Claims for Patent: 6,828,346

Summary for Patent: 6,828,346

Title:	Methods for administration of paclitaxel
Abstract:	Methods are provided for using paclitaxel for treating diseases associated with abnormal cell proliferation and angiogenesis. In particular, methods are provided for administration of paclitaxel formulated with vitamin E derivatives such as d-.alpha.-tocopherol polyethylene glycol succinate to a cancer patient. By administering to a patient paclitaxel in a vehicle containing a solubilizer other than Cremophor, acute hypersensitivity caused by Cremophor can be avoided and therapeutic index of paclitaxel may also be increased through potentiation of anti-neoplastic effects by the vitamin E derivatives.
Inventor(s):	Joshi-Hangal; Rajashree (Union City, CA), Sands; Howard (Wilmington, DE), Rubinfeld; Joseph (Danville, CA)
Assignee:	SuperGen, Inc. (Dublin, CA)
Application Number:	10/351,262
Patent Claims:	1. A method for treating a disease associated with undesirable cell proliferation or angiogenesis in a patient suffering therefrom, comprising: providing a water miscible, non-aqueous paclitaxel formulation comprising paclitaxel and ascorbic acid dissolved in a water-miscible non-aqueous solvent and a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures of wherein R.sub.1 is a derivative of d-.alpha.-tocopherol and R.sub.2 is a hydrophilic moiety; diluting the water miscible, non-aqueous paclitaxel formulation into a pharmaceutically acceptable aqueous solution; and parenterally administering to the patient the pharmaceutically acceptable aqueous solution comprising paclitaxel at a dose of 0.1-50 mg/Kg, wherein the said disease is sensitive to the effects of said non-aqueous paclitaxel formulation. 2. The method of claim 1, wherein the pharmaceutically acceptable aqueous solution is administered intravenously. 3. The method of claim 1, wherein paclitaxel is at a dose of 1-20 mg/Kg. 4. The method of claim 1, wherein paclitaxel is at a dose of 1-10 mg/Kg. 5. The method of claim 1, wherein paclitaxel is at a dose of 2-8 mg/Kg. 6. The method of claim 1, wherein paclitaxel is at a dose of 3-6 mg/Kg. 7. The method of claim 1, wherein the pharmaceutically acceptable aqueous solution is administered by infusion to the patient for less than 6 hours. 8. The method of claim 1, wherein the pharmaceutically acceptable aqueous solution is administered by infusion to the patient for less than 3 hours. 9. The method of claim 1, wherein the pharmaceutically acceptable aqueous solution is administered to the patient once every week. 10. The method of claim 1, wherein the pharmaceutically acceptable aqueous solution is administered to the patient once every two weeks. 11. The method of claim 1, wherein the pharmaceutically acceptable aqueous solution is administered to the patient once every three weeks. 12. The method of claim 1, wherein the solubilizer is d-.alpha.-tocopherol polyethylene glycol succinate. 13. The method of claim 12, wherein the d-.alpha.-tocopherol polyethylene glycol succinate is d-.alpha.-tocopherol polyethylene glycol 1000 succinate. 14. The method of claim 1, wherein the water-miscible non-aqueous solvent is an alcohol. 15. The method of claim 14, wherein the solvent is selected from the group consisting of ethanol, propylene glycol, benzyl alcohol, and polyethylene glycol (PEG). 16. The method of claim 1, wherein the solvent is an amide. 17. The method of claim 16, wherein the solvent is selected from the group consisting of 2-pyrrolidone, N-methyl-pyrrolidone and N,N-dimethyl acetamide. 18. The method of claim 13, wherein the weight ratio of d-.alpha.-tocopherol polyethylene glycol succinate to the solvent is between about 90:10 and 40:60. 19. The method of claim 13, wherein the weight ratio of d-.alpha.-tocopherol polyethylene glycol succinate to the solvent is between about 70:30 and 45:55. 20. The method of claim 13, wherein the weight ratio of d-.alpha.-tocopherol polyethylene glycol succinate to the solvent is between about 50:50. 21. The method of claim 1, wherein the water-miscible, non-aqueous paclitaxel formulation is diluted with infusion fluid to form the pharmaceutically acceptable aqueous solution. 22. The method of claim 1, wherein the amount of ascorbic acid in the paclitaxel formulation before the dilution is between about 0.1-5% w/w. 23. The method of claim 1, wherein the amount of ascorbic acid in the paclitaxel formulation before the dilution is between about 0.4-2% w/w. 24. The method of claim 1, wherein the amount of ascorbic acid in the paclitaxel formulation before the dilution is between about 0.5-1% w/w. 25. The method of claim 1, further comprising: administering to the patient a desensitizer that reduces allergic effects of the pharmaceutical composition on the patient. 26. The method of claim 25, wherein the desensitizer is a steroid, antihistamine or an H-2 receptor blocker. 