Pharmaceutical formulation for the treatment of endometriosis, uterine fibroids, polycystic ovarian syndrome or adenomyosis
阅读说明：本技术 用于治疗子宫内膜异位症、子宫肌瘤、多囊卵巢综合症或子宫腺肌症的药物配制物 (Pharmaceutical formulation for the treatment of endometriosis, uterine fibroids, polycystic ovarian syndrome or adenomyosis ) 是由 J.贾延思 K.C.斯潘塞 G.A.麦克利兰 A.V.斯蒂芬宁科 K.克瓦利什 C.D.欧 于 2018-08-20 设计创作，主要内容包括：本公开涉及包括促性腺激素释放激素(GnRH)拮抗剂的药物组合物,以及制备和使用此类组合物的方法。本公开还涉及促进GnRH拮抗剂从药物组合物释放的方法。(The present disclosure relates to pharmaceutical compositions comprising gonadotropin releasing hormone (GnRH) antagonists, and methods of making and using such compositions. The disclosure also relates to methods of promoting the release of a GnRH antagonist from a pharmaceutical composition.)
1. A pharmaceutical composition comprising about 150mg, about 200mg, or about 300mg of 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the pharmaceutical composition comprises at least 10% by weight of compound a or said pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition according to claim 1 or claim 2, wherein the anti-gelling agent is a water-soluble salt of a weak acid, base, basic amino acid, basic salt, or basic polymer.
3. The pharmaceutical composition according to claim 1 or claim 2, wherein the antigelling agent also acts as a stabilizer for reducing the formation of (R) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methyl-3- (2- (2-oxopyrrolidin-1-yl) -2-phenylethyl) pyrimidine-2, 4(1H,3H) -dione (compound B) in the composition relative to an otherwise identical composition without the antigelling agent.
4. The pharmaceutical composition of claim 3, wherein the anti-gelling agent comprises an alkali metal salt or a basic salt.
5. The pharmaceutical composition of claim 4, wherein the alkali metal salt or the basic salt is selected from the group consisting of: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, calcium hydroxide, guanidine, magnesium hydroxide, meglumine, piperidine, glucosamine, piperazine, or TRIS (TRIS) and combinations thereof.
6. The pharmaceutical composition according to claim 4, wherein the alkali metal salt is sodium carbonate, such as sodium carbonate monohydrate.
7. The pharmaceutical composition according to any one of claims 3 to 6, wherein the weight ratio of Compound A or the pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 20:1 or from about 1:1 to about 4:1, such as about 2: 1.
8. The pharmaceutical composition according to any one of claims 3 to 6, wherein the anti-gelling agent is present in an amount from about 5% to about 35% by weight of the pharmaceutical composition, such as in an amount from about 10% to about 25% by weight of the pharmaceutical composition.
9. The pharmaceutical composition of any one of the preceding claims, further comprising (a) at least one water-soluble filler or (b) at least one water-insoluble filler and a surfactant.
10. The pharmaceutical composition of any one of the preceding claims, wherein the composition releases at least about 80% of compound a or the pharmaceutically acceptable salt thereof within about 45 minutes as measured using USP apparatus II at 37 ℃ and paddle speed of 50rpm in 900mL of sodium pH6.8 phosphate.
11. The pharmaceutical composition of any one of the preceding claims, further comprising at least one lubricant.
12. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is a solid oral dosage form.
13. The pharmaceutical composition of claim 12, wherein the solid oral dosage form is a tablet.
14. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises a salt of compound a.
15. The pharmaceutical composition of claim 14, wherein the salt of compound a is sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate.
16. The pharmaceutical composition according to claim 14, wherein the salt of compound a is sodium amorphous 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate.
17. The pharmaceutical composition of claim 15, wherein the composition, when administered in a single dose to a population of human subjects, provides an average T of less than about 3 hours, such as from about 0.5 to about 2.0 hoursmaxThe value is obtained.
18. The pharmaceutical composition of claim 15, wherein 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butyrate is present in an amount equivalent to about 150mg of compound a and the composition, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean C of about 400ng/mL to about 660ng/mLmaxThe value is obtained.
19. The pharmaceutical composition of claim 15, wherein 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butyrate is present in an amount equivalent to about 150mg of compound a and the composition, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC of about 1000 ng-hr/mL to about 1600 ng-hr/mLt。
20. The pharmaceutical composition of claim 15, wherein 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butyrate is present in an amount equivalent to about 150mg of compound a and the composition, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC of about 1010 ng-hr/mL to about 1610 ng-hr/mL∞。
21. The pharmaceutical composition of claim 15, wherein 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butyrate is present in an amount equivalent to about 200mg of compound a and the solid oral dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean C of about 590ng/mL to about 1100ng/mLmax。
22. The pharmaceutical composition of claim 15, wherein 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butyrate is present in an amount equivalent to about 200mg of compound a and the solid oral dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC of about 1510 ng-hr/mL to about 2980 ng-hr/mLt。
23. The pharmaceutical composition of claim 15, wherein 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butyrate is present in an amount equivalent to about 200mg of compound a and the solid oral dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC of about 1520 ng-hr/mL to about 2990 ng-hr/mL∞。
24. The pharmaceutical composition of claim 15, wherein 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butyrate is present in an amount equivalent to about 300mg of compound a and the solid oral dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean C of about 1100ng/mL to about 1730ng/mLmax。
25. The pharmaceutical composition of claim 15, wherein Compound A or the pharmaceutically acceptable salt thereof is present in an amount equivalent to about 300mg Compound A and the solid oral dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC of about 2990 ng-hr/mL to about 4670 ng-hr/mLt。
26. The pharmaceutical composition of claim 15, wherein Compound A or the pharmaceutically acceptable salt thereof is present in an amount equivalent to about 300mg Compound A and the solid oral dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC of about 3020 ng-hr/mL to about 4720 ng-hr/mL∞。
27. The pharmaceutical composition of any one of the preceding claims, wherein the composition provides rapid suppression of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) levels when administered to a female subject.
28. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises less than about 0.7% of (R) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methyl-3- (2- (2-oxopyrrolidin-1-yl) -2-phenylethyl) pyrimidine-2, 4(1H,3H) -dione after storage for at least one month at 25 ℃ and 60% relative humidity.
29. The pharmaceutical composition according to any one of claims 1 to 27, wherein the pharmaceutical composition comprises less than about 0.7% of (R) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methyl-3- (2- (2-oxopyrrolidin-1-yl) -2-phenylethyl) pyrimidine-2, 4(1H,3H) -dione after storage for about one month to about three months at 25 ℃ and 60% relative humidity.
30. A pharmaceutical composition comprising about 150mg of 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of compound a or said pharmaceutically acceptable salt thereof is from about 0.5:1 to about 20:1 or from about 1:1 to about 4:1, such as about 2: 1.
31. A pharmaceutical composition comprising about 200mg of 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of compound a or said pharmaceutically acceptable salt thereof is from about 0.5:1 to about 20:1 or from about 1:1 to about 4:1, such as about 2: 1.
32. A pharmaceutical composition comprising about 300mg of 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof; and an anti-gelling agent; wherein the weight ratio of compound a or said pharmaceutically acceptable salt thereof is from about 0.5:1 to about 20:1 or from about 1:1 to about 4:1, such as about 2: 1.
33. The pharmaceutical composition of any one of claims 30-32, wherein the anti-gelling agent is sodium carbonate.
34. The pharmaceutical composition according to claim 33, wherein the weight ratio of compound a or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2: 1.
35. The pharmaceutical composition of any one of claims 30-34, further comprising a water-soluble filler.
36. The pharmaceutical composition of any one of claims 30 to 34, further comprising a water-insoluble filler and a surfactant.
37. The pharmaceutical composition of any one of claims 30 to 36, further comprising a binder.
38. The pharmaceutical composition of claim 37, wherein the binder is polyvinylpyrrolidone.
39. The pharmaceutical composition of any one of claims 30-38, wherein the pharmaceutical composition comprises a salt of compound a.
40. The pharmaceutical composition according to claim 39, wherein the salt of Compound A is sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate.
41. A pharmaceutical composition, comprising:
(a) about 20 to about 50 weight percent 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof;
(b) a binder;
(c) an anti-gelling agent; and
(d) a water-soluble filler.
42. The pharmaceutical composition of claim 41, wherein the binder is selected from the group consisting of: polyvinylpyrrolidone, Hydroxymethylpropylcellulose (HPMC), hydroxypropylethylcellulose, microcrystalline cellulose, starch, and combinations thereof.
43. The pharmaceutical composition of claim 41, wherein the binder comprises polyvinylpyrrolidone.
44. The pharmaceutical composition according to any one of claims 41 to 43, wherein the binder is present in an amount of about 1% to about 10% by weight.
45. The pharmaceutical composition of any one of claims 41-44, wherein the anti-gelling agent comprises an alkali metal salt or a basic salt.
46. The pharmaceutical composition of claim 45, wherein the alkali metal salt or the basic salt is selected from the group consisting of: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, calcium hydroxide, guanidine, magnesium hydroxide, meglumine, piperidine, glucosamine, piperazine, or TRIS (TRIS) and combinations thereof.
47. The pharmaceutical composition according to claim 41, wherein the anti-gelling agent comprises sodium carbonate, such as sodium carbonate monohydrate.
48. The pharmaceutical composition of any one of claims 41-47, wherein the anti-gelling agent is present in an amount from about 10% to about 25% by weight.
49. The pharmaceutical composition of any one of claims 41-48, wherein the water soluble filler comprises mannitol and pregelatinized starch.
50. The pharmaceutical composition of any one of claims 41-49, wherein the water soluble filler is present in an amount of about 30% to about 50% by weight.
51. The pharmaceutical composition of any one of claims 41 to 50, further comprising about 1 to about 5% of a lubricant.
52. The composition according to claim 51, wherein the lubricant is magnesium stearate.
53. The pharmaceutical composition of any one of claims 41-52, wherein the pharmaceutical composition is a solid oral dosage form.
54. The pharmaceutical composition of claim 53, wherein the solid oral dosage form is a tablet.
55. The pharmaceutical composition of claim 54, wherein the tablet comprises a film coating.
56. The pharmaceutical composition according to any one of claims 41-55, wherein the pharmaceutical composition comprises a salt of Compound A.
57. The pharmaceutical composition according to claim 56, wherein the salt of Compound A is sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate.
58. The pharmaceutical composition according to claim 56, wherein the salt of Compound A is sodium amorphous 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate.
59. A solid oral dosage form comprising:
(a) about 33.2% by weight sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate;
(b) about 16.7 wt% of an alkali metal salt; and
(c) about 51.1% by weight of one or more excipients.
