Stable polymeric micelle-type drug composition and method for the preparation thereof
A biocompatible stable composition containing a hydrophobic drug, such as paclitaxel. The composition, which forms a syringeable polymeric micellar solution in aqueous or body fluids, is a freeze-dried product comprising a hydrophobic drug, i.e. paclitaxel, and an amphiphilic block copolymer wherein a hydrophobic group having affinity or attraction with the hydrophobic drug, such as paclitaxel, is incorporated on its end.
1. A composition capable of forming a polymeric micelle in a body fluid or an aqueous medium, said composition comprising an amphiphilic block copolymer having a hydrophilic A block component and a hydrophobic biodegradable B block component, wherein the hydrophobic biodegradable B block component of the copolymer is capped with an acyl group or carbamyl group of C 1 to C 9 alkyl, aryl, alkaryl or aralkyl group.
2. The composition of claim 1 , wherein the amphiphilic block copolymer is selected from the group consisting of AB diblock and BAB triblock copolymers.
3. The composition of claim 1 , wherein the amphiphilic block copolymer is represented by formula (I) below:
wherein x is an integer of 20–300, and y is an integer of 15–70, R 1 is H, a C 1 to C 4 alkyl, a C 1 to C 4 acyl or is represented by formula (II):
wherein R 2 is a C 1 to C 9 alkyl, aryl, alkaryl or aralkyl group, or NH—R 3 wherein R 3 is a C 1 to C 9 alkyl, aryl, alkaryl or aralkyl group, x is an integer of 20–300, and y is an integer of 15–70.
4. The composition of claim 3 , wherein R 2 is a member selected from the group consisting of methyl, ethyl, propyl and butyl.
5. The composition of claim 3 , wherein R2 is a phenyl group or a heterocyclic group selected from the group consisting of thienyl, furyl, pyridinyl groups.
6. The composition of claim 3 , wherein R2 is a benzyl group.
7. The composition of claim 3 , wherein R2 is a tolyl group.
8. The composition of claim 3 , wherein R1 is a methyl group and R2 is a methyl, phenyl or enthylamino group.
9. The composition of claim 2 , wherein the hydrophilic A block component is within a range of 40 to 80 wt % based on total weight of the block copolymer.
10. The composition of claim 2 , wherein the hydrophilic A block component is poly(ethylene glycol) or monomethoxy poly(ethylene glycol).
11. The composition of claim 1 , wherein the block copolymer has an average molecular weight of from 1,000 to 15,000 Daltons.
12. The composition of claim 1 , wherein the hydrophobic biodegradable polymer B block component is selected from the group consisting of a polylactide, copolymer of lactide and glycolide, a copolymer of caprolactone and glycolide, polycaprolactone, a polyanhydride, a polyorthoester, a copolymer of lactide and 1,4-dioxan-2-one, and a copolymer of caprolactone and 1,4-dioxan-2-one.
13. A hydrophobic drug containing polymeric composition capable of forming stable polymeric micelles in an aqueous environment, said composition comprising a hydrophobic drug and a composition of claim 1 , wherein in an aqueous environment said drug is physically entrapped within, but not covalently bound to, a hydrophobic core formed by the hydrophobic B block component and its terminal hydrophobic group.
14. The composition of claim 13 , wherein the content of the hydrophobic drug is up to 50 wt % based on the total weight of the block copolymer and the drug.
15. The composition of claim 13 , wherein the hydrophobic drug has a solubility of less than 10 mg/mL.
16. The composition of claim 13 , wherein the hydrophobic drug is selected from the group consisting of anticancer agents, antifungal agents, steroids, antiinflammatory agents, sex hormones, immunosuppressants, antiviral agents, anesthetics, antiemetics, and antihistamine agents.
17. The composition of claim 13 , wherein the hydrophobic drug is selected from the group consisting of a taxane analog, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, cyclosporine A, amphotericin B, itraconazole, ketoconazole, indomethacin, testosterone, estradiol, dexamethasone, prednisolone, and triamcinolone acetonide.
18. The composition of claim 17 , wherein the hydrophobic drug is a taxane analog.
19. The composition of claim 18 , wherein the taxane analog is paclitaxel.
20. An aqueous formulation for parenteral administration of a taxane analog comprising the composition according to claim 18 , which is dissolved in an aqueous medium and has a concentration of the taxane analog in the range of 0.1˜3 mg/mL.
