Methods of preparing low-toxicity drug-lipid complexes
First Claim
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.
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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.
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Citations
11 Claims
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1. A method of preparing a drug-lipid complex comprising the steps of:
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(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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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Specification