Claims
- 1. A method for preparing a micelle composition comprising a hydrophobic passenger compound and an amphiphilic block copolymer, said method comprising the steps of:
(a) dissolving the hydrophobic passenger compound and the amphiphilic block copolymer in a solvent which is miscible with water and has a boiling temperature lower than that of water; (b) adding water at a rate and in an amount sufficient to promote micelle formation; (c) adding water to excess over that to promote micelle formation; (d) optionally adding a lyoprotectant; (e) after step (c) or (d), evaporating to remove solvent with the result of leaving a substantially solvent-free aqueous micelle solution; and (f) optionally after steps (d) and (e), evaporating the aqueous solution to produce a dried micelle composition.
- 2. The method of claim 1, wherein the solvent is selected from the group consisting of acetonitrile, methanol, ethanol, and acetone.
- 3. The method of claim 1, wherein the lyoprotectant is selected from the group consisting of sucrose, trehalose, raffinose and poly(ethylene glycol).
- 4. The method of claim 1, wherein the hydrophobic passenger compound is a therapeutic agent.
- 5. The method of claim 1, wherein the amphiphilic block copolymer is selected from the group consisting of a methoxypoly(oxyethylene)-block-poly(ε-caprolactone) and a methoxypoly(oxyethylene) poly(ethylene glycol)-block-poly(N-hexyl-L-aspartamideacyl ester) where the acyl is selected from the group consisting of acetate, hexaoate, laurate and stearate.
- 6. The method of claim 4, wherein the therapeutic agent is selected from the group consisting of fenofibrate, paclitaxel, adriamycin and amphotericin B.
- 7. The method of claim 6, wherein the therapeutic agent is amphotericin B and the amphiphilic block copolymer is methoxy poly(ethylene glycol)-block-poly(N-hexyl-L-aspartamide-stearate ester).
- 8. The method of claim 7, wherein the stearate acyl moiety is present at a level of substitution from 70% to 95%.
- 9. The method of claim 7, wherein the solvent is acetonitrile and the lyoprotectant is selected from the group consisting of sucrose, trehalose and raffinose.
- 10. The method of claim 6, wherein the therapeutic agent is fenofibrate and the amphiphilic block copolymer is methoxy poly(ethylene glycol)-block-(ε-polycaprolactone) (CH3O—(CH2—CH2—O—)N—(CO(CH2)5—O—)M—CO(CH2),—OH, where N is from 50 to 150 and M is from 8 to 175.
- 11. The method of claim 10, wherein N is from 75 to 125 and wherein M is from 8 to 40.
- 12. The method of claim 11, wherein N is 113 and M is 8, 21 or 34.
- 13. The method of claim 10, wherein the solvent is acetonitrile and the lyoprotectant is selected from the group consisting of sucrose, trehalose and raffinose.
- 14. The method of claim 10, wherein the lyoprotectant is added at a ratio of weight of polymer to weight of lyoprotectant from 1:1 to 1:10.
- 15. A method for reducing the toxicity of a polyene antibiotic, said method comprising the step of incorporating a polyene antibiotic in poly(ethylene glycol)-block-poly(N-hexyl-L-aspartamide)-acyl ester micelles, wherein the general chemical structure for the final block copolymer products is given in FIG. 1, where n can be from 8 to 28, z can be from about 250 to about 300; and wherein 25-x is from 1 to 5, said method comprising the steps of:
(a) dissolving the polyene antibiotic and the poly(ethylene glycol)-block-poly(N-hexyl-L-aspartamide)-acyl ester in a solvent; (b) adding water in an amount and at a rate sufficient to promote micelle formation; (c) adding water to excess over that sufficient to promote micelle formation; (d) removing solvent to produce a substantially solvent-free aqueous solution of micelles; (e) optionally, after step (c) or step (d), adding and dissolving a lyoprotectant; (f) optionally after step (e), removing the water to produce a dried micelle preparation.
- 16. The method of claim 15, wherein the polyene antibiotic is amphotericin B and the poly(ethylene glycol)-block-poly(N-hexyl-L-aspartamide)-acyl ester is a poly(ethylene glycol)-block-poly(N-hexyl-L-aspartamide)-stearate ester.
- 17. The method of claim 15, wherein the lyoprotectant is selected from the group consisting of sucrose, trehalose, raffinose and poly(ethylene glycol).
- 18. The method of claim 15, wherein n is 12 to 18.
- 19. The method of claim 18, wherein n is 16.
- 20. The method of claim 15, wherein z is 273.
- 21. The method of claim 15, wherein the polyene is Amphotericin B.
- 22. The product of the method of claim 15.
- 23. The product of claim 22 further comprising a pharmaceutically acceptable carrier.
- 24. The composition of claim 23, wherein the pharmaceutically acceptable carrier is a dextrose solution.
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of United States Provisional Application 60/368,771, filed Mar. 29, 2002, which is incorporated by reference herein.
ACKNOWLEDGMENT OF FEDERAL RESEARCH SUPPORT
[0002] This invention was made, at least in part, with funding from the National Institutes of Health (NIH grant AI-43346). Accordingly, the United States Government has certain rights in this invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60368771 |
Mar 2002 |
US |