1. A pharmaceutical formulation, comprising:
a compound of formula I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof,
and
at least one ingredient selected from the group consisting of (i) cellulose; (ii) lactose, starch, or a mixture thereof; (iii) povidone; (iv) silicon dioxide or talc; (v) a pharmaceutically acceptable lubricant; and (vi) an ingredient selected from crospovidone, croscarmellose sodium; or sodium starch glycolate.
2. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable lubricant is selected from the group consisting of a C16-22 fatty acid, a salt of a C16-22 fatty acid, a C16-22 fatty acid ester, a salt of a C16-22 fatty acid ester; a polyethylene glycol having an average molecular weight of 6,000 to 10,000.
3. The pharmaceutical formulation of claim 1, wherein the formulation comprises:
(i) cellulose;
(ii) silicon dioxide;
(iii) stearic acid or a salt of stearic acid; and
(iv) at least one ingredient selected from crospovidone, starch, lactose, croscarmellose sodium, or sodium starch glycolate.
4. The pharmaceutical formulation of claim 1, wherein the formulation comprises a lactic acid salt of the compound of formula I.
5. The formulation of claims 1, wherein the lactic acid salt of the compound of formula I is in an anhydrous crystalline form.
6. The formulation of claim 5 wherein the anhydrous crystalline form is Form A.
7. The pharmaceutical formulation of claim 1, wherein the formulation comprises:
(i) microcrystalline cellulose;
(ii) silicon dioxide;
(iii) magnesium stearate;
(iv) at least one ingredient selected from crospovidone, partially pregelatinized starch, and lactose.
8. The pharmaceutical formulation of claim 1, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 10% to 50% by weight based on the total weight of the formulation.
9. The pharmaceutical formulation of claim 8, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 20% to 45% by weight based on the total weight of the formulation.
10. The pharmaceutical formulation of claim 8, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 30% to 40% by weight based on the total weight of the formulation.
11. The pharmaceutical formulation of claim 1, wherein the cellulose is microcrystalline cellulose.
12. The pharmaceutical formulation of claims 1, wherein the formulation comprises the cellulose in an amount ranging from 10% to 70% by weight based on the total weight of the formulation.
13. The pharmaceutical formulation of claim 12, wherein the formulation comprises the cellulose in an amount ranging from 20% to 50% by weight based on the total weight of the formulation, and the formulation comprises crospovidone in an amount ranging from 2% to 6% by weight based on the total weight of the formulation.
14. The pharmaceutical formulation of claim 1, wherein the formulation comprises the cellulose in an amount ranging from 20% to 45% by weight based on the total weight of the formulation, and the formulation comprises starch or lactose in an amount ranging from 10% to 40% by weight based on the total weight of the formulation.
15. The pharmaceutical formulation of claim 14, wherein the formulation comprises the starch in an amount ranging from 10% to 40% by weight based on the total weight of the formulation, and the starch is partially pregelatinized starch.
16. The pharmaceutical formulation of claims 1, wherein the formulation comprises the silicon dioxide in an amount ranging from 0.3% to 2% by weight based on the total weight of the formulation.
17. The pharmaceutical formulation of claim 1, wherein the formulation comprises magnesium stearate in an amount ranging from 0.1% to 2% by weight based on the total weight of the formulation.
18. The pharmaceutical formulation of claims 1, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 30% to 40% by weight based on the total weight of the formulation; the silicon dioxide in an amount ranging from 0.3% to 2% by weight based on the total weight of the formulation, the cellulose in an amount ranging from 25% to 40% of the total weight of the formulation, magnesium stearate in an amount ranging from 0.1% to 2% by weight based on the total weight of the formulation, and the crospovidone in an amount ranging from 2% to 4% by weight based on the total weight of the formulation.
19. The pharmaceutical formulation of claims 1, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 50% to 80% by weight based on the total weight of the formulation; the silicon dioxide in an amount ranging from 0.3% to 2% by weight based on the total weight of the formulation, the cellulose in an amount ranging from 0% to 50% of the total weight of the formulation, magnesium stearate in an amount ranging from 0.1% to 2% by weight based on the total weight of the formulation, and the starch in an amount ranging from 10% to 40% by weight based on the total weight of the formulation.
