Claims
- 1. A solid formulation, said formulation comprising 5-60% w/w of an indolinone of formula I:
- 2. The formulation of claim 1, wherein the salt of said indolinone is the malate salt.
- 3. The formulation of claim 1, wherein the salt of said indolinone is the maleate salt.
- 4. The formulation of claim 1, wherein the salt of said indolinone is the L-malate salt of
- 5. The formulation of claim 1, wherein the salt of said indolinone is the maleate salt of
- 6. The formulation of claim 1, wherein the salt of said indolinone is the maleate salt of
- 7. The formulation of claim 1, wherein the salt of said indolinone is a mixture of the maleate salt of
- 8. The formulation of claim 1, wherein each of said one or more pharmaceutically acceptable diluents is selected from the group consisting of pregelatinized starch, lactose monohydrate, lactose monohydrate regular grade, mannitol, calcium phosphate and microcrystalline cellulose.
- 9. The formulation of claim 1, wherein each of said one or more pharmaceutically acceptable binders is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropylcellulose and starch.
- 10. The formulation of claim 1, wherein each of said one or more pharmaceutically acceptable disintegrants is selected from the group consisting of crosscarmellose sodium, sodium starch glycolate, crospovidone, and starch.
- 11. The formulation of claim 1, wherein each of said one or more pharmaceutically acceptable lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl behenate and stearic acid.
- 12. The formulation of claim 1, wherein the amount of indolinone is from 5-55% w/w.
- 13. The formulation of claim 1, wherein the amount of indolinone is from 10-60% w/w.
- 14. The formulation of claim 1, wherein the amount of indolinone is from 15-50% w/w.
- 15. The formulation of claim 1, wherein the amount of indolinone is from 35-45% w/w.
- 16. The formulation of claim 1, wherein the amount of indolinone is from 39-43% w/w.
- 17. The formulation of claim 1, wherein the amount of indolinone is from 10-60% w/w.
- 18. The formulation of claim 1, wherein the amount of indolinone is from 10-40% w/w.
- 19. The formulation of claim 1, wherein the amount of indolinone is from 20-50% w/w.
- 20. The formulation of claim 1, wherein the amount of indolinone is from 38-42% w/w.
- 21. The formulation of claim 1, wherein the amount of indolinone is from 38-41% w/w.
- 22. The formulation of claim 1, wherein the amount of indolinone is from 39-41% w/w.
- 23. The formulation of claim 1, wherein the amount of indolinone is from 10-45% w/w.
- 24. The formulation of claim 1, wherein the amount of indolinone is from 15-40% w/w.
- 25. The formulation of claim 1, wherein the amount of diluent is from 10-80% w/w.
- 26. The formulation of claim 1, wherein the amount of diluent is from 20-86% w/w.
- 27. The formulation of claim 1, wherein the amount of diluent is from 30-80% w/w
- 28. The formulation of claim 1, wherein the amount of diluent is from 10-25% w/w.
- 29. The formulation of claim 1, wherein the amount of diluent is from 25-50% w/w.
- 30. The formulation of claim 1, wherein the amount of diluent is from 34-60% w/w.
- 31. The formulation of claim 1, wherein the amount of diluent is from 34-77%.
- 32. The formulation of claim 1, wherein the amount of diluent is from 45-65% w/w.
- 33. The formulation of claim 1, wherein the amount of diluent is from 39-80% w/w
- 34. The formulation of claim 1, wherein the amount of diluent is from 45-49% w/w.
- 35. The formulation of claim 1, wherein the amount of diluent is from 46-50% w/w.
- 36. The formulation of claim 1, wherein the amount of diluent is from 45-48% w/w.
- 37. The formulation of claim 1, wherein the amount of diluent is from 46-48% w/w.
- 38. The formulation of claim 1, wherein the amount of binder is from 2-10% w/w.
- 39. The formulation of claim 1, wherein the amount of binder is from 5-20% w/w.
- 40. The formulation of claim 1, wherein the amount of binder is from 5-10% w/w.
- 41. The formulation of claim 1, wherein the amount of binder is from 3-6% w/w.
- 42. The formulation of claim 1, wherein the amount of binder is from 3-8% w/w.
- 43. The formulation of claim 1, wherein the amount of binder is from 4-6% w/w.
- 44. The formulation of claim 1, wherein the amount of binder is from 5-10% w/w.
- 45. The formulation of claim 1, wherein the amount of binder is from 4-8% w/w.
- 46. The formulation of claim 1, wherein the amount of binder is from 5-9% w/w.
- 47. The formulation of claim 1, wherein the amount of binder is from 4-7% w/w.
- 48. The formulation of claim 1, wherein the amount of binder is from 5-7% w/w.
- 49. The formulation of claim 1, wherein the amount of disintegrant is from 2-10% w/w.
- 50. The formulation of claim 1, wherein the amount of disintegrant is from 5-20 w/w.
- 51. The formulation of claim 1, wherein the amount of disintegrant is from 5-10% w/w.