27. The method of claim 26, wherein the steroid is selected from the group consisting of dexamethasone, prednisone and hydrocortisone. 28. The method of claim 26, wherein the antihistamine is diphenhydramine. 29. The method of claim 26, wherein the H-2 receptor blocker is cimetidine or ranitidine 30. The method of claim 25, wherein the desensitizer is administered to the patient prior to administration of the pharmaceutically acceptable aqueous solution. 31. The method of claim 1, further comprising: administering to the patient granulocyte-colony stimulating factor. 32. The method of claim 31, wherein granulocyte-colony stimulating factor is administered to the patient at least 24 hours after the administration of the pharmaceutical composition. 33. The method of claim 1, further comprising: administering to the patient an antineoplastic agent selected from the group consisting of an alkylating agent, antibiotic agent, antimetabolic agent, hormonal agent, plant-derived agent, and biologic agent. 34. The method of claim 33, wherein the alkylating agent is selected from the group consisting of bischloroethylamines, aziridines, alkyl alkone sulfonates, nitrosoureas, nonclassic alkylating agents and platinum compounds. 35. The method of claim 33, wherein the antibiotic agent is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione, mitomycin C, bleomycin, dactinomycin, and plicatomycin. 36. The method of claim 33, wherein the antimetabolic agent is selected from the group consisting of fluorouracil, floxuridine, methotrexate, leucovorin, hydroxyurea, thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine phosphate, cladribine, asparaginase, and gemcitabine. 37. The method of claim 33, wherein the hormonal agent is selected from the group consisting of diethylstibestrol, tamoxifen, toremifene, fluoxymesterol, raloxifene, bicalutamide, nilutamide, flutamide, aminoglutethimide, tetrazole, ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone. 38. The method of claim 33, wherein the plant-derived agent is selected from the group consisting of vincristine, vinblastine, vindesine, vinzolidine, vinorelbine, etoposide teniposide, camptothecin. 39. The method of claim 33, wherein the biologic agent is selected from the group consisting of immuno-modulating proteins, monoclonal antibodies against tumor antigens, tumor suppressor genes, and cancer vaccines. 40. The method of claim 39, wherein the immuno-modulating protein is selected from the group consisting of interleukin 2, interleukin 4, interleukin 12, interferon .alpha., interferon .beta., interferon .gamma., erytbropoietin, granulocyte-CSF, granulocyte, macrophage-CSF, bacillus Calmette-Guerin, levamisole, and octreotide. 41. The method of claim 39, wherein the monoclonal antibody against tumor antigen is HERCEPTIN.RTM. (Trastruzumab), or RITUXAN.RTM. (Rituximab). 42. The method of claim 39, wherein the tumor suppressor gene is selected from the group consisting of DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA, and BRCA2. 43. The method of claim 1, wherein the disease associated with undesirable cell proliferation or angiogenesis is selected from the group consisting of restenosis, benign tumors, malignant tumors and tumor metastasis, atherosclerosis, insults to body tissue due to surgery, abnormal wound healing, fibrosis of tissue, repetitive motion disorders, and proliferative responses associated with organ transplants. 44. A method for treating a disease associated with undesirable cell proliferation or angiogenesis in a patient suffering therefrom, comprising: orally administering to the patient a water-miscible, non-aqueous pharmaceutical composition comprising paclitaxel at a dose of 0.1-100 mg/Kg, wherein the pharmaceutical composition further comprises ascorbic acid, both paclitaxel and ascorbic acid being dissolved in a water-miscible, non-aqueous solvent and a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures of R.sub.1 COOR.sub.2, R.sub.1 CONR.sub.2, and R.sub.1 COR.sub.2, wherein R.sub.1 is a derivative of d-.alpha.-tocopherol and R.sub.2 is a hydrophilic moiety; and said disease is sensitive to the effects of said non-aqueous paclitaxel composition. 45. The method of claim 44, wherein the solubilizer is d-.alpha.-tocopherol polyethylene glycol succinate. 46. The method of claim 45, wherein the d-.alpha.-tocopherol polyethylene glycol succinate is d-.alpha.-tocopherol polyethylene glycol 1000 succinate. 47. The method of claim 44, wherein the pharmaceutical composition further comprises polyethylene glycol (PEG). 48. The method of claim 47, wherein said polyethylene glycol is PEG 300 or PEG. 400.

Details for Patent 6,828,346

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2019-10-25
Merck Teknika Llc	TICE BCG	bcg live	For Injection	102821	06/21/1989		2019-10-25
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2019-10-25
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2019-10-25