60. The solid oral dosage form of claim 59, wherein the one or more excipients comprise a binder, a water-soluble filler, a lubricant, and a film coating.
61. A solid oral dosage form comprising:
(d) about 33.2% by weight sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate;
(e) about 2.9 wt% binder;
(f) about 16.7 wt% of an alkali metal salt;
(g) about 41.6% by weight of a water-soluble filler;
(h) about 1.8 wt.% of a lubricant; and
(i) about 3.8% by weight of a film coating.
62. The solid oral dosage form of claim 61, wherein the binder is polyvinylpyrrolidone.
63. The solid oral dosage form of claim 61 or claim 62, wherein the alkali metal salt is sodium carbonate, such as sodium carbonate monohydrate.
64. The solid oral dosage form of any of claims 61-63, wherein the water-soluble filler comprises mannitol and/or pregelatinized starch.
65. The solid oral dosage form of claim 64, wherein the solid oral dosage form comprises about 32% mannitol and about 9% pregelatinized starch by weight.
66. The solid oral dosage form of any of claims 61-65, wherein the lubricant is magnesium stearate.
67. The solid oral dosage form of any of claims 61-66, wherein the dosage form comprises an intragranular portion and an extragranular portion.
68. A pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof and compound B or a salt thereof; wherein compound a is 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid; compound B is (R) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methyl-3- (2- (2-oxopyrrolidin-1-yl) -2-phenylethyl) pyrimidine-2, 4(1H,3H) -dione; and compound B is present in the composition in an amount less than about 0.7% by weight.
69. The pharmaceutical composition of claim 68, wherein the amount of Compound B present in the composition is less than about 0.7% by weight after storage at 25 ℃ and 60% relative humidity for at least one month, at least two months, or at least six months.
70. A method of treating endometriosis, the method comprising administering to a patient in need thereof a pharmaceutical composition according to claims 1 to 58 or 68 to 69 or a solid oral dosage form according to claims 59 to 67.
71. A method of treating uterine fibroids, the method comprising administering to a patient in need thereof a pharmaceutical composition according to claims 1 to 58 or claims 68 to 69 or a solid oral dosage form according to claims 59 to 67.
72. A method for providing partial to substantially complete inhibition of estradiol in a female patient suffering from endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS) or adenomyosis, the method comprising administering to the patient a pharmaceutical composition according to claims 1-58 or 68-69 or a solid oral dosage form according to claims 59-67.
73. The method of claim 72, wherein the estradiol level in the female patient is less than about 50 pg/mL.
74. The method of claim 72, wherein the estradiol level in the female patient is less than about 20 pg/mL.
75. A method of treating non-dominant adenomyosis or symptomatic adenomyosis, the method comprising administering to a patient in need thereof the pharmaceutical composition of claims 1 to 58 or claims 68 to 69 or the solid oral dosage form of claims 59 to 67.
76. The method of claim 75, wherein Compound A is administered 300mg twice a day or 600mg once a day
77. The method of claim 75, wherein another counter-addition therapy selected from the group consisting of: estradiol, norethindrone or a salt thereof.
78. The method of any one of claims 77, further wherein 1mg estradiol, 0.5mg norethindrone acetate, or a combination thereof is administered once a day to a patient in need thereof.
79. The method of claim 75, wherein the treatment of non-dominant adenomyosis or symptomatic adenomyosis comprises:
(a) at month 6, heavy menstrual bleeding decreased to <80ml/mo and Menstrual Blood Loss (MBL) decreased > 50% from baseline;
(b) at month 3, there was a clinically significant reduction in pelvic pain (defined as > 30% reduction from baseline);
(c) at month 3, heavy menstrual bleeding decreased to <80ml/mo and MBL decreased > 50% from baseline;
(d) at 12 months, heavy menstrual bleeding decreased to <80ml/mo and MBL decreased > 50% from baseline;
(e) at month 6, pelvic pain appeared to be reduced clinically from baseline (defined as > 30% reduction);
(f) MBL volume mean decreased from baseline relative to placebo;
(g) bleeding inhibition as defined by drop/drop bleeding;
(h) suppression of menstrual pain for extended periods;
(i) reduced pain during intercourse; or
(j) The blood clot shed during menstruation is reduced.
80. A method of treating severe menstrual bleeding and pelvic pain in a female with symptomatic adenomyosis, the method comprising administering a pharmaceutical composition comprising about 300mg of a compound a equivalent, wherein the composition comprises:
(j) about 33.2% by weight sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate;
(k) about 16.7 wt% of an alkali metal salt; and
(l) About 51.1% by weight of one or more excipients, wherein the excipients include a binder, a water soluble filler, a lubricant, and a film coating.
81. The method of claim 80, the method comprising:
(a) about 33.2% by weight sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate;
(b) about 2.9 wt% binder;
(c) about 16.7 wt% of an alkali metal salt;
(d) about 41.6% by weight of a water-soluble filler;
(e) about 1.8 wt.% of a lubricant; and
(f) about 3.8% by weight of a film coating.
82. The method of claim 80, wherein the treatment further comprises a counter-additive therapy selected from the group consisting of: estradiol, norethindrone acetate, or a combination thereof.
83. The method of claim 82, wherein the counter-addition therapy comprises 1mg estradiol, 0.5mg norethindrone acetate, or a combination thereof, and wherein the counter-addition therapy is administered once a day to a patient in need thereof.
84. The method of claim 80, wherein the treatment of symptomatic adenomyosis comprises:
(a) at month 6, heavy menstrual bleeding decreased to <80ml/mo and Menstrual Blood Loss (MBL) decreased > 50% from baseline;
(b) at month 3, there was a clinically significant reduction in pelvic pain (defined as > 30% reduction from baseline);
(c) at month 3, heavy menstrual bleeding decreased to <80ml/mo and MBL decreased > 50% from baseline;
(d) at 12 months, heavy menstrual bleeding decreased to <80ml/mo and MBL decreased > 50% from baseline;
(e) at month 6, pelvic pain appeared to be reduced clinically from baseline (defined as > 30% reduction);
(f) MBL volume mean decreased from baseline relative to placebo;
(g) bleeding inhibition as defined by drop/drop bleeding;
(h) suppression of menstrual pain for extended periods;
(i) reduced pain during intercourse; or
(j) The blood clot shed during menstruation is reduced.
85. A method of treating severe menstrual bleeding and pelvic pain in a female with non-dominant adenomyosis, the method comprising administering a pharmaceutical composition comprising about 300mg of a compound a equivalent, wherein the composition comprises:
a) about 33.2% by weight sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate;
b) about 16.7 wt% of an alkali metal salt; and
c) about 51.1% by weight of one or more excipients, wherein the excipients include a binder, a water soluble filler, a lubricant, and a film coating.
86. The method of claim 85, the method comprising:
a) about 33.2% by weight sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate;
b) about 2.9 wt% binder;
c) about 16.7 wt% of an alkali metal salt;
d) about 41.6% by weight of a water-soluble filler;
e) about 1.8 wt.% of a lubricant; and
f) about 3.8% by weight of a film coating.
87. The method of claim 85, wherein the treatment further comprises a counter-additive therapy selected from the group consisting of: estrogen, norethindrone acetate, or a combination thereof.
88. The method of claim 86, wherein the counter-addition therapy comprises 1mg estradiol, 0.5mg norethindrone acetate, or a combination thereof, and wherein the counter-addition therapy is administered once a day to a patient in need thereof.
89. The method of claim 85, wherein the treatment of non-dominant adenomyosis comprises:
(a) at month 6, heavy menstrual bleeding decreased to <80ml/mo and Menstrual Blood Loss (MBL) decreased > 50% from baseline;
(b) at month 3, there was a clinically significant reduction in pelvic pain (defined as > 30% reduction from baseline);
(c) at month 3, heavy menstrual bleeding decreased to <80ml/mo and MBL decreased > 50% from baseline;
(d) at 12 months, heavy menstrual bleeding decreased to <80ml/mo and MBL decreased > 50% from baseline;
(e) at month 6, pelvic pain appeared to be reduced clinically from baseline (defined as > 30% reduction);
(f) MBL volume mean decreased from baseline relative to placebo;
(g) bleeding inhibition as defined by drop/drop bleeding;
(h) suppression of menstrual pain for extended periods;
(i) reduced pain during intercourse; or
(j) The blood clot shed during menstruation is reduced.
90. A method of treating pain associated with endometriosis, wherein the method additionally reduces fatigue in a patient suffering from moderate to severe endometriosis, the method comprising administering to a patient in need thereof a pharmaceutical composition according to claims 1 to 58 or 68 to 69 or a solid oral dosage form according to claims 59 to 67.
91. The method of claim 89, wherein Compound A is administered 150mg once a day, 200mg twice a day, 300mg twice a day, or 600mg once a day.
92. The method of claim 89, wherein the treatment further comprises a counter-additive therapy selected from the group consisting of: estrogen, norethindrone acetate, or a combination thereof.
93. A method of treating pain associated with endometriosis, wherein the method additionally reduces the use of an analgesic drug by a patient suffering from moderate to severe endometriosis, the method comprising administering to a patient in need thereof a pharmaceutical composition according to claims 1 to 58 or claims 68 to 69 or a solid oral dosage form according to claims 59 to 67.
94. The method of claim 91, wherein compound a is administered 150mg once a day, 200mg twice a day, 300mg twice a day, or 600mg once a day.
95. The method of claim 92, wherein the treatment further comprises a counter-additive therapy selected from the group consisting of: estrogen, norethindrone acetate, or a combination thereof.
Technical Field
The present invention relates to pharmaceutical compositions of compound a and pharmaceutically acceptable salts, and methods of using such compositions.
Background
Endometriosis is a disease in which the tissue normally present in the uterine cavity (i.e., the endometrium) is present outside the uterus, usually implanted in the intraperitoneal layers of the pelvic cavity. It is estimated that 1 out of 10 women of childbearing age has endometriosis, and the disease causes pain, infertility and sexual dysfunction. The growth of endometrial tissue outside the uterine cavity is thought to be estrogen dependent.
Uterine fibroids (leiomyoma) are benign tumors and are very common in women of childbearing age. Symptoms associated with uterine fibroids most often include severe menstrual bleeding or menostaxis, pelvic pressure and pelvic organ compression, back pain, and adverse reproductive consequences. Heavy menstrual bleeding (HMB; Menorrhagia, defined as more than 80mL per menstrual cycle) (Menorrhagia Research team: quantification of menstrual blood loss (The Menorrhagia Research group, quantification of menstrual blood loss.), (The obsteriologists & Gynaecologist.), (6: 88-92) is highly inconvenient and may lead to iron deficiency anemia, which is The main cause of surgical intervention including hysterectomy. Other symptoms, particularly compression symptoms, depend to a large extent on the size, number and location of the tumor.
