Details for Patent: 5,616,334
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| Title: | Low toxicity drug-lipid systems |
| Abstract: | Methods and compositions are described for nonliposomal lipid complexes in association with toxic hydrophobic drugs such as the polyene antibiotic amphotericin B. Lipid compositions are preferably a combination of the phospholipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) in about a 7:3 mole ratio. The lipid complexes contain a bioactive agent, and may be made by a number of procedures, at high drug:lipid ratios. These compositions of high drug:lipid complexes (HDLCs) may be administered to mammals such as humans for the treatment of infections, with substantially equivalent or greater efficacy and reduced drug toxicities as compared to the drugs in their free form. Also disclosed is a novel liposome-loading procedure, which may also be used in the formation of the HDLCs. |
| Inventor(s): | Janoff; Andrew S. (Yardley, PA), Boni; Lawrence (Monmouth Junction, NJ), Madden; Thomas D. (Vancouver, CA), Cullis; Pieter R. (Vancouver, CA), Lenk; Robert P. (Lambertville, NJ), Kearns; John J. (Princeton, NJ), Durning; Anthony G. (Yardley, PA), Klimchak; Robert (Flemington, NJ), Portnoff; Joel (Richboro, PA) |
| Assignee: | The Liposome Company, Inc. (Princeton, NJ) |
| Filing Date: | Apr 28, 1995 |
| Application Number: | 08/430,699 |
| Claims: | 1. A composition comprising a bioactive agent-lipid complex ("HDLC"), wherein the HDLC is a non-liposomal structure having no captured volume, the lipid comprises a phospholipid, and the concentration of the bioactive agent in the complex is at least about 6 mole percent, the bioactive agent is a polyene antifungal antibiotic, the complex is substantially free of liposomes and The toxicity of the bioactive agent in the complex is less than the toxicity of the free form of the bioactive agent. 2. The composition of claim 1 wherein the phospholipid is a a saturated phospholipid. 3. The composition of claim 2 wherein the saturated phospholipid comprises a phosphatidylcholine and a phosphatidylglycerol. 4. The composition of claim 3 wherein the phosphatidylcholine is dimyristoylphosphatidylcholine and the phosphatidylglycerol is dimyristoylphosphatidylglycerol. 5. The composition of claim 3 wherein the phosphatidylcholine and the phosphatidylglycerol are in a mole ratio of about 7:3. 6. The composition of claim 1 wherein the concentration of the polyene antifungal agent in the complex is between about 6 and 50 mole percent. 7. The composition of claim 6 wherein the concentration of the polyene antifungal agent in the complex is between about 25 and 50 mole percent. 8. The composition of claim 7 wherein the concentration of the polyene antifungal agent in the complex is about 33 mole percent. 9. The composition of claim 1 wherein the antifungal agent is amphotericin B. 10. The composition of claim 9 wherein the concentration of amphotericin B in the complex between about 6 and 50 mole percent. 11. The composition of claim 10 wherein the concentration of the amphotericin B in the complex is between about 25 and 50 mole percent. 12. The composition of claim 1 wherein the antifungal agent is nystatin. 13. A pharmaceutical composition comprising the HDLC of claim 1 and a pharmaceutically acceptable carrier or diluent. 14. The pharmaceutical composition of claim 13 which is adapted for parenteral administration in the form of a sterile aqueous suspension. 15. The pharmaceutical composition of claim 13 wherein the polyene antifungal antibiotic is amphotericin B. 16. The pharmaceutical composition of claim 15 wherein the concentration of the amphotericin B in the complex is between about 25 and 50 mole percent. 17. The pharmaceutical composition of claim 13 wherein the size of the HDLC is between about 0.2 and about 10 microns. 18. The pharmaceutical composition of claim 17 wherein the antifungal agent is nystatin. 19. A method for treating an infectious disease comprising administering to a mammal in need of such treatment an anti-infectious disease-effective amount of the pharmaceutical composition of claim 13. 20. The method of claim 19 wherein the infectious disease is a fungal infection. 21. The method of claim 19 wherein the infectious disease is a vital infection. 22. A composition comprising a bioactive agent-lipid complex ("HDLC"), wherein the bioactive agent is a polyene antifungal antibiotic, the lipid comprises a phospholipid, the complex has no captured volume and is substantially free of liposomes, and wherein the concentration of the bioactive agent in the complex is from about 25 mole percent to about 50 mole percent. 23. The composition of claim 22, wherein the antibiotic is amphotericin B and the phospholipid comprises dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol. |