21. The aqueous formulation of claim 20 , wherein the aqueous medium is a 0.9% sodium chloride water solution, 5% dextrose water solution, 5% dextrose and 0.9% sodium chloride water solution, or a 5% dextrose Ringer's solution.
22. A method of preparing the composition according to claim 13 , which is capable of forming a stable polymeric micelle in aqueous environments, comprising the steps of:
a) preparing a drug-polymer mixture by dissolving the amphiphilic block copolymer of claim 1 and a hydrophobic drug in an organic solvent followed by evaporation of the solvent;
b) dissolving the drug-polymer mixture in an aqueous environment to obtain a stable micellar solution; and,
c) freeze-drying the aqueous micellar solution.
23. The method of claim 22 , wherein the content of the hydrophobic drug is up to 50 wt % based on the total weight of the block copolymer and the drug.
24. The method of claim 22 , wherein the hydrophobic drug has a solubility of less than 10 mg/mL.
25. The method of claim 24 , wherein the hydrophobic drug is selected from the group consisting of a taxane analog, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, cyclosporine A, amphotericin B, itraconazole, ketoconazole, indomethacin, testosterone, estradiol, dexamethasone, prednisolone, and triamcinolone acetonide.
26. The method of claim 25 , wherein the hydrophobic drug is a taxane analog.
27. The method of claim 26 , wherein the taxane analog is paclitaxel.
28. A hydrophobic drug containing polymeric composition capable of forming stable polymeric micelles in an aqueous environment, said composition comprising a hydrophobic drug and a composition of claim 3 , wherein said drug is physically entrapped within, but not covalently bound to, a hydrophobic core formed by the hydrophobic B block component and its terminal hydrophobic group.
29. The composition of claim 28 , wherein the content of the hydrophobic drug is up to 50 wt % based on the total weight of the block copolymer and the drug.
30. The composition of claim 28 , wherein the hydrophobic drug has a solubility of less than 10 mg/mL.
31. The composition of claim 28 , wherein the hydrophobic drug is selected from the group consisting of anticancer agents, antifungal agents, steroids, antiinflammatory agents, sex hormones, immunosuppressants, antiviral agents, anesthetics, antiemetics, and antihistamine agents.
32. The composition of claim 28 , wherein the hydrophobic drug is selected from the group consisting of a taxane analog, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, cyclosporine A, amphotericin B, itraconazole, ketoconazole, indomethacin, testosterone, estradiol, dexamethasone, prednisolone, and triamcinolone acetonide.
33. The composition of claim 32 , wherein the hydrophobic drug is a taxane analog.
34. The composition of claim 33 , wherein the taxane analog is paclitaxel.
35. An aqueous formulation for parenteral administration of a taxane analog comprising the composition according to claim 33 , which is dissolved in an aqueous medium and has a concentration of the taxane analog in the range of 0.1˜3 mg/mL.
36. The aqueous formulation of claim 35 , wherein the aqueous medium is a 0.9% sodium chloride water solution, 5% dextrose water solution, 5% dextrose and 0.9% sodium chloride water solution, or a 5% dextrose in Ringer's solution.
37. A method of preparing the composition according to claim 28 , which is capable of forming a stable polymeric micelle in aqueous environments, comprising the steps of: a) preparing a drug-polymer mixture by dissolving the amphiphilic block copolymer of claim 3 and a hydrophobic drug in an organic solvent followed by evaporation of the solvent; b) dissolving the drug-polymer mixture in an aqueous environment to obtain a stable micellar solution; and,
c) freeze-drying the aqueous micellar solution.
38. The method of claim 37 , wherein the content of the hydrophobic drug is up to 50 wt % based on the total weight of the block copolymer and the drug.
39. The method of claim 37 , wherein the hydrophobic drug has a solubility of less than 10 mg/mL.
40. The method of claim 39 , wherein the hydrophobic drug is selected from the group consisting of a taxane analog, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, cyclosporine A, amphotericin B, itraconazole, ketoconazole, indomethacin, testosterone, estradiol, dexamethasone, prednisolone, and triamcinolone acetonide.
41. The method of claim 37 , wherein the hydrophobic drug is a taxane analog.
42. The method of claim 38 , wherein the taxane analog is paclitaxel.