Although the pathogenesis has not been fully elucidated, it is known that the growth of uterine fibroids is largely dependent on estrogens and progestogens. After menopause, myomas tend to shrink due to reduced hormone production.
Adenomyosis is a condition in which the inner layer of the uterus (endometrium) penetrates the myometrium wall (myometrium). Adenomyosis causes menstrual pain, pressure in the lower abdomen, and premenstrual bloating, and may lead to increased menstrual flow. The condition may be spread throughout the uterus or localized to a point. Adenomyosis is a common condition. The condition is most often diagnosed in middle-aged women and women with past childbearing. Some studies have also shown that women who have previously undergone uterine surgery may be at risk for adenomyosis. The most common complaints are menorrhagia and mid-menstrual bleeding, followed by pain, especially menstrual pain, and bladder and rectal pressure sensations. Only surgery (myomectomy or hysterectomy) is considered curative.
Polycystic ovary syndrome (PCOS) is the most common hormonal disorder in women of reproductive age. Women with PCOS may experience infrequent or prolonged periods of time or excessive levels of androgens (androgens). The ovary may produce multiple smaller collections of fluid (follicles) and may not regularly release the ova.
Thus, there is a need in the art for novel orally administered treatments for endometriosis, uterine fibroids, PCOS and adenomyosis, and in particular for the management of pain associated with endometriosis, uterine fibroids, PCOS or adenomyosis, and severe menstrual bleeding associated with endometriosis, uterine fibroids, PCOS or adenomyosis. Furthermore, there is a need in the art to develop orally bioavailable dosage forms that include such treatments, and in particular, to develop non-peptide GnRH antagonists.
Disclosure of Invention
The present disclosure relates to pharmaceutical compositions comprising 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof; methods of using such compositions; and methods of promoting the release of compound a from such compositions.
The present application identifies at least two challenges in developing pharmaceutical formulations comprising compound a or a pharmaceutically acceptable salt thereof. One problem is that compound a, and in particular the monosodium salt of compound a, has a tendency to form a gel when administered orally in a solid dosage form, particularly when present at greater than about 10% by weight in the absence of an appropriate anti-gelling agent. This gel formation limits the dissolution of the API and may ultimately lead to a very variable bioavailability from patient to patient and within the patient. Another difficulty is that compound a can degrade to form a compound having a lactam moiety (referred to herein as compound B). For example, to maintain safety and efficacy over the life of the product, it is necessary to convert the drug substance reductively into its lactam-containing degradation products. Thus, the applicants have determined that the pharmaceutical composition reduces gelation of the API and/or reduces the production of lactam degradation products (i.e., compound B). Mutagenic impurities such as compound B are undesirable and should be reduced to very low levels, or to the lowest level possible, to maintain product safety and efficacy.
In one aspect, a disclosed pharmaceutical composition includes compound a, or a pharmaceutically acceptable salt thereof, and at least one anti-gelling agent.
In certain embodiments, the salt of compound a is the monosodium salt (sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate).
In certain embodiments, the anti-gelling agent facilitates the release of compound a, or a pharmaceutically acceptable salt thereof, from a solid dosage form, such as from a tablet.
In certain embodiments, the antigelling agent also acts as a stabilizer, e.g., to reduce the formation of (R) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methyl-3- (2- (2-oxopyrrolidin-1-yl) -2-phenylethyl) pyrimidine-2, 4(1H,3H) -dione (compound B) in the composition relative to an otherwise identical composition that does not contain the antigelling agent.
In certain embodiments, the anti-gelling agent acts as a pH adjuster, such as a buffer.
In certain embodiments, the anti-gelling agent is an alkali metal salt, such as sodium carbonate. The sodium carbonate may be sodium carbonate monohydrate or anhydrous sodium carbonate. The other antigelling agent may be a base. Examples of bases include calcium hydroxide, guanidine, magnesium hydroxide, meglumine, piperidine, glucosamine, piperazine or TRIS (hydroxymethyl aminomethane). In certain embodiments, the anti-gelling agent can be a basic amino acid. Examples of basic amino acids include L-ornithine, L-lysine or L-arginine. In certain other embodiments, the anti-gelling agent may be an alkaline salt. Examples of basic salts include sodium carbonate, potassium carbonate, trisodium phosphate, disodium hydrogen phosphate, trisodium citrate dihydrate, guanidine carbonate. In certain embodiments, the anti-gelling agent may be Eudragit EPO.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 1:1 to about 20: 1. The weight ratio may be selected within different ranges, selected from the group consisting of: 1:1, 2:1, 4:1, 6:1, 10:1 or 20: 1. Thus, the ratio may be, for example, in the range of 1:1 to 2:1, or 1:1 to 4:1, or 1:1 to 6:1, or 1:1 to 10:1, or 1:1 to 20: 1.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is about 2: 1.
In certain embodiments, the antigelling agent is present in the pharmaceutical composition in an amount from about 5% to about 35% by weight of the pharmaceutical composition.
In certain embodiments, the antigelling agent is present in the pharmaceutical composition in an amount from about 15% to about 25% by weight of the pharmaceutical composition.
In certain embodiments, the pharmaceutical composition further comprises at least one additional excipient selected from the group consisting of: binders, fillers, lubricants, glidants, and combinations thereof.
In certain embodiments, the binder is polyvinylpyrrolidone.
In certain embodiments, the bulking agent is starch and/or mannitol. In certain embodiments, the filler is a water soluble filler, such as mannitol or pregelatinized starch, or a combination thereof. In certain embodiments, the filler is a water-insoluble filler, such as microcrystalline cellulose. In some such embodiments, the pharmaceutical composition further comprises a surfactant, such as sodium lauryl sulfate.
In certain embodiments, the lubricant is magnesium stearate.
In certain embodiments, the glidant is colloidal silicon dioxide.
In certain embodiments, the pharmaceutical composition is an oral dosage form. In some such embodiments, the oral dosage form is a tablet.
In certain embodiments, the pharmaceutical composition comprises compound a or a pharmaceutically acceptable salt thereof in an amount of about 100mg to about 600 mg; and at least about 10% by weight of an antigelling agent. In certain embodiments, the pharmaceutical composition comprises compound a or a pharmaceutically acceptable salt thereof in an amount of about 100mg to about 350 mg; and at least about 10% by weight of an antigelling agent.
In one aspect, the disclosed pharmaceutical composition comprises about 150mg of compound a or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent, and optionally at least one binder. In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate. In some such embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2: 1. In certain embodiments, the binder is polyvinylpyrrolidone. In certain embodiments, the salt of compound a is the monosodium salt (sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate). In some such embodiments, the weight ratio of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate to sodium carbonate monohydrate is about 2: 1.
In another aspect, the disclosed pharmaceutical composition comprises about 200mg of compound a or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent, and optionally at least one binder. In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate. In some such embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2: 1. In certain embodiments, the binder is polyvinylpyrrolidone. In certain embodiments, the salt of compound a is the monosodium salt (sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate). In some such embodiments, the weight ratio of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate to sodium carbonate monohydrate is about 2: 1.
In yet another aspect, the disclosed pharmaceutical composition comprises about 300mg of compound a or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent, and optionally at least one binder. In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate. In some such embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2: 1. In certain embodiments, the binder is polyvinylpyrrolidone. In certain embodiments, the salt of compound a is the monosodium salt (sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate). In some such embodiments, the weight ratio of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate to sodium carbonate monohydrate is about 2: 1.
In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 125mg to about 175mg, such as about 150mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean Tmax value of less than about 3 hours, such as less than about 2 hours. In certain embodiments, the pharmaceutical composition is a tablet, an amount equivalent to about 175mg to about 225mg, such as about 200mg, of compound a of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean Tmax value of less than about 3 hours, such as less than about 2 hours. In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate equivalent to about 275mg to about 325mg, such as about 300mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean Tmax value of less than about 3 hours, such as less than about 2 hours.
In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 125mg to about 175mg, such as about 150mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet when administered in a single dose to a population of human subjects provides the population of human subjects with a mean Cmax value of at least about 380ng/mL (about 75% of 510). In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 175mg to about 225mg, such as about 200mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet when administered in a single dose to a population of human subjects provides the population of human subjects with a mean Cmax value of at least about 550ng/mL (about 75% of 738). In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate equivalent to about 275mg to about 325mg, such as about 300mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet when administered in a single dose to a population of human subjects provides the population of human subjects with a mean Cmax value of at least about 1030ng/mL (about 75% of 1378).
In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 125mg to about 175mg, such as about 150mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet when administered in a single dose to a population of human subjects provides the population of human subjects with an average AUCt value of at least about 940 ng-h/mL (about 75% of 1263). In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 175mg to about 225mg, such as about 200mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with an average AUCt value of at least about 1410 ng-h/mL (about 75% of 1890). In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate equivalent to about 275mg to about 325mg, such as about 300mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with an average AUCt value of at least about 2800 ng-h/mL (about 75% of 3732).
In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 125mg to about 175mg, such as about 150mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC ∞ value of at least about 950 ng-h/mL (about 75% of 1271). In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 175mg to about 225mg, such as about 200mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC ∞ value of at least about 1430 ng-h/mL (about 75% of 1900). In certain embodiments, the pharmaceutical composition is a tablet comprising an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate equivalent to about 275mg to about 325mg, such as about 300mg of compound a; and at least about 10 wt%, such as between about 15 wt% and about 20 wt%, of an anti-gelling agent; wherein the tablet, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean AUC ∞ value of at least about 2820 ng-h/mL (about 75% of 3772).
The present disclosure also relates to a pharmaceutical composition in a single unit dosage form for oral administration in the form of a tablet comprising one or more pharmaceutically acceptable carriers and an amount of 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof, wherein the amount of compound a is 150, 200 or 300 mg.
Also provided is a pharmaceutical composition comprising:
a) about 20 to about 60 weight percent 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof;
b) a binder;
c) an antigelling agent, wherein the antigelling agent acts as a stabilizer for reducing the formation of (R) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methyl-3- (2- (2-oxopyrrolidin-1-yl) -2-phenylethyl) pyrimidine-2, 4(1H,3H) -dione (compound B) in the composition; and
d) a water-soluble filler.
Also provided is a pharmaceutical composition comprising:
a) about 33% by weight sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate;
b) about 3% by weight of a binder;
c) about 17% by weight of an alkali metal salt;
d) about 41% by weight of a water-soluble filler;
e) about 2 wt.% of a lubricant; and
f) about 4% by weight of a film coating.
Also provided is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and an amount of 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (Compound A) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is bioequivalent to an immediate release formulation of compound a or a pharmaceutically acceptable salt thereof having about the same amount of compound a or a pharmaceutically acceptable salt thereof.