20. The pharmaceutical formulation of claim 19, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 55% to 75% by weight based on the total weight of the formulation, the cellulose in an amount ranging from 5% to 40% of the total weight of the formulation, and the starch in an amount ranging from 15% to 30% by weight based on the total weight of the formulation.
21. The pharmaceutical formulation of claim 19, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 60% to 70% by weight based on the total weight of the formulation and the cellulose in an amount ranging from 5% to 25% of the total weight of the formulation.
22. The pharmaceutical formulation of claims 1, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 50% to 80% by weight based on the total weight of the formulation; the silicon dioxide in an amount ranging from 0.3% to 2% by weight based on the total weight of the formulation, the cellulose in an amount ranging from 0% to 50% of the total weight of the formulation, magnesium stearate in an amount ranging from 0.1% to 2% by weight based on the total weight of the formulation, and the lactose in an amount ranging from 10% to 40% by weight based on the total weight of the formulation.
23. The pharmaceutical formulation of claim 22, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 55% to 75% by weight based on the total weight of the formulation and the cellulose in an amount ranging from 5% to 40% of the total weight of the formulation.
24. The pharmaceutical formulation of claim 22, wherein the formulation comprises the lactic acid salt of the compound in an amount ranging from 60% to 70% by weight based on the total weight of the formulation and the cellulose in an amount ranging from 5% to 40% of the total weight of the formulation.
25. A pharmaceutical formulation, comprising:
a compound of formula I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof,
and
at least one ingredient selected from the group consisting of cellulose, povidone, silicon dioxide, talc, and a pharmaceutically acceptable lubricant; and at least one ingredient selected from the group consisting of lactose, starch, crospovidone, croscarmellose sodium, and sodium starch glycolate.
26. The pharmaceutical formulation of claims 1 further comprising an antioxidant, a chelating agent, ascorbic acid, a reducing sugar, or a mixture of any two or more thereof.
27. The pharmaceutical formulation of 1, wherein the formulation is contained within a capsule.
28. The pharmaceutical formulation of 1, wherein the formulation is contained within a tablet.
29. The pharmaceutical formulation of claim 27, wherein the total mass of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof in the capsule or tablet ranges from 25 mg to 500 mg.
30. The pharmaceutical formulation of claim 1, wherein the amount of degradants of the compound of formula I is less than 10% by weight based on the total weight of the formulation after storage of the formulation for three months at 40\xb0 C. and 75% room humidity.
31. A method for producing a pharmaceutical formulation, comprising:
(a) blending a first mixture to provide a first blended mixture, the first mixture comprising:
(i) a compound of formula I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, and
(ii) at least one ingredient selected from the group consisting of cellulose; lactose, starch, or a mixture thereof; povidone; silicon dioxide or talc; a pharmaceutically acceptable lubricant; and an ingredient selected from crospovidone, croscarmellose sodium; or sodium starch glycolate.
32. The method of claim 31, wherein the compound of formula I is blended with (i) cellulose; (ii) silicon dioxide; and (iii) an ingredient selected from crospovidone, starch, or lactose.
33. The method of claim 32 further comprising
(b) blending stearic acid, a salt of stearic acid, or a mixture thereof with the first blended mixture to provide a second blended mixture.
34. The method of claim 33 further comprising (c) forming at least one capsule or at least one tablet from the second blended mixture.
35. A method for producing a pharmaceutical formulation, comprising:
(a) blending a mixture of ingredients to provide a first blended mixture, the blended mixture comprising:
(i) a compound of formula I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof,
(ii) at least one ingredient selected from the group consisting of cellulose; starch; lactose; and povidone;
(iii) at least one ingredient selected from the consisting of crospovidone; croscarmellose sodium; and sodium starch glycolate;
(iv) a granulating fluid selected from the group consisting of aqueous acid; alcohol; aqueous alcohol, or a mixture of any two or more thereof;
(b) removing the granulating fluid;
(c) producing a second blended mixture by blending the first blended mixture with at least one additional ingredient selected from the group consisting of:
(i) crospovidone, croscarmellose sodium, or sodium starch glycolate;
(ii) stearic acid or a salt of stearic acid; and
(iii) silicon dioxide or talc.
