Claims for Patent: 6,506,405

Summary for Patent: 6,506,405

Title:	Methods and formulations of cremophor-free taxanes
Abstract:	In accordance with the present invention, there are provided composition and methods useful for the in vivo delivery of a pharmaceutically active agent, wherein the agent is associated with a polymeric biocompatible material.
Inventor(s):	Desai; Neil P. (Los Angeles, CA), Soon-Shiong; Patrick (Los Angeles, CA)
Assignee:	American BioScience, Inc. (Santa Monica, CA)
Application Number:	09/628,388
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,506,405
Patent Claims:	1. A pharmaceutically acceptable formulation of paclitaxel for treatment of primary tumors in a subject which achieves high local concentration of said paclitaxel at the tumor site, said formulation being substantially free of cremophor and comprising paclitaxel in a dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2. 2. The formulation of claim 1, wherein said formulation is free of cremophor. 3. The formulation of claim 1, wherein said primary tumors are selected from cancers of prostate, testes, lung, kidney, pancreas, bone, spleen, liver or brain. 4. The formulation of claim 1 further comprising albumin. 5. The formulation of claim 1, wherein said formulation shows reduced cerebral or neurologic toxicity. 6. A paclitaxel containing formulation suitable for the delivery of a total dose of paclitaxel in the range of about 50 mg/m.sup.2 to about 800 mg/m.sup.2, with an administration period of no greater than about 3 hours. 7. A formulation according to claim 6, wherein said total dose is in the range of about 70 mg/m.sup.2 to about 400 mg/m.sup.2. 8. A paclitaxel containing formulation suitable for the delivery of a total dose of paclitaxel in the range of about 80 mg/m.sup.2 to about 700 mg/m.sup.2, with a treatment cycle of no greater than about 3 weeks. 9. A formulation according to claim 8, wherein said total dose is in the range of about 70 mg/m.sup.2 to about 400 mg/m.sup.2. 10. A unit dosage form comprising a vessel containing a sufficient quantity of paclitaxel to allow systemic administration at a dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 over an administration period of less than 3 hours, wherein said paclitaxel is administered as a non-aqueous formulation, and wherein said non-aqueous formulation is substantially free of cremophor. 11. A unit dosage form according to claim 10, wherein said formulation is free of cremophor. 12. A unit dosage form according to claim 10, wherein said paclitaxel is administered as a dry powder formulation. 13. A method for administration of paclitaxel to a subject in need thereof, said method comprising systemically administering a dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 of said paclitaxel to said subject in a pharmaceutically acceptable formulation substantially free of cremophor, without the use of premedication. 14. The method of claim 13, wherein said formulation is free of cremophor. 15. The method of claim 13, wherein said paclitaxel is administered over an administration period of less than about 3 hours. 16. The method of claim 13, wherein said administration period is less than about 2 hours. 17. The method of claim 13, wherein said administration period is less than about 1 hour. 18. The method of claim 13, wherein said method does not require use of agents which aid recovery from hematologic toxicity of paclitaxel. 19. The method of claim 13, wherein said dose is at least about 135 mg/m.sup.2. 20. The method of claim 13, wherein said dose is at least about 175 mg/m.sup.2. 21. The method of claim 13, wherein said dose is at least about 250 mg/m.sup.2. 22. The method of claim 13, wherein said dose is greater than about 80 mg/m.sup.2 and up to about 700 mg/m.sup.2. 23. The method of claim 13, wherein said pharmaceutically acceptable formulation is administered as a bolus injection. 24. The method of claim 23, wherein said dose is at least 135 mg/m.sup.2. 25. The method of claim 13, wherein said administration has a treatment cycle of no greater than about 2 weeks. 26. The method of claim 13, wherein said dose is at least about 50 mg/m.sup.2. 27. A method for reducing the hematologic toxicity of paclitaxel in a subject undergoing treatment with paclitaxel, said method comprising systemically administering a dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 of said paclitaxel to said subject in a pharmaceutically acceptable formulation, wherein said pharmaceutically acceptable formulation is substantially free of cremophor. 28. The method of claim 27, wherein said formulation is free of cremophor. 29. The method of claim 27, wherein said pharmaceutically acceptable formulation further comprises albumin. 30. A method for reducing the cerebral or neurologic toxicity of paclitaxel in a subject undergoing treatment with paclitaxel, said method comprising systemically administering a dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 of said paclitaxel to said subject in a pharmaceutically acceptable formulation, wherein said pharmaceutically acceptable formulation is substantially free of cremophor. 31. The method of claim 30, wherein said formulation is free of cremophor. 32. The method of claim 30, wherein said pharmaceutically acceptable formulation further comprises albumin. 33. A method for treatment of primary tumors in a subject by achieving high local concentration of paclitaxel at the tumor site, said method comprising systemically administering a dose in the range of about 30 mg/m.sup.2 go about 1000mg/m.sup.2 of said paclitaxel to said subject in a pharmaceutically acceptable formulation substantially free of cremophor. 34. The method of claim 33, wherein said formulation is free of cremophor. 35. The method of claim 33, wherein said primary tumors are selected from cancers of prostate, testes, lung, kidney, pancreas, bone, spleen, liver or brain. 36. The method of claim 33, wherein said pharmaceutically acceptable formulation further comprises albumin. 