The present disclosure also relates to pharmaceutical compositions comprising compound a or a pharmaceutically acceptable salt thereof and an alkali metal salt in an amount sufficient to facilitate release of compound a or said pharmaceutically acceptable salt thereof from the composition.
In certain embodiments, the release is measured in 900mL of sodium phosphate pH6.8 using USP apparatus II at 37 ℃ and 50rpm paddle speed.
In certain embodiments, the release is measured in 900mL of 0.1N hydrochloric acid pH 1.2 using USP apparatus II at 37 ℃ and a paddle speed of 50 rpm.
In certain embodiments, the release is measured in 900mL of 0.1N hydrochloric acid pH 1.2 using USP apparatus I at 37 ℃ and 100rpm speed.
In certain embodiments, the alkali metal salt also acts as a stabilizer.
In certain embodiments, the alkali metal salt acts as a pH adjuster, such as a buffer.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the alkali metal salt is from about 1:1 to about 4: 1.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to alkali metal salt is about 2: 1.
In certain embodiments, the alkali metal salt is present in the pharmaceutical composition in an amount from about 10% to about 30% by weight of the pharmaceutical composition.
In certain embodiments, the alkali metal salt is present in the pharmaceutical composition in an amount from about 15% to about 25% by weight of the pharmaceutical composition.
In certain embodiments, the pharmaceutical composition is an oral dosage form.
In certain embodiments, the oral dosage form is a tablet.
The present disclosure also relates to a solid oral dosage form, such as a tablet, comprising compound a or a pharmaceutically acceptable salt thereof and sodium carbonate.
In certain embodiments, the salt of compound a is a sodium salt.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to sodium carbonate is from about 1:1 to about 4: 1.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to sodium carbonate is about 2: 1.
In certain embodiments, the sodium carbonate is present in the pharmaceutical composition in an amount from about 10% to about 30% by weight of the pharmaceutical composition.
In certain embodiments, the sodium carbonate is present in the pharmaceutical composition in an amount from about 15% to about 25% by weight of the pharmaceutical composition.
The present disclosure also relates to methods of promoting the release of compound a or a pharmaceutically acceptable salt thereof from an oral dosage form.
In certain embodiments, the method comprises preparing a pharmaceutical composition comprising at least one anti-gelling agent and compound a, or a pharmaceutically acceptable salt thereof.
Compound a tends to form a gel in the presence of water, further complicating the development process. Accordingly, in one aspect, the present disclosure provides a method of manufacturing a pharmaceutical composition comprising compound a, or a pharmaceutically acceptable salt thereof, substantially free of water. In certain embodiments, the pharmaceutical composition is manufactured using a roll-to-roll process.
The present disclosure also relates to methods for treating endometriosis in a subject in need of such treatment, wherein the methods comprise administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the subject twice daily (BID).
The present disclosure also relates to pharmaceutical compositions for the treatment of endometriosis.
The present disclosure also relates to methods for treating uterine fibroids in a subject in need of such treatment, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the subject twice daily (BID).
The present disclosure also relates to pharmaceutical compositions for treating uterine fibroids.
The present disclosure also relates to methods for treating adenomyosis or adenomyomas in a subject in need of such treatment, wherein the methods comprise administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the subject twice daily (BID).
The present disclosure also relates to pharmaceutical compositions for treating adenomyosis or adenomyomas.
The present disclosure also relates to methods for treating PCOS in a subject in need of such treatment, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the subject twice daily (BID).
The present disclosure also relates to pharmaceutical compositions for treating PCOS.
The present disclosure also relates to a method for providing rapid inhibition of Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH) in a female patient suffering from endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS) or adenomyosis, wherein said method comprises administering to said female patient a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
The present disclosure also relates to a method for providing rapid inhibition of Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH) in a female patient suffering from endometriosis, wherein said method comprises administering to said female patient a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
The present disclosure also relates to a method for providing rapid suppression of Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH) in a female patient suffering from uterine fibroids, wherein said method comprises administering to said female patient a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
The present disclosure also relates to a method for providing rapid inhibition of Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH) in a female patient suffering from polycystic ovary syndrome (PCOS), wherein the method comprises administering to the female patient a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
The present disclosure also relates to a method for providing rapid inhibition of Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH) in a female patient suffering from adenomyosis, wherein the method comprises administering to the female patient a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the subject. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
The present disclosure also relates to pharmaceutical compositions for providing rapid suppression of LH and/or FSH in a female patient suffering from endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), or adenomyosis.
In one embodiment, the present disclosure also relates to a pharmaceutical composition for providing rapid suppression of LH and/or FSH in a female patient suffering from endometriosis.
In one embodiment, the present disclosure also relates to a pharmaceutical composition for providing rapid suppression of LH and/or FSH in a female patient suffering from uterine fibroids.
In one embodiment, the present disclosure also relates to a pharmaceutical composition for providing rapid suppression of LH and/or FSH in a female patient suffering from polycystic ovary syndrome.
In one embodiment, the present disclosure also relates to a pharmaceutical composition for providing rapid suppression of LH and/or FSH in a female patient suffering from adenomyosis.
The present disclosure also relates to methods for providing partial to substantially complete inhibition of estradiol in a female patient suffering from endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), or adenomyosis, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the female patient. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
In one embodiment, the present disclosure also relates to a method for providing partial to substantially complete inhibition of estradiol in a female patient suffering from endometriosis, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the female patient. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
In one embodiment, the present disclosure also relates to a method for providing partial to substantially complete inhibition of estradiol in a female patient with uterine fibroids, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the female patient. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
In one embodiment, the present disclosure also relates to a method for providing partial to substantially complete inhibition of estradiol in a female patient with polycystic ovary syndrome, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the female patient. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
In one embodiment, the present disclosure also relates to a method for providing partial to substantially complete inhibition of estradiol in a female patient suffering from adenomyosis, wherein the method comprises administering to the subject a pharmaceutical composition of the present disclosure. In some such embodiments, the pharmaceutical composition is administered once daily (QD) to the female patient. In some such embodiments, the pharmaceutical composition is administered to the female patient twice daily (BID).
The present disclosure also relates to pharmaceutical compositions for providing partial to substantially complete inhibition of estradiol in a female patient suffering from endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), or adenomyosis.
In one embodiment, the present disclosure also relates to a pharmaceutical composition for providing partial to substantially complete inhibition of estradiol in a female patient suffering from endometriosis.
In one embodiment, the present disclosure also relates to pharmaceutical compositions for providing partial to substantially complete inhibition of estradiol in female patients with uterine fibroids.
In one embodiment, the present disclosure also relates to a pharmaceutical composition for providing partial to substantially complete inhibition of estradiol in a female patient with polycystic ovary syndrome.
In one embodiment, the present disclosure also relates to a pharmaceutical composition for providing partial to substantially complete inhibition of estradiol in a female patient suffering from adenomyosis.
The present disclosure also relates to methods of preparing such pharmaceutical compositions.
These and other objects of the invention will be described in the following paragraphs. These objects should not be construed as narrowing the scope of the present invention.
Drawings
FIG. 1 is a flow chart of the roll-compaction process.
Fig. 2 is a graph showing the apparent solubility of compound a in water.
Fig. 3 is a flow diagram of a two-step wet granulation process.
Fig. 4 is a graph showing the in vitro dissolution profile of formulation F5 after 18 or 24 months of storage.
Fig. 5 is a graph showing the in vitro dissolution profile of formulation F6 after 1, 3,6, or 9 months of storage.
Fig. 6 is a graph showing the in vitro dissolution profile of formulation F10 (uncoated and film coated tablets).
Figure 7 is a graph showing in vitro dissolution profiles of compositions containing varying amounts of sodium carbonate monohydrate.
Figure 8 is a bar graph showing the percentage of degradation products (compound B) after one week of storage.
Figure 9 is a bar graph showing the rate of formation of degradation products (compound B) under various storage conditions.
FIG. 10: dissolution curves of the
FIG. 11: the mean change from baseline in the mean dysmenorrhea pain score in study EM-I and the response maintenance over 12 months in its extended study EM-III are depicted.
FIG. 12: the mean change from baseline in the mean NMPP score in study EM-I and the maintenance of the response over 12 months in its extended study EM-III are depicted.
FIG. 13: the mean change from baseline in the pain score for mean intercourse pain in study EM-I and the maintenance of response over 12 months in its extended study EM-III are depicted.
FIG. 14: lumbar BMD Z fraction box plots at baseline,
FIG. 15: rescue opioid pill count results are depicted as a mean percent change from baseline. The ANCOVA model indicated that the significance relative to placebo was P <.05 (. x.) and P <.001 (. x.). The month is 35 days apart.
FIG. 16: plot baseline Promis fatigue SF-6a T score higher than population norm by 1SD on average [ mean 50; SD ═ 10 ]. Denotes P < 0.01; statistical significance of the group of falagolide from the fatigue ANOVA model relative to placebo, including treatment as the primary factor. The maximum SF-6a T score is 76.8.
FIG. 17: it is depicted that the fatigue score of a patient with endometriosis decreased from baseline by the loragolide. Statistical significance relative to placebo from the fatigue ANCOVA model is shown, P <0.05, <0.01, <0.001(,) including treatment as the primary factor and baseline fatigue as the covariate, comparing each treatment group to placebo.
Detailed Description
This detailed description is merely intended to acquaint others skilled in the art with the invention, its principles, and its practical application to enable others skilled in the art to make and use the invention in its various forms, as may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. Therefore, the present invention is not limited to the embodiments described in the present patent application and various modifications can be made.
A. Definition of
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the indicated meanings:
as used herein, the term "API" means "active pharmaceutical ingredient". A preferred API as disclosed herein is 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof, such as 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, sodium 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate.
As used herein, the term "pharmaceutical composition" means a composition comprising compound a or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
The term "pharmaceutically acceptable" is used as an adjective, meaning that the modified noun is suitable for use as, or as part of, a pharmaceutical product for human use.
The term "subject" includes humans and other primates, as well as other mammals. The term subject encompasses, for example, healthy premenopausal women, as well as female patients suffering from, for example, endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), or adenomyosis. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult female. In certain embodiments, the subject is a female with endometriosis, typically a pre-menopausal female. In certain embodiments, the subject is a female with uterine fibroids, typically a pre-menopausal female. In certain embodiments, the subject is a female with adenomyosis, typically a pre-menopausal female. In certain embodiments, the subject is a female with PCOS, typically a pre-menopausal female.
The term "therapeutically effective amount" means an amount of an API or pharmaceutical composition sufficient to treat a condition, disorder or disease at a reasonable benefit/risk ratio applicable to any drug treatment.
The term "treating" refers to a method of alleviating or eliminating a condition, disorder or disease and/or its attendant signs and symptoms.