36. The method of claim 35 further comprising (d) forming at least one capsule or at least one tablet from the second blended mixture.
37. The method of claim 34, wherein the total mass of the compound of formula I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof in the capsule or tablet ranges from 25 mg to 500 mg.
38. The method of claim 35 wherein steps (a), (b), and (c) are performed simultaneously.
39. The method of claim 33, wherein the second blended mixture comprises a lactic acid salt of the compound of formula I.
40. The method of claim 39, wherein the second blended mixture comprises the lactic acid salt of the compound in an amount ranging from 10% to 50% by weight based on the total weight of the second blended mixture.
41. The method of claim 39, wherein the second blended mixture comprises the lactic acid salt of the compound in an amount ranging from 20% to 45% by weight based on the total weight of the second blended mixture.
42. The method of claim 39, wherein the second blended mixture comprises the lactic acid salt of the compound in an amount ranging from 30% to 40% by weight based on the total weight of the second blended mixture.
43. The method of claim 33, wherein the second blended mixture comprises the cellulose in an amount ranging from 10% to 70% by weight based on the total weight of the second blended mixture.
44. The method of claim 43, wherein the second blended mixture comprises the cellulose in an amount ranging from 20% to 50% by weight based on the total weight of the second blended mixture, and the second blended mixture comprises crospovidone in an amount ranging from 2% to 6% by weight based on the total weight of the second blended mixture.
45. The method of any one of claims 33-43, wherein the second blended mixture comprises the cellulose in an amount ranging from 20% to 50% by weight based on the total weight of the second blended mixture, and the second blended mixture comprises starch or lactose in an amount ranging from 10% to 40% by weight based on the total weight of the second blended mixture.
46. The method of claim 31, wherein the cellulose is microcrystalline cellulose.
47. The method of claim 33, wherein the second blended mixture comprises the starch in an amount ranging from 20% to 40% by weight based on the total weight of the second blended mixture, and the starch is partially pregelatinized starch.
48. The method of claim 33, wherein the second blended mixture comprises the silicon dioxide in an amount ranging from 0.3% to 2% by weight based on the total weight of the second blended mixture.
49. The method of claim 33, wherein the second blended mixture comprises the magnesium stearate in an amount ranging from 0.1% to 2% by weight based on the total weight of the second blended mixture.
50. The method of claim 33, wherein the second blended mixture comprises a lactic acid salt of the compound in an amount ranging from 50% to 80% by weight based on the total weight of the second blended mixture.
51. The method of claim 50 wherein the second blended mixture comprises a lactic acid salt of the compound in an amount ranging from 55% to 75% by weight based on the total weight of the second blended mixture.
52. The method of claim 50 wherein the second blended mixture comprises a lactic acid salt of the compound in an amount ranging from 60% to 70% by weight based on the total weight of the second blended mixture.
53. The method of claim 50, wherein the second blended mixture further comprises silicon dioxide in an amount ranging from 0.3% to 2% by weight based on the total weight of the second blended mixture.
54. The method of claim 50, wherein the second blended mixture further comprises the cellulose in an amount ranging from 20% to 45% of the total weight of the second blended mixture.
55. The method of claim 50, wherein the second blended mixture further comprises the magnesium stearate in an amount ranging from 0.1% to 2% by weight based on the total weight of the second blended mixture.
56. The method of claim 50, wherein the second blended mixture further comprises the crospovidone in an amount ranging from 2% to 6% by weight based on the total weight of the second blended mixture.
57. The method of claim 50, wherein the second blended mixture comprises silicon dioxide in an amount ranging from 0.5% to 2% by weight based on the total weight of the second blended mixture, the cellulose in an amount ranging from 20% to 45% of the total weight of the second blended mixture, the magnesium stearate in an amount ranging from 0.5% to 2% by weight based on the total weight of the second blended mixture, and the crospovidone in an amount ranging from 2% to 4% by weight based on the total weight of the second blended mixture.
58. A pharmaceutical packaging container, comprising: a storage vessel comprising two or more capsules or tablets, the capsules or tablets comprising the pharmaceutical formulation of claim 1.
59. The pharmaceutical packaging container of claim 58, wherein the storage vessel comprises high density polyethylene.
60. The pharmaceutical packaging container of claim 59, wherein the storage vessel further comprises a cotton or rayon coil.