37. A method for treatment of metastatic tumors in a subject by achieving high local concentration of paclitaxel at the site of metastases, said method comprising systemically administering a dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 of said paclitaxel to said subject in a pharmaceutically acceptable formulation substantially free of cremophor. 38. The method of claim 37, wherein said formulation is free of cremophor. 39. The method of claim 37, wherein said site of metastases are selected from lung, bone, liver or brain. 40. The method of claim 37, wherein said pharmaceutically acceptable formulation further comprises albumin. 41. The method for treatment of prostatic cancer in a subject by administering a dose of paclitaxel in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of cremophor, thereby inducing a medical orchiectomy. 42. The method of claim 41, wherein said formulation is free of cremophor. 43. The method of claim 41, wherein said pharmaceutically acceptable formulation further comprises albumin. 44. A method for administration of taxane to a subject in need thereof, said method comprising administering a therapeutically effective amount of said taxane in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of cremophor with a treatment cycle no greater than about 3 weeks. 45. A method for administration of docetaxel to a subject in need thereof, said method comprising administering a therapeutically effective amount of said docetaxel in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of cremophor with a treatment cycle no greater than about 3 weeks. 46. A method for administration of taxane to a subject in need thereof, said method comprising administering a therapeutically effective amount of said taxane in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of cremophor with an administration period no greater than about 3 hours. 47. A method for administration of docetaxel to a subject in need thereof, said method comprising administering a therapeutically effective amount of said docetaxel in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of cremophor with an administration period no greater than about 13 hours. 48. A method for administration of taxane to a subject in need thereof, said method comprising administering a therapeutically effective amount of said taxane in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of cremophor, wherein the treatment of said subject receiving said taxane does not include the administration of agents which aid in the recovery from hematologic toxicity. 49. A method for administration of docetaxel to a subject in need thereon said method comprising administering a therapeutically effective amount of said docetaxel in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of surfactants, wherein the treatment of said subject receiving said docetaxel does not include the administration of agents which aid in the recovery from hematologic toxicity. 50. A method for administration of taxane to a subject in need thereof, said method comprising administering a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said taxane remains stable for greater than about 24 hours and less than about 3 days following addition thereto of an aqueous diluent. 51. A method for administration of docetaxel to a subject in need thereof, said method comprising administering a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of docetaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said docetaxel remains stable for greater than about 24 hours and less than about 3 days following addition thereto of an aqueous diluent. 52. A method for administration of taxane to a subject in need thereof, said method comprising administering a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein refrigeration does not adversely affect the stability of said taxane. 53. A method for administration of docetaxel to a subject in need thereof, said method comprising administering a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of docetaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein refrigeration does not adversely affect the stability of said docetaxel. 54. A method for treatment of primary tumors, said method comprising administration to a subject in need thereof a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2. 55. A method for treatment of primary tumors, said method comprising administration to a subject in need thereof a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of docetaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2. 56. A method for treatment of metastatic tumors, said method comprising administration to a subject in need thereof a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m to about 1000 mg/m.sup.2. 57. A method for treatment of metastatic tumors, said method comprising administration to a subject in need thereof a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of docetaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2. 58. A method for administration of taxane to a subject in need thereof, said method comprising administering a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 100 mg/m.sup.2, wherein said taxane does not leach plasticizer from administration devices used to administer said unit dosage formulation. 59. A method for administration of docetaxel to a subject in need thereof, said method comprising administering a unit dosage form substantially free of cremophor comprising a vessel containing a sufficient quantity of docetaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said docetaxel does not leach plasticizer from administration devices used to administer said unit dosage formulation. 60. A method for administration of paclitaxel to a subject in need thereof, said method comprising administering a unit dosage form comprising a vessel containing a sufficient quantity of paclitaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing cremophor. 61. A unit dosage form comprising a vessel containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing cremophor. 62. A unit dosage form according to claim 61, wherein said total dose is in the range of about 70 mg/m.sup.2 to about 400 mg/m.sup.2. 