B. Raw material medicine
The pharmaceutical compositions disclosed herein comprise at least one active pharmaceutical ingredient: 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid (compound a) or a pharmaceutically acceptable salt thereof.
Compound a has the formula:
compound a is an orally active non-peptide GnRH antagonist and is distinct from other GnRH agonists and injectable (peptide) GnRH antagonists. Compound a produces a dose-dependent inhibitory effect on pituitary and ovarian hormones in women. Methods for preparing compound a and pharmaceutically acceptable salts thereof and similar compounds are described in WO2001/055119, WO 2005/007165 and WO2017/221144, the contents of which are incorporated herein by reference. Deuterated forms of the drug substance are also encompassed within the scope of the present invention. Deuterated forms of the drug substance are described in patent application CN108129400A, the content of which is incorporated herein by reference. The reference to the drug substance refers to the alternative use of oxagolide and oxagolide sodium. Unless specifically indicated, the range of oxagorskili encompasses oxagorskili sodium.
In certain embodiments, 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid is present in zwitterionic form. For example, carboxylic acids and tertiary amines are ionized and, therefore, the molecule does not have an overall charge, but rather a charge separation. Such zwitterionic forms are encompassed within the term "compound a or a pharmaceutically acceptable salt thereof".
Compound a may be present in the pharmaceutical composition in the form of an acid or base addition salt. The acid addition salts of the free amino compounds of the present invention can be prepared by methods well known in the art and can be formed from organic and inorganic acids. Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methane sulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzene sulfonic acid. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Suitable base addition salts include salts with carboxylate anions and include salts with organic and inorganic cations such as those selected from alkali and alkaline earth metals (e.g., lithium, sodium, potassium, magnesium, barium, and calcium), as well as ammonium ions and substituted derivatives thereof (e.g., benzhydrylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term "pharmaceutically acceptable salt" of compound a is intended to encompass any and all acceptable salt forms.
In certain embodiments, compound a is present in the pharmaceutical composition in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt of compound a is the sodium salt of compound a. The monosodium salt of compound A has the formula C32H29F5N3O5Na, corresponding to molecular weights of about 653.6 (salt) and about 631.6 (free form). The monosodium salt of compound a has the formula:
the pKa of the loragolide is about 8 and about 4, such as about 7.89 and about 4.15.
In certain embodiments, the monosodium salt is in the form of an amorphous solid. In certain embodiments, the monosodium salt is in a crystalline form, such as a partially crystalline form. In some embodiments, the X-ray powder diffraction (XRPD) pattern of the monosodium form of the amorphous compound shows a lack of crystallinity. The active substance is given by the replaceable use of oxagorskili and oxagorskili sodium. Unless specifically indicated, the range of oxagorskili encompasses oxagorskili sodium.
As used herein, and without specific reference to a particular pharmaceutically acceptable salt of compound a, any dose, whether expressed in milligrams or weight percent or in ratio to another ingredient, should be considered as referring to the amount of compound a in free form.
In certain embodiments, compound a or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount from about 25mg to about 650mg of compound a. In certain embodiments, compound a or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount from about 45mg to about 650mg of compound a. In certain embodiments, the amount of compound a or a pharmaceutically acceptable salt thereof is about 50mg to about 400 mg. In certain embodiments, the amount of compound a or a pharmaceutically acceptable salt thereof is about 100mg to about 350 mg. In some such embodiments, the amount of compound a, or a pharmaceutically acceptable salt thereof, is from about 140mg to about 160mg, such as about 150 mg. In other such embodiments, the amount of compound a, or a pharmaceutically acceptable salt thereof, is from about 190mg to about 210mg, such as about 200 mg. In yet other embodiments, the amount of compound a or a pharmaceutically acceptable salt thereof is about 290mg to about 310mg, such as about 300 mg.
C. Pharmaceutical composition
Pharmaceutical compositions comprising compound a or a pharmaceutically acceptable salt thereof are useful for treating endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), or adenomyosis. In one embodiment, a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof can be used to treat endometriosis. In one embodiment, a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof is useful for treating uterine fibroids. In one embodiment, a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof is useful for treating polycystic ovary syndrome (PCOS). In one embodiment, a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof can be used to treat adenomyosis. The pharmaceutical compositions or dosage forms described herein may be oral dosage forms, and specifically solid oral dosage forms, that can be administered to humans. Oral dosage forms may be in the form of tablets.
The present disclosure provides pharmaceutical formulations and functional excipients that particularly facilitate drug dissolution and/or enhance the stability of a drug product and/or drug substance (e.g., by controlling the formation of degradation products).
The oral drug administration route is most convenient for the patient and tablets are the most common solid oral dosage form used today. However, the development of immediate release tablets of compound a is not easy. The initial tablets prepared by granulating compound a in the presence of typical pharmaceutical excipients showed that compound a was not completely soluble in 900mL of 0.1N HCL buffer at pH 1.2. If the percentage of drug in the tablet exceeds 10%, only 30-40% of the drug load is dissolved. The balance of compound a is present as an insoluble precipitate at the top of the dissolution vessel.
In certain embodiments, the pharmaceutical composition is an immediate release pharmaceutical composition. In at least one aspect, a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof comprises an anti-gelling agent.
As referred to herein, an "anti-gelling agent" is an agent that reduces or prevents gel formation. In certain embodiments, the anti-gelling agent reduces or prevents gel formation relative to an otherwise identical composition that does not contain the anti-gelling agent. In certain embodiments, the anti-gelling agent reduces or prevents gel formation, thereby facilitating release of compound a, or a pharmaceutically acceptable salt thereof, from the composition. In certain embodiments, the anti-gelling agent improves the release of compound a, or a pharmaceutically acceptable salt thereof, from the pharmaceutical composition relative to the same pharmaceutical composition without the anti-gelling agent.
In certain embodiments, the anti-gelling agent acts as a pH adjuster, such as a buffer.
In certain embodiments, the anti-gelling agent is an alkali metal salt, such as sodium carbonate. The sodium carbonate may be sodium carbonate monohydrate or anhydrous sodium carbonate. The other antigelling agent may be a base. Examples of bases include calcium hydroxide, guanidine, magnesium hydroxide, meglumine, piperidine, glucosamine, piperazine or TRIS (hydroxymethyl aminomethane). In certain embodiments, the anti-gelling agent can be a basic amino acid. Examples of basic amino acids include L-ornithine, L-lysine or L-arginine. In certain other embodiments, the anti-gelling agent may be an alkaline salt. Examples of basic salts include sodium carbonate, potassium carbonate, trisodium phosphate, disodium hydrogen phosphate, trisodium citrate dihydrate, guanidine carbonate. In certain embodiments, the anti-gelling agent may be Eudragit EPO.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 1:1 to about 20: 1. The weight ratio may be selected within different ranges, selected from the group consisting of: 1:1, 2:1, 4:1, 6:1, 10:1 or 20: 1. Thus, the ratio may be, for example, in the range of 1:1 to 2:1, or 1:1 to 4:1, or 1:1 to 6:1, or 1:1 to 10:1, or 1:1 to 20: 1.
In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 3% to about 60% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 3% to about 50% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 5% to about 35% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 10% to about 25% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the anti-gelling agent is present in the pharmaceutical composition in an amount from about 15% to about 20% by weight (w/w) of the pharmaceutical composition.
In certain embodiments, the pharmaceutical composition is a film-coated tablet. In some such embodiments, the anti-gelling agent is present in an amount of from about 3% to about 60%, alternatively from about 3% to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the uncoated tablet. In some such embodiments, the anti-gelling agent is present in an amount of from about 3% to about 60%, alternatively from about 3% to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the coated tablet.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 20: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 10: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 6: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 4: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 1:1 to about 3: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is about 2: 1.
In some embodiments, the pharmaceutical composition further comprises an anti-gelling agent in an amount effective to prevent gel clot formation, so that the release rate and bioavailability of the API can be reduced when the pharmaceutical composition is administered to a patient.
In some embodiments, the anti-gelling agent reduces or prevents gel formation, thereby facilitating release of compound a, or a pharmaceutically acceptable salt thereof, from the pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises an anti-gelling agent in an amount effective to alter the microenvironment of compound a or a pharmaceutically acceptable salt thereof, to facilitate release of compound a or a pharmaceutically acceptable salt thereof from the pharmaceutical composition when administered to a patient. In some embodiments, the anti-gelling agent is present in an amount sufficient to provide a microenvironment to facilitate release of compound a or a pharmaceutically acceptable salt thereof from the tablet in an aqueous medium. In some embodiments, promoting the release of compound a or a pharmaceutically acceptable salt thereof results in a more predictable release and absorption rate compared to a pharmaceutical composition that does not contain an anti-gelling agent. In some embodiments, the anti-gelling agent improves the release of compound a, or a pharmaceutically acceptable salt thereof, from the pharmaceutical composition relative to the same pharmaceutical composition without the anti-gelling agent. In some embodiments, the pharmaceutical composition further comprises an anti-gelling agent in an amount effective to increase the release of compound a or a pharmaceutically acceptable salt thereof from the composition, wherein the release is measured in 900mL of pH6.8 sodium phosphate using USP apparatus II at 37 ℃ and 50rpm paddle speed.
In some embodiments, the pharmaceutical composition further comprises an anti-gelling agent in an amount effective to reduce or prevent formation of the zwitterionic form of compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-gelling agent acts as a diluent.
In some embodiments, the pharmaceutical composition further comprises an anti-gelling agent in an amount effective to adjust the disintegration time of the pharmaceutical composition and/or the dissolution time of compound a or a pharmaceutically acceptable salt thereof, such as to provide a microenvironment in the gastrointestinal tract that facilitates dissolution of compound a or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition further comprises an anti-gelling agent in an amount effective to alter the microenvironment of compound a or a pharmaceutically acceptable salt thereof by increasing the dryness level of the microenvironment of compound a or a pharmaceutically acceptable salt thereof when administered to the patient.
In some embodiments, the anti-gelling agent is selected from the group consisting of amines, amides, ammonium compounds, and amino acids. In some embodiments, the anti-gelling agent is selected from the group consisting of ammonia, ammonium lactate, ammonium bicarbonate, ammonium hydroxide, diammonium phosphate, methylamine, dimethylamine, ethylamine, propylamine, trimethylamine, monoethanolamine, diethanolamine, triethanolamine, tris, ethylenediamine, allantoin, N-dimethylglycine, N-methylglucamide, 6N-methyl reduced glucamine, tromethamine, meglumine, L-ornithine, L-lysine, and L-arginine, or a combination thereof.
