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

• US 7,153,520 B2
• Filed: 12/07/2001
• Issued: 12/26/2006
• Est. Priority Date: 12/07/2000
• Status: Expired due to Term

• Current Assignee: Samyang Holdings Corporation
• Original Assignee: Samyang Corporation (Samyang Holdings Corporation)
• Inventors: Kim, Jae-Hong, Lee, Sang-Jun, Yi, Yil-Woong, Seo, Min-Hyo
• Primary Examiner(s): Woodward, Michael P.
• Assistant Examiner(s): SILVERMAN, ERIC E
• Application Number:
  US10/416,980
• Publication Number:
  US 20040037885A1
• Time in Patent Office: 1,845 Days
• Field of Search: None
• US Class Current: 424/426
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

A composition for the sustained delivery of a drug comprising an amphiphilic diblock copolymer; a poorly water-soluble drug; a biodegradable polymer; and liquid poly(ethylene glycol) or functional derivatives thereof and a process for preparing the composition are disclosed. When administered into a particular body site, the composition forms an implant containing the drug and drug containing polymeric micelles, which are slowly released from the implant to maintain a constant drug concentration for an extended period of time.

Claims

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).

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).

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.

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).

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).