Pharmaceutical formulations: liposomes incorporating aromatic polyene antibiotics

4,999,199

07/269,638

November 10, 1988

The present invention involves a pharmaceutical formulation comprising a liposome having a therapeutically effective concentration of an aromatic polyene macrolide antibiotic. The aromatic polyene macrolide antibiotic usable in the practice of the present invention is selected from the group consisting of candicidin, hamycin, aurefungin, ascosin, ayfattin, azacolutin, DJ400-B, trichomycin, levorin, heptamycin, candimycin or perimycin. The most preferred aromatic polyene macrolide antibiotic is candicidin. An important aspect of the present invention is a method for treating disseminated fungal infection in an animal comprising administering to an animal such as a human a pharmaceutical formulation comprising a liposome having a therapeutically effective amount of aromatic polyene macrolide antibiotic as described above. The preferred method of such administering is parenteral and the therapeutically effective amount is between about 1 mg/kg body weight and about 20 mg/kg body weight, more preferably between about 2.5 mg/kg body weight and about 6 mg/kg body weight. The parenteral administration is intravenous, intraarterial, subcutaneous, intramuscular, intralymphatic, intraperitoneal or intrapleural. The microorganisms which may be treated by the methods of the present invention comprise C. albicans, C. tropicalis, C. neoformans, aspergillus, cryptococcus, phycomycetes, fusarium, or trichosporin.

Anaissie, Elias J. (Houston, TX); Samonis, Georgios (Houston, TX); Krause, Hans (Worms-Horchheim, DEX); Bodey, Gerald P. (Houston, TX)

Board of Regents, The University of Texas System (Austin, TX)

What is claimed is

1. A pharmaceutical formulation comprising a liposome having a therapeutically effective concentration of polyene macrolide antibiotic having an attached p-aminoacetophenone or N-methyl-p-aminoacetophenone substituent.

2. The formulation of claim 1 wherein the polyene macrolide antibiotic is selected from the group consisting of candicidin, hamycin, aurefungin, ascosin, ayfattin, azacolutin, trichomycin, levorin, heptamycin, candimycin, and perimycin.

3. The formulation of claim 1 wherein the polyene macrolide antibiotic is candicidin.

4. The formulation of claim 1 wherein the polyene macrolide antibiotic is hamycin.

5. The formulation of claim 1 or 2 wherein the liposome comprises phospholipids.

6. The formulation of claim 5 wherein the phospholipids are one or more of phosphomonoglyceride, phosphatidic acid and sphingolipid.

7. The formulation of claim 5 wherein the phospholipids are one or more of phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, sphingomyelin and phosphatidic acid.

8. The formulation of claim 5 wherein the phospholipids are one or more of dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, phosphatidylcholine and phosphatidylglycerol.

9. The formulation of claim 5 wherein the phospholipids consist essentially of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol.

10. The formulation of claim 9 wherein the phospholipids are defined further as consisting essentially of dimyristoylphosphatidycholine and dimyristoylphosphatidylglycerol in a ratio of between about 1 to 10 and about 10 to 1.

11. The formulation of claim 9 wherein the phospholipids consist essentially of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol in a ratio of about 7:3.

12. The formulation of claim 1 or 2 wherein the liposome is defined further as being a stable multilamellar vesicle.

13. The formulation of claim 1 or 2 wherein the liposome is defined further as being a small unilammelar vesicle.

14. The formulation of claim 1 or 2 wherein the liposome is defined further as comprising a sterol.

15. The formulation of claim 14 wherein the sterol is cholesterol.

16. A method for treating disseminated fungal infection in an animal comprising administering to an animal a pharmaceutical formulation comprising a liposome having a therapeutically effective amount of a polyene macrolide antibiotic having an attached p-aminoacetophenone or N-methyl-p-aminoacetophenone substituent.

17. The method of claim 16 or 41 wherein the liposome comprises phospholipids.

18. The method of claim 17 wherein the phospholipids are one or more of phosphomonoglyceride, phosphatidic acid and sphingolipid.

19. The method of claim 17 wherein the phospholipids are one or more of phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, sphingomyelin, phosphatidic acid, egg phosphatidylcholine, and phosphatidylethanolamine.

20. The method of claim 17 wherein the phospholipids are one or more of dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, dielaidoylphosphatidylcholine, dioleoylphosphatidylcholine, distearyloylphosphatidylcholine and dipalmitoylphosphatidylcholine.

21. The method of claim 20 wherein the liposome comprises cholesterol.

22. The method of claim 16 or 41 wherein the administering is parenteral.

23. The method of claim 16 or 41 wherein the animal is a human.

24. The method of claim 16 or 41 wherein the therapeutically effective amount is between about 1 mg/kg body weight and about 10 mg/kg body weight.

25. The method of claim 16 or 41 wherein the therapeutically effective amount is between about 2.5 mg/kg body weight and about 6 mg/kg body weight.

26. The method of claim 17 wherein the phospholipids consist essentially of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol.

27. The method of claim 26 wherein the dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol are in a ratio of about 7 to 3.

28. The method of claim 16 or 41 wherein the administration is intravenous, intraarterial, subcutaneous, intramuscular, intralymphatic, intraperitoneal or intrapleural.

29. The method of claim 16 or 41 wherein the liposome is multilamellar.

30. The method of claim 16 or 41 wherein the liposome is unilamellar.

31. A method for the treatment of an infection in an animal caused by a microorganism which has sterols in its membrane, the treatment method comprising parenterally administering to such an animal a liposome containing a polyene macrolide antibiotic having an attached p-aminoacetophenone or N-methyl-p-aminoacetophenone substituent, in a therapeutically effective amount.

32. The method of claim 31 or 42 wherein the microorganism is one or more of C. albicans, C. tropicalis, C. neoformans, aspergillus, cryptococcus, zycomycetes, fusarium, and trichosporon.

33. The formulation of claim 1 wherein the therapeutically effective concentration is between about 100 ug(microgram)/ml and about 2.0mg/ml.

34. A method for treating disseminated fungal infection in an animal comprising administering to an animal a pharmaceutical formulation comprising a liposome having a therapeutically effective amount of a polyene macrolide antibiotic selected from the group consisting of candicidin, hamycin, aurefungin, ascosin, ayfattin, azacolutin, trichomycin, levorin, heptamycin, candimycin, and perimycin.

35. A method for the treatment of an infection in an animal caused by a microorganism which has sterols in its membrane, the treatment method comprising parenterally administering to such an animal a liposome comprising a therapeutically effective amount of a polyene macrolide antibiotic selected from the group consisting of candicidin, hamycin, aurefungin, ascosin, ayfattin, azacolutin, trichomycin, levorin, heptamycin, candimycin, and perimycin.

424/450; 424/417; 514/37; 264/41; 264/43; 264/46

A61K 3722

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