- 52. The formulation of claim 1, wherein the amount of disintegrant is from 4-8% w/w.
- 53. The formulation of claim 1, wherein the amount of disintegrant is from 5-8% w/w.
- 54. The formulation of claim 1, wherein the amount of disintegrant is from 3-7% w/w.
- 55. The formulation of claim 1, wherein the amount of disintegrant is from 3-6% w/w.
- 56. The formulation of claim 1, wherein the amount of disintegrant is from 4-6% w/w.
- 57. The formulation of claim 1, wherein the amount of lubricant is from 1-10% w/w.
- 58. The formulation of claim 1, wherein the amount of lubricant is from 0.1-2.5% w/w.
- 59. The formulation of claim 1, wherein the amount of lubricant is from 1-5% w/w.
- 60. The formulation of claim 1, wherein the amount of lubricant is from 0.5-2% w/w.
- 61. The formulation of claim 1, wherein the amount of lubricant is from 1-2% w/w.
- 62. The formulation of claim 1, wherein the amount of lubricant is from 1-1.5% w/w.
- 63. The formulation of claim 1, wherein the amount of lubricant is from 1-2.5% w/w.
- 64. The formulation of claim 1, wherein the amount of lubricant is from 1.3-1.7% w/w.
- 65. The formulation of claim 1, wherein the amount of lubricant is from 1.4-1.8% w/w.
- 66. The formulation of claim 1, wherein the amount of lubricant is from 1.3-1.6% w/w.
- 67. The formulation of claim 1, wherein the amount of lubricant is from 1.4-1.6% w/w.
- 68. The formulation of claim 1, wherein said diluent is mannitol.
- 69. The formulation of claim 1, wherein said binder is polyvinylpyrrolidone.
- 70. The formulation of claim 1, wherein said disintegrant is crosscaramellose sodium.
- 71. The formulation of claim 1, wherein said lubricant is magnesium stearate.
- 72. The formulation of claim 1, wherein:
R1 is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, —(CO)R15, —NR13R14, —(CH2)rR16 and —C(O)NR8R9; R2 is selected from the group consisting of hydrogen, halo, alkyl, trihalomethyl, hydroxy, alkoxy, cyano, —NR13R14, —NR13C(O)R14, —C(O)R15, aryl, heteroaryl, and —S(O)2NR13R14; R3 is selected from the group consisting of hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, —(CO)R15, —NR13R14, aryl, heteroaryl, —NR13S(O)2R14, —S(O)2NR13R14, —NR13C(O)R14, —NR13C(O)OR14 and —SO2R20 (wherein R20 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl); R4 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and —NR13R14; R5 is selected from the group consisting of hydrogen and alkyl; R6 is —C(O)R10 wherein R10 is —NR11(CH2)nR12 wherein:
R11 is hydrogen or lower unsubstituted alkyl; n is 2 or 3; and R12 is selected from the group consisting of —NR13R14,—N+(O−)R13R14, and —N(OH)R13; R7 is selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl and aryl; R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, lower alkyl substituted with hydroxy, alkylamino, cyanoalkyl, cycloalkyl, aryl and heteroaryl; or R13 and R14 may combine to form a heteroalicyclic or heteroaryl group; R15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy; R16 is selected from the group consisting of hydroxy, —C(O)R15, —NR13R14 and —C(O)NR13R14; and r is 1,2,3, or 4.
- 73. The formulation of claim 1, wherein R6 is —C(O)R10 wherein R10 is —NHCH2CH(OH)CH2R12, wherein R12 is selected from the group consisting of —NR13R14,—N+(O−)R13R14 and —N(OH)R13; and R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, lower alkyl substituted with hydroxy, alkylamino, cyanoalkyl, cycloalkyl, aryl and heteroaryl; or R13 and R14 may combine to form a heteroalicyclic or heteroaryl group.
- 74. The formulation of claim 1, wherein R6 is —C(O)R10 wherein R10 is —NR11(CH2)nR12 wherein:
R11 is hydrogen or lower unsubstituted alkyl; n is 2 or 3; and R12 is —NR13R14 wherein R13 and R14 are independently unsubstituted lower alkyl; and R7 is selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl.
- 75. The formulation of claim 1, wherein R6 is N-(2-dimethylaminoethyl)aminocarbonyl, N-(2-diethylaminoethyl)-N-methylaminocarbonyl, N-(3-dimethylaminopropyl)aminocarbonyl, N-(2-diethylaminoethyl)aminocarbonyl, N-(2-ethylaminoethyl)aminocarbonyl, N-(3-ethylaminopropyl)aminocarbonyl, N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-aminocarbonyl, N-(2-pyrrolidin-1-yl-ethyl)-aminocarbonyl or N-(3-diethylaminopropyl)aminocarbonyl.
- 76. The formulation of claim 1, wherein the compound of formula is selected from the group consisting of:
- 77. The formulation of claim 1, wherein the compound of formula I is:
- 78. The formulation of claim 1, wherein said formulation comprises 15-60% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 25-75% w/w mannitol, 4-8% w/w croscaramellose sodium, 4-6% w/w povidone and 0.5-2% w/w magnesium stearate.