61. The pharmaceutical packaging container of claim 59, wherein the storage vessel further comprises a heat induction seal.
62. A pharmaceutical packaging container, comprising a blister package, the blister package comprising at least one capsule or tablet comprising the pharmaceutical formulation of claim 1.
63. The pharmaceutical formulation of claim 29, wherein the tablet is coated with a substance selected from the group consisting of sugar, cellulose polymer, and polymethacrylate polymer.
64. The pharmaceutical formulation of claim 29, wherein the tablet is further coated with gelatin or encapsulated within a gelatin sheath.
65. The pharmaceutical formulation of claim 63, wherein the coating material further contains a pharmaceutically acceptable coloring agent.
66. The pharmaceutical formulation of claim 63, wherein the coating material further contains a pharmaceutically acceptable opacifier.
67. The method of claim 31, where in the pharmaceutical formulation is manufactured using at least one apparatus selected from the group consisting of (i) a fluidized bed granulator equipped with a bottom spray, a top spray, or a tangential spray mechanism; (ii) a high shear granulator; (iii) a low shear granulator; (iv) a roller compactor; and (V) a tablet press.
68. A method for treating cancer andor inhibiting angiogenesis in a subject, comprising: administering the formulation according to claim 1 to the subject.
69. The method of claim 68, wherein the formulation is administered in an amount sufficient to provide a Cmax of about 20 to 4000 ngmL of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof in the subject’s plasma or a Cmax of about 40 to 8000 ngmL of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof in the subject’s blood.
70. The method of claim 68, wherein the formulation is administered in an amount sufficient to provide about 10 to 2,000 ngmL of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof in the subject’s plasma 24 hours after administration or about 20 to 4,000 ngmL of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof in the subject’s blood 24 hours after administration.
71. The method of claim 68, wherein the formulation is administered in an amount sufficient to provide to provide an AUC of about 500 to 60,000 ng*hmL of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof in the subject’s plasma or about 750 to 120,000 ng*hmL of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof in the subject’s blood.
72. The method of claim 68, wherein the formulation is administered once, twice, three times, or four times daily.
73. The method of claim 68, wherein the amount of the compound of formula I, the tautomer of the compound, the lactic acid salt of the compound, the lactic acid salt of the tautomer, or the mixture thereof administered to the subject ranges from 0.25 to 30 mgkg body weight of the subject.
74. The method of claim 68, wherein the cancer to be treated is selected from prostate, colorectal, breast, multiple myeloma, pancreatic, small cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, myelo-proliferative disease, nonsmall cell lung, small cell lung, chronic lymphoid leukemia, sarcoma, melanoma, lymphoma, thyroid, neuroendocrine, renal cell, gastric, gastrointestinal stromal, glioma, brain, or bladder cancer.
75. The method of claim 68, further comprising administering the formulation as part of a treatment cycle, wherein the treatment cycle comprises administering the formulation daily for 7, 14, 21, or 28 days, followed by 7 or 14 days without administration of the formulation.
76. The method of claim 68, wherein the treatment cycle comprises administering the amount of the compound daily for 7 days, followed by 7 days without administration of the compound.
77. The method of claim 75, wherein the treatment cycle is repeated one or more times.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An electric power steering apparatus comprising a permanent magnet synchronous motor which is provided in a steering mechanism and which generates a steering assist torque; a drive circuit which outputs a three-phase drive voltage to the motor so as to drive the motor; and a 2-axis current control section which computes, through use of a d-q coordinate system whose d-axis extends along a magnetic field generated by a permanent magnet of the motor and whose q-axis extends perpendicular to the d-axis, drive instruction values for controlling a d-axis current which generates a magnetic field in the d-axis direction and a q-axis current which generates a magnetic field in the q-axis direction, and outputs drive control signals corresponding to the drive instruction values to the drive circuit, the electric power steering apparatus being characterized by comprising:
a high speed rotation state detection section which detects a high speed rotation state in which the motor is rotating at a high speed which is not detected during ordinary steering operation;
a current absolute value control section which computes a phase angle, in relation to the d-axis, of an output voltage vector of the drive circuit represented by the d-q coordinate system, at which the absolute value of motor current flowing through the motor becomes equal to a target current absolute value in a state in which the absolute value of the output voltage vector is set to a voltage limit value of the drive circuit, and outputs to the drive circuit the drive control signals which correspond to the computed phase angle and the voltage limit value; and
control changeover section which operates the current absolute value control section in place of the 2-axis current control section when the high speed rotation state is detected by the high speed rotation state detection section.