In some embodiments, the anti-gelling agent is a water-soluble salt of an acid selected from the group consisting of: acetic acid, acetic acid (N-acetylglycine), adipic acid, L-ascorbic acid, L-aspartic acid, butyric acid, capric acid, carbonic acid, citric acid, fumaric acid, galactaric acid, D-glucaric acid, D-glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, palmitic acid, phosphoric acid, pyruvic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, and thiocyanic acid, or a combination thereof. In some embodiments, the anti-gelling agent is a water-soluble salt of an acid selected from the group consisting of: acetic acid, adipic acid, L-ascorbic acid, carbonic acid, citric acid, L-glutamic acid, hydrochloric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, phosphoric acid, stearic acid, succinic acid, sulfuric acid, and L-tartaric acid, or combinations thereof.
In some embodiments, the anti-gelling agent is a water-soluble salt of an acid selected from the group consisting of: alginic acid, benzenesulfonic acid, benzoic acid, 2- (4-hydroxybenzoyl) -benzoic acid, (+) -camphoric acid, octanoic acid, cyclohexylamine sulfonic acid, di (tert-butyl) naphthalene disulfonic acid, di (tert-butyl) naphthalene sulfonic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, gentisic acid, alpha-oxo-glutaric acid, isobutyric acid, malonic acid, methanesulfonic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, enbo acid, propionic acid, L-pyroglutamic acid and p-toluenesulfonic acid, or combinations thereof. In some embodiments, the anti-gelling agent is a water-soluble salt of an acid selected from the group consisting of: alginic acid, benzoic acid, caprylic acid, nicotinic acid, and propionic acid, or combinations thereof.
In some embodiments, the anti-gelling agent is a salt of carbonic acid or bicarbonic acid, such as an alkali metal salt or alkaline earth metal salt formed with a calcium, magnesium, sodium, or potassium base, or a combination thereof, for example sodium carbonate. The sodium carbonate may be sodium carbonate monohydrate or anhydrous sodium carbonate. In some embodiments, the anti-gelling agent is selected from salts of citric acid with calcium, magnesium, sodium, and potassium bases, or combinations thereof. In some embodiments, the anti-gelling agent is selected from the group consisting of salts of phosphoric acid with calcium, magnesium, sodium, and potassium bases, or combinations thereof. In some embodiments, the anti-gelling agent is selected from the group consisting of: salts of acetic acid with calcium, magnesium, sodium and potassium bases or salts thereof. In some embodiments, the anti-gelling agent is selected from the group consisting of salts of sulfuric acid with calcium, magnesium, sodium, and potassium bases, or combinations thereof. In some embodiments, the anti-gelling agent is selected from the group consisting of salts of L-ascorbic acid with calcium, magnesium, sodium, and potassium bases, or combinations thereof. In some embodiments, the anti-gelling agent is selected from the group consisting of salts of L-aspartic acid with calcium, magnesium, sodium, and potassium bases, or combinations thereof. In some embodiments, the calcium base is calcium hydroxide. In some embodiments, the magnesium base is magnesium hydroxide. In some embodiments, the sodium base is sodium hydroxide. In some embodiments, the potash is potassium hydroxide. The other antigelling agent may be a base. Examples of bases include calcium hydroxide, guanidine, magnesium hydroxide, meglumine, piperidine, glucosamine, piperazine, or TRIS (TRIS) or combinations thereof. In certain other embodiments, the anti-gelling agent may be an alkaline salt. Examples of basic salts include sodium carbonate, potassium carbonate, trisodium phosphate, disodium hydrogen phosphate, trisodium citrate dihydrate, or guanidine carbonate, or combinations thereof.
In certain embodiments, the anti-gelling agent comprises a water soluble salt of a weak acid, such as a carbonate (e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate), an acetate (e.g., sodium acetate, potassium acetate, ammonium acetate), or a phosphate (e.g., monosodium phosphate, disodium phosphate, or trisodium phosphate), or a combination thereof.
In certain embodiments, the anti-gelling agent comprises a basic amino acid, such as arginine, lysine, histidine, or a combination thereof. In certain embodiments, the anti-gelling agent comprises a basic polymer, such as a poly (meth) acrylate polymer, such as Eudragit E100, Eudragit E12, Eudragit E5, Eudragit E PO, or a combination thereof.
In certain embodiments, the anti-gelling agent comprises an alkali metal salt or a combination thereof. Exemplary alkali metal salts include sodium carbonate, sodium bicarbonate, or sodium phosphate.
In certain embodiments, the alkali metal salt is present in an amount sufficient to provide a microenvironment that reduces or prevents gel formation. In certain embodiments, the alkali metal salt is present in an amount sufficient to provide a microenvironment that facilitates release of compound a or a pharmaceutically acceptable salt thereof from the tablet in an aqueous medium. In some embodiments, the pharmaceutical composition has a release profile such that release of compound a or a pharmaceutically acceptable salt thereof, or disintegration of the pharmaceutical composition occurs in the small intestine. In some embodiments, the pharmaceutical composition has a release profile such that release of compound a or a pharmaceutically acceptable salt thereof, or disintegration of the pharmaceutical composition occurs distal to the pyloric sphincter. In some embodiments, the pharmaceutical composition has a release profile such that release of compound a or a pharmaceutically acceptable salt thereof, or disintegration of the pharmaceutical composition occurs distal to the duodenal bulb. In some embodiments, the pharmaceutical composition has a release profile such that release of compound a or a pharmaceutically acceptable salt thereof, or disintegration of the pharmaceutical composition occurs distal to the middle duodenum. In some embodiments, the pharmaceutical composition has a release profile such that release of compound a or a pharmaceutically acceptable salt thereof, or disintegration of the pharmaceutical composition occurs distal to the duodenal jejunal junction. In some embodiments, the pharmaceutical composition has a release profile such that release of compound a or a pharmaceutically acceptable salt thereof, or disintegration of the pharmaceutical composition occurs distal to the proximal jejunum.
In some embodiments, the pharmaceutical composition has a release profile such that release of compound a or a pharmaceutically acceptable salt thereof, or disintegration of the pharmaceutical composition occurs at a pH high enough to avoid significant gelation of compound a.
In some embodiments, the pharmaceutical composition releases at least about 80% of compound a or a pharmaceutically acceptable salt thereof within about 45 minutes, such as releases at least about 80% of compound a or a pharmaceutically acceptable salt thereof within about 30 minutes, as measured in 900mL of sodium ph6.8 phosphate using USP apparatus II at 37 ℃ and 50rpm paddle speed. In some embodiments, the pharmaceutical composition releases at least about 80% of compound a or a pharmaceutically acceptable salt thereof in about 45 minutes, such as at least about 80% of compound a or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using USP apparatus II at 37 ℃ and 50rpm paddle speed in 900mL of pH 1.2 hydrochloric acid. In some embodiments, the pharmaceutical composition releases at least about 80% of compound a or a pharmaceutically acceptable salt thereof in about 45 minutes, such as releases at least about 80% of compound a or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured in 900mL of sodium pH6.8 phosphate using USP apparatus II at 37 ℃ and 50rpm paddle speed; and releasing at least about 80% of compound a or a pharmaceutically acceptable salt thereof in about 45 minutes, such as releasing at least about 80% of compound a or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using USP apparatus II at 37 ℃ and 50rpm paddle speed, at a pH of 900mL of 1.2 hydrochloric acid. In some embodiments, the pharmaceutical composition provides a microenvironment for release of compound a or a pharmaceutically acceptable salt thereof, wherein the release is independent of pH. Analysis may be accomplished by a High Performance Liquid Chromatography (HPLC) system with Ultraviolet (UV) detection.
In some embodiments, the pharmaceutical composition further comprises an anti-gelling agent in an amount effective to modulate the pH of the microenvironment of compound a or a pharmaceutically acceptable salt thereof in the gastrointestinal tract. In some embodiments, the microenvironment that facilitates release of compound a or a pharmaceutically acceptable salt thereof from the tablet comprises a pH value between the lower pKa limit of compound a or a pharmaceutically acceptable salt thereof and the upper pKa limit of compound a or a pharmaceutically acceptable salt thereof. These values can be determined empirically by one of ordinary skill in the art using methods known in the art. In certain embodiments, the microenvironment that facilitates release of compound a or a pharmaceutically acceptable salt thereof from the tablet comprises a pH of about 3.5 to about 8.0, such as about 4.0 to about 8.0.
In certain embodiments, the anti-gelling agent is sodium carbonate, such as sodium carbonate monohydrate or anhydrous sodium carbonate.
In certain embodiments, the sodium carbonate is present in the pharmaceutical composition in an amount from about 3% to about 60% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the sodium carbonate is present in the pharmaceutical composition in an amount from about 3% to about 50% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the sodium carbonate is present in the pharmaceutical composition in an amount from about 5% to about 35% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the sodium carbonate is present in the pharmaceutical composition in an amount from about 10% to about 25% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the sodium carbonate is present in the pharmaceutical composition in an amount from about 15% to about 20% by weight (w/w) of the pharmaceutical composition.
In certain embodiments, the pharmaceutical composition is a film-coated tablet. In some such embodiments, the sodium carbonate is present in an amount of from about 3% to about 60%, alternatively from about 3% to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the uncoated tablet. In some such embodiments, the sodium carbonate is present in an amount of from about 3% to about 60%, alternatively from about 3% to about 50%, alternatively from about 5% to about 35%, alternatively from about 10% to about 25%, alternatively from about 15% to about 20%, by weight of the coated tablet.
In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 20: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 10: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 6: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 0.5:1 to about 4: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is from about 1:1 to about 3: 1. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to the anti-gelling agent is about 2: 1.
In certain embodiments, the weight ratio of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate to sodium carbonate monohydrate is from about 0.5:1 to about 4: 1. In certain embodiments, the weight ratio of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate to sodium carbonate monohydrate is from about 1:1 to about 3: 1. In certain embodiments, the weight ratio of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate to sodium carbonate monohydrate is about 2: 1.
As used herein, and without explicitly mentioning the particular hydrate (or anhydrous) form of sodium carbonate, any amount, whether expressed in milligrams or weight percent or in ratio to another ingredient, should be considered as referring to the amount of sodium carbonate monohydrate.
Release profile the drug administered by an oral solid dosage form should dissolve in the body before systemic absorption can occur. There are many factors that affect the dissolution of a drug, including the physicochemical properties of the drug substance. Poorly water soluble drugs, such as class II BCS (low solubility and high permeability) often exhibit poor dissolution and bioavailability. Even highly soluble drugs, such as class III BCS (high solubility and low permeability), can exhibit poor dissolution and bioavailability. Incomplete dissolution may vary greatly in inter-and intra-patient bioavailability. Compound a has been identified herein as a class III BCS drug. It has also been determined herein that the monosodium salt of compound a has a tendency to form a gel when administered orally in a solid dosage form, particularly when present in an amount greater than about 10% by weight in the absence of sufficient anti-gelling agent. Accordingly, it is desirable to provide oral solid dosage forms that promote drug dissolution.
