Composition for sustained delivery of hydrophobic drugs and process for the preparation thereof

1. A liquid polymeric composition for the sustained delivery of a poorly water-soluble drug comprising:

i) an amphiphilic diblock copolymer;

ii) a poorly water-soluble drug;

iii) a biodegradable polymer; and,

iv) liquid poly(ethylene glycol); wherein said amphiphilic diblock copolymer, said poorly water-soluble drug and said biodegradable polymer are dissolved or dispersed in said liquid poly(ethylene glycol); and wherein said composition is an injectable liquid at a room temperature and, upon being injected into a body, forms an implant containing polymeric micelles wherein said poorly water-soluble drugs are physically trapped and wherein said amphiphilic diblock copolymer is composed of a hydrophilic polyalkylene glycol block selected from the group consisting of polyethylene glycol, monoalkoxypolyethylene glycol and monoacyloxypolyethylene glycol and a hydrophobic biodegradable polymer block selected from the group consisting of polylactides, polycaprolactone, poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-p-dioxanone), polyorthoesters, polyanhydrides, poly(amino acid) and polycarbonates.

2. The composition of claim 1 , wherein said hydrophilic polyalkylene glycol block and said hydrophobic biodegradable polymer block have molecular weights of 500 to 20,000 Daltons, respectively.

3. The composition according to claim 1 , wherein the content of said amphiphilic diblock copolymer is within the range of 3 to 70% by weight based on the total weight of the composition.

4. The composition according to claim 1 , wherein said poorly water-soluble drug is selected from the group consisting of anticancer agents, antifungal agents, steroids, anti-inflammatory agents, sex hormones, immunosuppressants, antiviral agents, anesthetics, anti-emetics and anti-histamines, having solubilities in water of 10 mg/ml or less at ambient temperatures.

5. The composition of claim 4 , wherein said poorly water-soluble drug is a member selected from the group consisting of paclitaxel, docetaxel, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide, camptothecin, testosterone, estrogen, estradiol, triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone, cyclosporines and prostaglandins.

6. The composition according to claim 1 , wherein the content of said poorly water-soluble drug is within the range of 0.1 to 50% by weight based on the total weight of the amphiphilic diblock copolymer.

7. The composition according to claim 1 , wherein said biodegradable polymer is a polylactide, polycaprolactone or poly(lactide-co-glycolide), or a mixture thereof.

8. The composition according to claim 1 , wherein the content of the biodegradable polymer is within the range of 5 to 80% by weight based on the total weight of the composition.

9. The composition according to claim 1 , wherein said biodegradable polymer has a molecular weight of 500 to 50,000 Daltons.

10. The composition of claim 1 , wherein the content of the liquid poly(ethylene glycol) is within the range of 5 to 80% by weight based on the total weight of the composition.

11. The composition according to claim 1 , wherein said liquid poly(ethylene glycol) has a molecular weight of 100 to 3,000 Daltons.

12. The composition according to claim 1 , wherein said liquid poly(ethylene glycol) is an alkyl or allyl derivative of poly(ethylene glycol).

13. A liquid polymeric composition for the sustained delivery of a poorly water-soluble drug comprising:

i) 3 to 70 wt % based on the total weight of the composition of an amphiphilic diblock copolymer;

ii) 0.1 to 50 wt % based on the total weight of the amphiphilic diblock copolymer of a poorly water-soluble drug;

iii) 5 to 80 wt % based on the total weight of the composition a biodegradable polymer; and,

iv) 5 to 80 wt % based on the total weight of the composition of liquid poly(ethylene glycol); wherein said amphiphilic diblock copolymer, said poorly water-soluble drug and said biodegradable polymer are dissolved or dispersed in said liquid poly(ethylene glycol); and wherein said composition is an injectable liquid at a room temperature and, upon being injected into a body, forms an implant containing polymeric micelles wherein said poorly water-soluble drugs are physically trapped and wherein said amphiphilic diblock copolymer is composed of a hydrophilic polyalkylene glycol block selected from the group consisting of polyethylene glycol, monoalkoxypolyethylene glycol and monoacyloxypolyethylene glycol and a hydrophobic biodegradable polymer block selected from the group consisting of polylactides, polycaprolactone, poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-p-dioxanone), polyorthoesters, polyanhydrides, poly(amino acid) and polycarbonates.

14. The composition according to claim 13 , wherein said amphiphilic diblock copolymer is composed of a hydrophilic polyalkylene glycol block and a hydrophobic biodegradable polymer block having molecular weights of 500 to 20,000 Daltons, respectively.

15. The composition according to claim 13 , wherein said poorly water-soluble drug is selected from the group consisting of anticancer agents, antifungal agents, steroids, anti-inflammatory agents, sex hormones, immunosuppressants, antiviral agents, anesthetics, anti-emetics and anti-histamines, having solubilities in water of 10 mg/ml or less at ambient temperatures.

16. The composition of claim 15 , wherein said poorly water-soluble drug is a member selected from the group consisting of paclitaxel, docetaxel, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide, camptothecin, testosterone, estrogen, estradiol, triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone, cyclosporines and prostaglandins.

17. The composition according to claim 13 , wherein said biodegradable polymer is a member selected from the group consisting of polylactide, polycaprolactone, poly(lactide-co-glycolide) and a mixture thereof and has a molecular weight of 500 to 50,000 Daltons.

18. The composition according to claim 13 , wherein said liquid poly(ethylene glycol) has a molecular weight of 100 to 3,000 Daltons and is an alkyl or allyl derivative of poly(ethylene glycol).