63. A unit dosage form comprising a vessel containing a sufficient quantity of docetaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing cremophor. 64. A unit dosage form according to claim 63, wherein said total dose is in the range of about 70 mg/m.sup.2 to about 400 mg/m.sup.2. 65. A pharmaceutically acceptable formulation of paclitaxel for treatment of primary tumors in a subject which achieves high local concentration of said paclitaxel at the tumor site, said formulation being substantially free of surfactants and comprising paclitaxel in a dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2. 66. A unit dosage form comprising a vessel containing a sufficient quantity of paclitaxel to allow systemic administration at a dose in the range of about 30 mg/m2 to about 1000 mg/m.sup.2 over an administration period of less than 3 hours, wherein said paclitaxel is administered as a non-aqueous formulation, and wherein said non-aqueous formulation is substantially free of surfactants. 67. A method for administration of taxane to a subject in need thereof, said method comprising administering a therapeutically effective amount of said taxane in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of surfactants with a treatment cycle no greater tan about 3 weeks. 68. A method for administration of docetaxel to a subject in need thereof, said method comprising administering a therapeutically effective amount of said docetaxel in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of surfactants with a treatment cycle no greater than about 3 weeks. 69. A method for administration of taxane to a subject in need thereof, said method comprising administering a therapeutically effective amount of said taxane in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially of surfactants with an administration period no greater than about 3 hours. 70. A method for administration of docetaxel to a subject in need thereof, said method comprising administering a therapeutically effective amount of said docetaxel in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of surfactants with an administration period no greater than about 3 hours. 71. A unit dosage form comprising a vessel containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing surfactants. 72. A unit dosage form comprising a vessel containing a sufficient quantity of docetaxel to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing surfactants. 73. A method for the reduction of serum testosterone levels in a subject by administering a dose of paclitaxel in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2 to said subject in a pharmaceutically acceptable formulation substantially free of cremophor. 74. The method of claim 73, wherein said formulation is free of cremophor. 75. The method of claim 73, wherein said pharmaceutically acceptable formulation further comprises albumin. 76. A unit dosage form substantially free of cremophor comprising a sealed vial containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing cremophor. 77. A unit dosage form according to claim 76, wherein said total dose is in the range of about 70 mg/m.sup.2 to about 400 mg/m.sup.2. 78. A unit dosage form of taxane comprising article of manufacture, wherein said article comprises a sealed vial containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said wit dosage form is substantially free of cremophor, and wherein said unit dosage form confers reduced incidence of hypersensitivity compared to a subject receiving a formulation containing cremophor. 79. A unit dosage form of taxane comprising an article of manufacture containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form is substantially free of cremophor, and wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing cremophor. 80. A unit dosage form of taxane comprising an article of manufacture containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said unit dosage form is substantially free of surfactants, and wherein said unit dosage form confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing surfactants. 81. An article of manufacture comprising taxane wherein said article comprises a sealed vial containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said article is substantially free of cremophor, and wherein said article confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing cremophor. 82. An article of manufacture comprising taxane wherein said article comprises a sealed vial containing a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said article is substantially free of surfactants, and wherein said article confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing surfactants. 83. An article of manufacture comprising taxane wherein said article contains a sufficient quantity of taxane to provide for administration to a subject at a total dose in the range of about 30 mg/m.sup.2 to about 1000 mg/m.sup.2, wherein said article is substantially free of cremophor, and wherein said article confers reduced incidence of hypersensitivity as compared to a subject receiving a formulation containing cremophor. 84. An article of manufacture comprising a lyophilized taxane substantially free of cremophor suitable for treatment of a subject in need thereof at a dose in the range of 30-1000 mg/m.sup.2. 85. An article of manufacture comprising a lyophilized taxane substantially free of surfactants suitable for treatment of a subject in need thereof at a dose in the range of 30-1000 mg/m.sup.2. 86. An article of manufacture according to claim 84, wherein said taxane is characterized by the ability to be reconstituted at concentrations greater than 1.3 mg/ml and remaining stable for at least 3 days. 87. An article of manufacture according to claim 84 wherein said taxane is characterized by the ability to be administered in standard infusion sets. 88. An article of manufacture according to claim 85, wherein said taxane is characterized by the ability to be reconstituted at concentrations greater than 1.3 mg/ml and remaining stable for at least 3 days. 89. An article of manufacture according to claim 85 wherein said taxane is characterized by the ability to be administered in standard infusion sets.