In certain embodiments, dissolution is evaluated in 900mL of pH6.8 sodium phosphate using USP apparatus II at 37 ℃ and 50rpm paddle speed. In certain embodiments, dissolution is evaluated using USP apparatus II at 37 ℃ and 50rpm paddle speed in 900mL of pH 1.2 hydrochloric acid. Analysis may be accomplished by a High Performance Liquid Chromatography (HPLC) system with Ultraviolet (UV) detection.
The solid oral dosage forms described herein will typically be in the form of tablets, particularly in the form of immediate release tablets. In certain embodiments, the immediate release tablet releases at least 80% of compound a or a pharmaceutically acceptable salt thereof within 30 minutes (AbbVie internal specification) as measured using USP apparatus II at 37 ℃ and 50rpm paddle speed in 900mL of sodium phosphate pH 6.8. In certain embodiments, the immediate release tablet releases at least 80% of compound a or a pharmaceutically acceptable salt thereof (FDA) within 45 minutes as measured using USP apparatus II at 37 ℃ and 50rpm paddle speed in 900mL of sodium phosphate pH 6.8.
(3) Stability in at least one aspect, the pharmaceutical compositions disclosed herein are stable for extended periods of time (e.g., up to two years at room/ambient conditions), such as storage, dispensing, and product shelf life. A stable pharmaceutical composition may, for example, exhibit less degradation of the API and/or a lower amount of degradation products. Degradation products generated during storage of the drug substance and/or drug product are undesirable and, in extreme cases, may even be harmful to patients treated with such drug products. It is therefore desirable to control the formation of degradation products, particularly potentially harmful impurities, in pharmaceutical products.
Analysis and degradation product determination of pharmaceutical compositions, particularly solid oral dosage forms, and more particularly tablets, can be performed using HPLC with UV detection.
Degradation products of a pharmaceutical composition can be assessed after storage for at least one week for at least two weeks, at least one month, at least two months, at least three months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In particular, degradation products may be assessed at intervals of one month, three months, six months, nine months, twelve months, eighteen months, twenty-four months, thirty-six months, and/or forty-eight months. The storage conditions may be long term, intermediate or accelerated conditions. Specifically, the storage conditions can be, for example, 25 ℃. + -. 2 ℃/40% Relative Humidity (RH). + -. 5% RH, 25 ℃. + -. 2 ℃/60% RH. + -. 5% RH, 30 ℃. + -. 2 ℃/35% RH. + -. 5% RH, 30 ℃. + -. 2 ℃/65% RH. + -. 5% RH, 40 ℃. + -. 2 ℃/25% RH. + -. 5% RH, 40 ℃. + -. 2 ℃/75% RH, 50 ℃. + -. 2 ℃/75% RH, 60 ℃. + -. 2 ℃/5% RH, 60 ℃. + -. 2 ℃/40% RH. + -. 5% RH, 70 ℃. + -. 2 ℃/75% RH. + -. 5% RH, and/or 80 ℃. + -. 2 ℃/40% RH. + -. 5% RH.
An exemplary degradation product of compound a is (R) -5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methyl-3- (2- (2-oxopyrrolidin-1-yl) -2-phenylethyl) pyrimidine-2, 4(1H,3H) -dione (compound B) having the following structure:
it has been identified in the present application that the formation of compound B in certain formulations cannot be adequately controlled. For example, compound B is present in an amount greater than 1% when a formulation without sodium carbonate monohydrate is stored for one week at 65 ℃/75% RH. Thus, in certain embodiments, sodium carbonate is included in a pharmaceutical composition as a stabilizer for reducing degradation and/or reducing or preventing gel formation.
In certain embodiments, sodium carbonate is present in an amount from about 10% to about 25% by weight of the pharmaceutical composition, such as from about 15% to about 20% by weight. In certain embodiments, the weight ratio of compound a or a pharmaceutically acceptable salt thereof to sodium carbonate is from about 1:1 to about 4:1, such as about 2:1 (bulk drug: sodium carbonate).
In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 1.0% by weight after storage at 25 ℃ and 60% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 0.7% by weight after storage at 25 ℃ and 60% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 0.5% by weight after storage at 25 ℃ and 60% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 0.03% by weight after storage at 25 ℃ and 60% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months.
In one aspect, the present disclosure provides a stable pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof. A stable pharmaceutical composition may for example contain less than 1% of compound B after storage for at least one week, and/or at least one month, at least three months, at least six months, at least nine months, at least twelve months, at least eighteen months or at least twenty-four months.
In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 1.0% by weight after storage at 40 ℃ and 75% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 0.7% by weight after storage at 40 ℃ and 75% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 0.5% by weight after storage at 40 ℃ and 75% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In certain embodiments, compound B is present in the pharmaceutical composition in an amount of less than about 0.03% by weight after storage at 40 ℃ and 75% relative humidity for at least one week, at least one month, at least two months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months.
Pharmacokinetics: the solid oral dosage forms described herein will typically be in the form of tablets. It is a particular advantage provided by the present invention to provide tablets having specific pharmacokinetic parameters. Pharmacokinetic parameters refer to any suitable pharmacokinetic parameters such as Tmax, Cmax and AUC. The parameters should be measured according to standards and practices acceptable to a drug regulatory agency, such as FDA, EMA, MHLW or WHO. These values may be based on measurements taken at appropriate time intervals after the time of tablet ingestion, such as every hour, or at increasingly sparse sampling time intervals after ingestion, such as 2,4, 6, 8, 10, 12, 16, and 24 hours. Pharmacokinetic parameters may be assessed after a single dose of drug or at steady state, such as after a single dose. In certain embodiments, the pharmacokinetic parameter is determined after a single dose of the pharmaceutical composition. In certain embodiments, the pharmacokinetic parameter is determined in a multiple dosing regimen. For example, pharmacokinetic parameters may be determined after several dosing intervals, e.g. at steady state. Pharmacokinetic parameters may be assessed under fasting or fed conditions, such as fasting conditions.
Cmax refers to the peak concentration, particularly the maximum drug plasma/serum concentration observed. Tmax refers to the time to reach peak concentration. AUCt refers to the area under the plasma concentration-time curve, where t is the time of the last measurable plasma concentration in the study. AUC ∞ refers to the area under the plasma concentration-time curve from time zero to an infinitely long time after a single dose.
In certain embodiments, provided are solid oral dosage forms (particularly tablets) as described herein, wherein the dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean Tmax of less than about 3 hours. In certain embodiments, provided is a solid oral dosage form (particularly a tablet) as described herein, wherein the dosage form, when administered in a single dose to a population of human subjects, provides the population of human subjects with a mean Tmax of about 0.5 hours to about 2.0 hours. In some such embodiments, the solid oral dosage form is administered under fasting conditions.
In certain embodiments, a solid oral dosage form (specifically, a tablet) as described herein is provided, wherein the dose comprises an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 150mg of compound a, and wherein the dosage form, when administered to a population of human subjects in a single dose, provides the population of human subjects with a mean Cmax, or cma of about 400 (about 80% of 510) to about 660 (about 125% of 523) ng/mL, An average AUCt of about 1000 (about 80% of 1263) to about 1600 (about 125% of 1273) ng-hr/mL, and/or an average AUC ∞ of about 1010 (about 80% of 1271) to about 1610 (about 125% of 1281) ng-hr/mL. In some such embodiments, the solid oral dosage form is administered under fasting conditions.
In certain embodiments, a solid oral dosage form (specifically, a tablet) as described herein is provided, wherein the dose comprises an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butyrate equivalent to about 200mg of compound a, and wherein the dosage form, when administered to a population of human subjects in a single dose, provides the population of human subjects with from about 590 (about 80% of 738) ng/mL to about 1100 (about 125% of 879) ng/mL, such as a mean Cmax of about 590 (about 80% of 738) to about 930 (about 125% of 738) ng/mL; an average AUCt of about 1510 (about 80% of 1890) to about 2980 (about 125% of 2384) ng hr/mL, such as about 1520 (about 80% of 1910) to about 2390 (about 125% of 1910) ng hr/mL; and/or an average AUC ∞ of about 1520 (about 80% of 1900) ng-hr/mL to about 2990 (about 125% of 2391) ng-hr/mL, such as about 1530 (about 80% of 1920) ng-hr/mL to about 2400 (about 125% of 1920). In some such embodiments, the solid oral dosage form is administered under fasting conditions.
In certain embodiments, a solid oral dosage form (specifically, a tablet) as described herein is provided, wherein the dose comprises an amount of sodium 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate equivalent to about 300mg of compound a, and wherein the dosage form, when administered to a population of human subjects in a single dose, provides the population of human subjects with a mean Cmax, or cma of about 1100 (about 80% of 1378) to about 1730 (about 125% of 1378) ng/mL, An average AUCt of about 2990 (about 80% of 3732) ng-hr/mL to about 4670 (about 125% of 3732) ng-hr/mL, and/or an average AUC ∞ of about 3020 (about 80% of 3772) ng-hr/mL to about 4720 (about 125% of 3772) ng-hr/mL. In some such embodiments, the solid oral dosage form is administered under fasting conditions.
In some embodiments, there is provided a solid oral dosage form (particularly a tablet) as described herein for which the 90% confidence interval for the logarithmic transformed Cmax, logarithmic transformed AUCt, and/or logarithmic transformed AUC ∞ of compound a or a pharmaceutically acceptable salt thereof in a population of human subjects is completely within the 80-125% range of the logarithmic transformed Cmax, logarithmic transformed AUCt, and/or logarithmic transformed AUC ∞ of a reference tablet, respectively, wherein the reference tablet comprises 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3 in an amount equivalent to about 150mg of compound a, 6-dihydro-2H-pyrimidin-1-yl]-sodium 1-phenyl-ethylamino) butyrate; about 150mg mannitol; about 44mg pregelatinized starch; about 14mg povidone; about 78mg sodium carbonate monohydrate; about 8mg magnesium stearate; and a mixture of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and high-tone carmine (e.g. carmineII pink) film coating.