19. A process for preparing the composition according to claim 1 , comprising the steps of:

i) mixing liquid polyethylene glycol, an amphiphilic diblock copolymer and a poorly water-soluble drug to form a polymeric micellar polyethylene glycol liquid composition;

ii) dissolving or dispersing a biodegradable polymer in liquid poly(ethylene glycol) to form a biodegradable polymer liquid composition; and

iii) mixing together said liquid compositions of steps i) and ii).

20. The process according to claim 19 , wherein said amphiphilic diblock copolymer is composed of a hydrophilic polyalkylene glycol block and a hydrophobic biodegradable polymer block.

21. The process according to claim 20 , wherein said hydrophilic polyalkylene glycol block is a member selected from the group consisting of polyethylene glycol, monoalkoxypolyethylene glycol and monoacyloxypolyethylene glycol, and said hydrophobic biodegradable polymer block is a member selected from the group consisting of polylactides, polycaprolactone, poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-p-dioxanone), polyorthoesters, polyanhydrides, poly(amino acid) and polycarbonates.

22. The process of claim 21 , wherein said hydrophilic polyalkylene glycol block and said hydrophobic biodegradable polymer block have molecular weights of 500 to 20,000 Daltons, respectively.

23. The process according to claim 19 , wherein the content of said amphiphilic diblock copolymer is within the range of 3 to 70% by weight based on the total weight of the composition.

24. The process according to claim 19 , wherein said poorly water-soluble drug is selected from the group consisting of anticancer agents, antifungal agents, steroids, anti-inflammatory agents, sex hormones, immunosuppressants, antiviral agents, anesthetics, anti-emetics and anti-histamines, having solubilities in water of 10 mg/ml or less at ambient temperatures.

25. The process of claim 24 , wherein said poorly water-soluble drug is a member selected from the group consisting of paclitaxel, docetaxel, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide, camptothecin, testosterone, estrogen, estradiol, triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone, cyclosporines and prostaglandins.

26. The process according to claim 19 , wherein the content of said poorly water-soluble drug is within the range of 0.1 to 50% by weight based on the total weight of the amphiphilic diblock copolymer.

27. The process according to claim 19 , wherein said biodegradable polymer is a polylactide, polycaprolactone or poly(lactide-co-glycolide), or a mixture thereof.

28. The process according to claim 19 , wherein the content of the biodegradable polymer is within the range of 5 to 80% by weight based on the total weight of the composition.

29. The process according to claim 19 , wherein said biodegradable polymer has a molecular weight of 500 to 50,000 Daltons.

30. The process of claim 19 , wherein the content of the liquid poly(ethylene glycol) is within the range of 5 to 80% by weight based on the total weight of the composition.

31. The process according to claim 19 , wherein said liquid poly(ethylene glycol) has a molecular weight of 100 to 3,000 Daltons.

32. The process according to claim 19 , wherein said liquid poly(ethylene glycol) is an alkyl or allyl derivative of poly(ethylene glycol).

33. A process for preparing the composition according to claim 13 , comprising the steps of:

i) mixing liquid polyethylene glycol, an amphiphilic diblock copolymer and a poorly water-soluble drug to form a polymeric micellar polyethylene glycol liquid composition;

ii) dissolving or dispersing a biodegradable polymer in liquid poly(ethylene glycol) to form a biodegradable polymer liquid composition; and

iii) mixing together said liquid compositions of steps i) and ii).

34. The process according to claim 33 , wherein said amphiphilic diblock copolymer is composed of a hydrophilic polyalkylene glycol block and a hydrophobic biodegradable polymer block having molecular weights of 500 to 20,000 Daltons, respectively.

35. The process according to claim 34 , wherein said hydrophilic polyalkylene glycol block is a member selected from the group consisting of polyethylene glycol, monoalkoxypolyethylene glycol and monoacyloxypolyethylene glycol, and said hydrophobic biodegradable polymer block is a member selected from the group consisting of polylactides, polycaprolactone, poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-p-dioxanone), polyorthoesters, polyahhydrides, poly(amino acid) and polycarbonates.

36. The process according to claim 33 , wherein said poorly water-soluble drug is selected from the group consisting of anticancer agents, antifungal agents, steroids, anti-inflammatory agents, sex hormones, immunosuppressants, antiviral agents, anesthetics, anti-emetics and anti-histamines, having solubilities in water of 10 mg/ml or less at ambient temperatures.

37. The process of claim 36 , wherein said poorly water-soluble drug is a member selected from the group consisting of paclitaxel, docetaxel, doxorubicin, cisplatin, carboplatin, 5 -FU, etoposide, camptothecin, testosterone, estrogen, estradiol, triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone, cyclosporines and prostaglandins.

38. The process according to claim 33 , wherein said biodegradable polymer is a member selected from the group consisting of polylactide, polycaprolactone, poly(lactide-co-glycolide) and a mixture thereof and has a molecular weight of 500 to 50,000 Daltons.

39. The process according to claim 33 , wherein said liquid poly(ethylene glycol) has a molecular weight of 100 to 3,000 Daltons and is an alkyl or allyl derivative of poly(ethylene glycol).

40. A method for the sustained delivery of a poorly water-soluble drug to a warm blooded animal comprising preparing the composition according to claim 1 by

i) mixing liquid polyethylene glycol, an amphiphilic diblock copolymer and a poorly water-soluble drug to form a polymeric micellar polyethylene glycol liquid composition;

ii) dissolving or dispersing a biodegradable polymer in liquid poly(ethylene glycol) to form a biodegradable polymer liquid composition; and

iii) mixing together said liquid compositions of steps i) and ii); and administering the liquid composition to said warm blooded animal.