- 79. The formulation of claim 1, wherein said formulation comprises 30-50% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 35-60% w/w mannitol, 5-8% w/w croscaramellose sodium, 4-6% w/w povidone and 1-2% w/w magnesium stearate.
- 80. The formulation of claim 1, wherein said formulation comprises 40% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 47.5% w/w mannitol, 6% w/w croscararnellose sodium, 5% w/w povidone and 1.5% w/w magnesium stearate.
- 81. The formulation of claim 1, wherein said formulation comprises 10-16% w/w of an indolinone of formnula I, or a pharmaceutically acceptable salt thereof, 65-80% w/w mannitol, 5-10% w/w croscaramellose sodium, 4-8% w/w povidone and 1-2% w/w magnesium stearate.
- 82. The formulation of claim 1, wherein said formulation comprises 15.2% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 72.7% w/w mannitol, 6% w/w croscaramellose sodium, 5.1% w/w povidone and 1% w/w magnesium stearate.
- 83. The formulation of claim 1, wherein said formulation comprises 38-42% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 45-49% w/w mannitol, 4-8% w/w croscaramellose sodium, 3-7% w/w povidone and 1.3-1.7% w/w magnesium stearate.
- 84. The formulation of claim 1, wherein said formulation comprises 39-43% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 46-50% w/w mannitol, 5-9% w/w croscaramellose sodium, 4-8% w/w povidone and 1.4-1.8% w/w magnesium stearate.
- 85. The formulation of claim 1, wherein said formulation comprises 38-41% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 45-48% w/w mannitol, 4-7% w/w croscararnellose sodium, 3-6% w/w povidone and 1.3-1.6% w/w magnesium stearate.
- 86. The formulation of claim 1, wherein said formulation comprises 39-43% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 46-50% w/w mannitol, 5-9% w/w croscaramellose sodium, 4-8% w/w povidone and 1.4-1.8% w/w magnesium stearate.
- 87. The formulation of claim 1, wherein said formulation comprises 39-41% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 46-48% w/w mannitol, 5-7% w/w croscaramellose sodium, 4-6% w/w povidone and 1.4-1.6% w/w magnesium stearate.
- 88. The formulation of claim 1, wherein said formulation comprises 39-43% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 46-50% w/w mannitol, 5-9% w/w croscaramellose sodium, 4-8% w/w povidone and 0.8-1.5% w/w magnesium stearate.
- 89. The formulation of claim 1, wherein said formulation comprises 39-43% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 46-50% w/w mannitol, 5-9% w/w croscaramellose sodium, 4-8% w/w povidone and 0.8-1.2% w/w magnesium stearate.
- 90. A solid formulation, said formulation comprising 5-60% w/w of an indolinone of formula I:
- 91. A solid formulation, said formulation consisting essentially of 5-60% w/w of an indolinone of formula I:
- 92. A solid formulation, said formulation comprising 5-60% w/w of the malate salt of an indolinone of formula I:
- 93. A solid formulation comprising an indolinone compound of formula I:
- 94. The formulation of 93, wherein the bulk density of said solid formulation is about 2 to about 8 fold higher than the bulk density of the indolinone compound by itself.
- 95. The formulation of 93, wherein the bulk density of said formulation is about 0.55, 0.56, 0.57, 0.58, 0.59. 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.69 or 0.7 kg/L.
- 96. The formulation of one of claims 93, wherein the ratio of tap density to bulk density of said formulation is from about 1.10 to about 1.30.
- 97. The formulation of claim 93, wherein the ratio is from about 1.10 to about 1.33, or about 1.10 to about 1.25, or about 1.10 to about 1.20, or about 1.10 to about 1.15.
- 98. The formulation of claim 93, wherein said salt of said compound is
- 99. The formulation of claim 93, wherein said formulation comprises 15-40% of the indolinone compound.
- 100. The formulation of claim 93, wherein said formulation comprises 40% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 47.5% w/w mannitol, 6% w/w croscaramnellose sodiumn, 5% w/w povidone and 1.5% w/w magnesium stearate.
- 101. A solid formulation comprising an indolinone compound of formula I:
- 102. The formulation of claim 101, wherein said salt of said compound is
- 103. The formulation of claim 101, wherein said formulation comprises 15-40% of the indolinone compound.
- 104. The formulation of claim 101, wherein said formulation comprises 40% w/w of an indolinone of formula I, or a pharmaceutically acceptable salt thereof, 47.5% w/w mannitol, 6% w/w croscaramellose sodium, 5% w/w povidone and 1.5% w/w magnesium stearate.
- 105. A solid formulation comprising an indolinone compound of formula I:
- 106. A solid formulation comprising the malate salt of an indolinone compound of formula I:
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application Serial No. 60/421,133, filed Sep. 10, 2002, the disclosure of which is incorporated by reference herein in its entirety.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60421133 |
Sep 2002 |
US |