2. An electric power steering apparatus according to claim 1, wherein the current absolute value control section comprises:
a rotational speed detection section which detects the rotational speed of the motor; and
a phase angle computation section which computes the phase angle of the output voltage vector in relation to the d-axis on the basis of the target current absolute value, the voltage limit value of the drive circuit, and the rotational speed of the motor detected by the rotational speed detection section.
3. An electric power steering apparatus according to claim 2, wherein the current absolute value control section comprises:
a current detection section which detects the absolute value of the motor current; and
a feedback control section which adjusts the phase angle computed by the phase angle computation section, on the basis of a deviation between the target current absolute value and the absolute value of the motor current detected by the current detection section.
4. An electric power steering apparatus according to claim 3, wherein the feedback control section comprises a direction determination section which determines whether or not a direction in which the motor is rotating coincides with a direction in which torque is generated by the motor, wherein, in the case where the rotation direction of the motor coincides with the direction in which the torque is generated, the feedback control section increases the phase angle when the detected absolute value of the motor current is smaller than the target current absolute value and decreases the phase angle when the detected absolute value of the motor current is greater than the target current absolute value, and, in the case where the rotation direction of the motor does not coincide with the direction in which the torque is generated, the feedback control section decreases the phase angle when the detected absolute value of the motor current is smaller than the target current absolute value and increases the phase angle when the detected absolute value of the motor current is greater than the target current absolute value.
5. An electric power steering apparatus according to claim 1, wherein the target current absolute value is set to the current limit value of the drive circuit.
6. An electric power steering apparatus according to claim 1, wherein the high speed rotation state detection section comprises a rotational speed detection section which detects the rotational speed of the motor, and the high speed rotation state detection section determines that the motor is in the high speed rotation state when the detected rotational speed is higher than a reference speed.
7. An electric power steering apparatus according to claim 6, further comprising a reference speed changing section which decreases the reference speed as the rotational acceleration of the motor increases.
8. An electric power steering apparatus according to claim 6, further comprising a reference speed changing section which decreases the reference speed as a steering torque input to the steering mechanism increases.
9. An electric power steering apparatus according to claim 6, further comprising:
a second high speed rotation state detection section which detects a state in which the rotational speed detected by the rotational speed detection section is higher than a second reference speed which is higher than the reference speed; and
a second phase angle computation section which stores a map defining the relation between the rotational speed of the motor and the phase angle of the output voltage vector in relation to the d-axis and which computes the phase angle from the rotational speed of the motor detected by the rotational speed detection section, while referring to the map, when the second high speed rotation state detection section detects the state in which the rotational speed of the motor is higher than the second reference speed.
10. An electric power steering apparatus according to claim 2, wherein the target current absolute value is set to the current limit value of the drive circuit.
11. An electric power steering apparatus according to claim 3, wherein the target current absolute value is set to the current limit value of the drive circuit.
12. An electric power steering apparatus according to claim 4, wherein the target current absolute value is set to the current limit value of the drive circuit.
13. An electric power steering apparatus according to claim 2, wherein the high speed rotation state detection section comprises a rotational speed detection section which detects the rotational speed of the motor, and the high speed rotation state detection section determines that the motor is in the high speed rotation state when the detected rotational speed is higher than a reference speed.
14. An electric power steering apparatus according to claim 3, wherein the high speed rotation state detection section comprises a rotational speed detection section which detects the rotational speed of the motor, and the high speed rotation state detection section determines that the motor is in the high speed rotation state when the detected rotational speed is higher than a reference speed.
15. An electric power steering apparatus according to claim 4, wherein the high speed rotation state detection section comprises a rotational speed detection section which detects the rotational speed of the motor, and the high speed rotation state detection section determines that the motor is in the high speed rotation state when the detected rotational speed is higher than a reference speed.