome c, low density lipoprotein, acyl carrier protein, and alphafeto protein.

21. The composition according to claim 3, wherein the protein is a modified protein.

22. The composition according to claim 21, wherein the modified protein contains a modification selected from the group consisting of glycosylation, phosphorylation, myristylation, sulfation and hydroxylation.

23. The composition according to claim 2, wherein the weight ratio of PEG to LPA is 1-100,000 to 1.

24. The composition according to claim 2, wherein the PEG has an average molecular weight from about 8,000 to about 40,000.

25. The composition according to claim 2, wherein the PEG has an average molecular weight of about 20,000.

26. The composition according to claim 1, further comprising pharmaceutically acceptable excipients.

27. The composition according to claim 26, wherein the pharmaceutically acceptable excipient is selected from the group consisting of topical pharmaceutically acceptable carrier, cosmetic carrier, sterile solutions, sterile isotonic solutions, ingestable liquids, pharmaceutically acceptable aerosols and solutions for organ/tissue/cell preservation and/or transplantation.

28. The composition according to claim 1, further comprising a pharmaceutically effective agent.

29. The composition according to claim 28, wherein the pharmaceutically effective agent is selected from the group consisting of drugs, antibiotics, wound healing agents and antioxidants.

30. The composition according to claim 29, wherein the drug is selected from the group consisting of antipyretic and anti-inflammatory, analgesics, antiarthritics, antispasmodics, antidepressants, antipsychotics, tranquilizers, antianxiety drugs, narcotic antagonists, antiparkinsonism agents, cholinergic antagonists, chemotherapeutic agents, immuno-suppressive agents, antiviral agents, parasiticides, appetite suppressants, antiemetics, antihistamines, antimigraine agents, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, hormonal agents, contraceptives, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs, opioids, and vitamins.

31. The composition according to claim 30, wherein the antibiotic is selected from the group consisting of ampicillin, tetracycline, chloramphenicol, erythromycin, amphotericin B and penicillin.

32. The composition according to claim 30, wherein the wound healing agent is selected from the group consisting of transforming growth factors, platelet-derived growth factors, epidermal growth factors and fibroblast growth factors.

33. The composition according to claim 32, wherein the antioxidant is selected from the group consisting of Vitamin C, Vitamin E , Vitamin A, dihydrolipoamide, flavenoids, butylated hydroxytoluene, butylated hydroxyanisole, Trolox®

, propyl gallate, phenolic antioxidants, phenothiazines, desferrioxamide, HBED and CP130.

34. The composition according to claim 1, wherein the composition is in aqueous solution and the aqueous solution is in a pH range of from about 2-10.

35. The composition according to claim 34, wherein the pH is from about 4 to about 8.

36. A method of preserving an organ comprising adding an effective amount of the composition according to claim 1 to the solution with which the organ is treated.

37. A method of organ preservation comprising administering to the host animal at least one intravenous bolus of an effective amount of the composition according to claim 1.

38. A method of treating an organ transplant recipient comprising administering to the recipient an amount of the composition according to claim 1 effective to enhance function of the transplanted organ.