Generated: May 28, 2017
|Title:||Methods of preparing low-toxicity drug-lipid complexes|
|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), Madden; Thomas D. (Vancouver, CA), Cullis; Pieter R. (Vancouver, CA), Kearns; John J. (Princeton, NJ), Durning; Anthony G. (Yardley, PA)|
|Assignee:||The Liposome Company, Inc. (Princeton, NJ)|
1. A method of preparing a drug-lipid complex comprising the steps of:
(a) dissolving a lipid which comprises a fatty acid or a phospholipid in an organic solvent selected from the group consisting of chloroform, methanol, dimethylsulfoxide (DMSO), methylene chloride, chloroform:methanol mixtures and benzene:methanol mixtures;
(b) dissolving a polyene antifungal agent in an organic solvent;
(c) combining the product of step (a) and the product of step (b) so as to obtain a mixture of the lipid solution and the agent solution;
(d) adding an aqueous phase to the product of step (c); and,
(e) removing organic solvent from the mixture of step (c),
wherein the complex has no captured volume, wherein the complex is substantially free of liposomes and wherein the relative amount of polyene antifungal agent used is such that the agent comprises from about 25 to 50 mole percent of the complex.
2. The method of claim 1, wherein the lipid comprises a phospholipid selected from the group consisting of a phosphatidylcholine and a phosphatidylglycerol.
3. The method of claim 2, wherein the phosphatidylcholine is dimyristoyl phosphatidylcholine and the phosphatidylglycerol is dimyristoyl phosphatidylglycerol.
4. The method of claim 3, wherein the dimyristoyl phosphatidylcholine and the dimyristoyl phosphatidylglycerol are combined in a 7:3 molar ratio.
5. The method of claim 4, wherein the organic solvent of step (a) is methylene chloride.
6. The method of claim 1, wherein the agent is amphotericin B.
7. The method of claim 1, wherein the organic solvent of step (b) is dimethylsulfoxide.
8. The method of claim 1, wherein the organic solvent of step (b) is acidified ethanol.
9. The method of claim 1, wherein the aqueous phase of step (e) is a buffered saline solution.
10. The method of claim 1, further comprising heating the product of step (e) to a temperature of from about 25 deg. C. to about 60 deg. C. for from about 10 to about 400 minutes.
11. The method of claim 1, wherein the lipid comprises dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol combined in a 7:3 molar ratio, the agent is amphotericin B, the organic solvent of step (a) is methylene chloride, the organic solvent of step (b) is dimethyl sulfoxide, the aqueous phase is a buffered saline solution and the concentration of the agent in the complex is from about 25 to about 50 mole percent.
Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.