In some embodiments, there is provided a method as described hereinA solid oral dosage form (in particular, a tablet) for which the 90% confidence interval for the logarithmic transformed Cmax, logarithmic transformed AUCt and/or logarithmic transformed AUC ∞ of Compound A or a pharmaceutically acceptable salt thereof in a population of human subjects is completely within the range of 80-125% of the logarithmic transformed Cmax, logarithmic transformed AUCt and/or logarithmic transformed AUC ∞ of a reference tablet, respectively, wherein the reference tablet comprises 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl) in an amount equivalent to about 200mg of Compound A.]-sodium 1-phenyl-ethylamino) butyrate; about 200mg mannitol; about 59mg pregelatinized starch; about 18mg povidone; about 104mg sodium carbonate monohydrate; about 11mg magnesium stearate; and polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide red (such as
In some embodiments, there is provided a solid oral dosage form (particularly a tablet) as described herein for which the 90% confidence interval for the logarithmic transformed Cmax, logarithmic transformed AUCt, and/or logarithmic transformed AUC ∞ of compound a or a pharmaceutically acceptable salt thereof in a population of human subjects is completely within the 80-125% range of the logarithmic transformed Cmax, logarithmic transformed AUCt, and/or logarithmic transformed AUC ∞ of a reference tablet, respectively, wherein the reference tablet comprises 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3 in an amount equivalent to about 300mg of compound a, sodium 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) butanoate; mannitol; pregelatinized starch; povidone; sodium carbonate monohydrate; magnesium stearate; and a film coating.
(5) In some embodiments, the pharmaceutical composition is a tablet comprising compound a or a pharmaceutically acceptable salt thereof, wherein the bioavailability or exposure level of the tablet is equal to or greater than the bioavailability or exposure level of an oral solution formulation having the same amount of compound a or a pharmaceutically acceptable salt thereof.
In certain embodiments, administration of a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof results in rapid suppression of Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH) levels in a female patient suffering from endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), or adenomyosis. In certain embodiments, administration of a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof results in partial to substantially complete inhibition of estradiol levels in a female patient suffering from endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), or adenomyosis. In some such embodiments, the estradiol level is less than about 50 pg/mL. In some such embodiments, the estradiol level is between about 20pg/mL and about 50 pg/mL. In some such embodiments, the estradiol level is less than about 20 pg/mL. In some such embodiments, the estradiol level is less than about 12pg/mL (e.g., below the minimum quantitation limit).
(6) Additional excipients pharmaceutical compositions may include other excipients such as excipients that act as fillers, binders, disintegrants, glidants and lubricants. Accordingly, a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof optionally further comprises one or more conventional pharmaceutically acceptable excipients.
(6a) Fillers in certain embodiments, the disclosed pharmaceutical compositions include at least one excipient that acts as a filler. Fillers may include polyols such as dextrose, isomalt, mannitol, sorbitol, lactose, and sucrose; native or pregelatinized potato or corn starch; microcrystalline cellulose (e.g. cellulose acetate)
In certain embodiments, the disclosed pharmaceutical compositions include at least one water-soluble filler. In some such embodiments, the water-soluble filler is a polyol, such as mannitol, sorbitol, lactose, or sucrose; pregelatinized starch; or a combination thereof. In some such embodiments, the water-soluble filler is mannitol. In some such embodiments, the water soluble bulking agent is mannitol and pregelatinized starch. In certain embodiments, the disclosed pharmaceutical compositions include at least one water-insoluble filler. In some such embodiments, the water-insoluble filler is starch, microcrystalline cellulose (e.g., cellulose acetate, sodium alginate) Or a calcium phosphate. In some such embodiments, the disclosed pharmaceutical compositions include a water-insoluble filler and a surfactant, such as Sodium Lauryl Sulfate (SLS).
In certain embodiments, the filler is present in the pharmaceutical composition in an amount from about 5% to about 70% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the filler is present in the pharmaceutical composition in an amount from about 10% to about 60% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the filler is present in the pharmaceutical composition in an amount from about 20% to about 50% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the filler is present in the pharmaceutical composition in an amount from about 30% to about 45% by weight (w/w) of the pharmaceutical composition.
In certain embodiments, the pharmaceutical composition comprises a first filler in an amount from about 20% to about 50% by weight of the pharmaceutical composition and a second filler in an amount from about 1% to about 20% by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a first filler in an amount from about 25% to about 40% by weight of the pharmaceutical composition and a second filler in an amount from about 5% to about 15% by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a first filler in an amount from about 30% to about 35% by weight of the pharmaceutical composition and a second filler in an amount from about 8% to about 12% by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a first filler in an amount of about 33% by weight of the pharmaceutical composition and a second filler in an amount of about 10% by weight of the pharmaceutical composition. In certain embodiments, the first bulking agent is mannitol and the second bulking agent is pregelatinized starch.
(6b) Binders in certain embodiments, the disclosed pharmaceutical compositions include at least one excipient that acts as a binder. The binder may comprise polyvinylpyrrolidone (e.g., povidone), a copolymer of vinylpyrrolidone and vinyl acetate (e.g., copovidone); cellulose, such as Hydroxymethylpropylcellulose (HPMC), hydroxypropylethylcellulose or microcrystalline cellulose; sucrose, starch, and combinations thereof. In certain embodiments, the binder is a hydrophilic polymer. The hydrophilic polymer may be selected from copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, polyalkylene glycols, polyacrylates, polymethacrylates, polyacrylamides, polyvinyl alcohols, vinyl acetate polymers, oligosaccharides, polysaccharides, or combinations thereof. In some such embodiments, the binder is polyvinylpyrrolidone.
In certain embodiments, the binder is present in the pharmaceutical composition in an amount from about 0.1% to about 20% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the binder is present in the pharmaceutical composition in an amount from about 1% to about 10% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the binder is present in the pharmaceutical composition in an amount from about 2% to about 5% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises about 3% by weight of the binder. In certain embodiments, the binder is polyvinylpyrrolidone.
(6c) Glidants in certain embodiments, the disclosed pharmaceutical compositions include at least one excipient that acts as a glidant. Glidants may include, for example, colloidal silicon dioxide, including highly dispersed silicon dioxide
In certain embodiments, the glidant is present in the pharmaceutical composition in an amount from about 0.1% to about 5% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the glidant is present in the pharmaceutical composition in an amount from about 0.3% to about 2% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the glidant is present in the pharmaceutical composition in an amount from about 0.3% to about 1.2% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises about 0.5% by weight of a glidant. In certain embodiments, the glidant is colloidal silicon dioxide.
In certain embodiments, the glidant is contained in the intra-granular portion of the pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.1 weight percent to about 5 weight percent (w/w), based on the weight of the total pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.5 weight percent to about 3 weight percent (w/w), based on the weight of the total pharmaceutical composition.
In certain embodiments, the glidant is included in the extra-granular portion of the pharmaceutical composition. In certain embodiments, the extra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.1 weight percent to about 5 weight percent (w/w), based on the weight of the total pharmaceutical composition. In certain embodiments, the extra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.5 weight percent to about 3 weight percent (w/w), based on the weight of the total pharmaceutical composition.
In certain embodiments, the glidant is contained in both the intra-and extra-granular portions of the pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.1 weight percent to about 5 weight percent (w/w), based on the weight of the total pharmaceutical composition, and the extra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.1 weight percent to about 5 weight percent (w/w), based on the weight of the total pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.5 weight percent to about 3 weight percent (w/w), based on the weight of the total pharmaceutical composition, and the extra-granular portion of the pharmaceutical composition comprises a glidant in an amount of about 0.5 weight percent to about 3 weight percent (w/w), based on the weight of the total pharmaceutical composition.
(6c) Lubricant in certain embodiments, the disclosed pharmaceutical compositions include at least one excipient that acts as a lubricant. The lubricant may comprise, for example, magnesium and calcium stearate, sodium stearyl fumarate, talc, or any other suitable lubricant.
In certain embodiments, the lubricant is present in the pharmaceutical composition in an amount from about 0.1% to about 10% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the lubricant is present in the pharmaceutical composition in an amount from about 0.5% to about 5% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the lubricant is present in the pharmaceutical composition in an amount from about 1% to about 3% by weight (w/w) of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises about 1.9% by weight of the lubricant. In certain embodiments, the lubricant is magnesium stearate.
In certain embodiments, the lubricant is contained in the intra-granular portion of the pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 0.5 weight% to about 5 weight% (w/w) based on the weight of the total pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 1 weight percent to about 3 weight percent (w/w), based on the weight of the total pharmaceutical composition.
In certain embodiments, the lubricant is contained in the extra-granular portion of the pharmaceutical composition. In certain embodiments, the extra-granular portion of the pharmaceutical composition comprises a lubricant in an amount of about 0.5 weight% to about 5 weight% (w/w) based on the weight of the total pharmaceutical composition. In certain embodiments, the extra-granular portion of the pharmaceutical composition comprises a lubricant in an amount of about 1 weight% to about 3 weight% (w/w) based on the weight of the total pharmaceutical composition. In certain embodiments, magnesium stearate is used as a lubricant and is in the extragranular portion.
In certain embodiments, the lubricant is contained in both the intra-and extra-granular portions of the pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 0.5 weight percent to about 5 weight percent (w/w), based on the weight of the total pharmaceutical composition, and the extra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 0.5 weight percent to about 5 weight percent (w/w), based on the weight of the total pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 1 weight percent to about 3 weight percent (w/w), based on the weight of the total pharmaceutical composition, and the extra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 1 weight percent to about 3 weight percent (w/w), based on the weight of the total pharmaceutical composition. In certain embodiments, the intra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 0.9 weight percent (w/w) based on the weight of the total pharmaceutical composition, and the extra-granular portion of the pharmaceutical composition comprises the lubricant in an amount of about 1 weight percent (w/w) based on the weight of the total pharmaceutical composition. In certain embodiments, magnesium stearate is used as a lubricant in the formulation at a level of about 1.9% (weight/weight), with 0.9% being added intragranularly and about 1% being added extragranularly.
(6d) Disintegrants in certain embodiments, the disclosed pharmaceutical compositions include at least one excipient that acts as a disintegrant. Disintegrants may include, for example, sodium starch glycolate (e.g., Explotab), cross-linked polymers such as cross-linked modified starch, cross-linked polyvinylpyrrolidone (also known as cross-linked povidone), and cross-linked carboxymethylcellulose (also known as cross-linked carboxymethylcellulose). In certain embodiments, the disintegrant is present in the pharmaceutical composition in an amount from about 0.1% to about 20% by weight (w/w) of the pharmaceutical composition.
(7) Film coating on certainIn embodiments, the pharmaceutical composition is a tablet, which may be coated with any suitable coating, such as a film coating. Film coatings may be used, for example, to facilitate easy swallowing of tablets. Film coatings can also be used to improve taste and provide a pleasing appearance. The film coating may include polyvinyl alcohol-polyethylene glycol graft copolymers, e.g.
In at least one aspect, the present disclosure relates to the provision of compound a or a pharmaceutically acceptable salt thereof in a pharmacologically effective and physically acceptable single stable solid oral dosage form. The solid oral dosage forms disclosed herein are intended for pharmaceutical use in a human subject. Thus, in addition to being therapeutically effective, the solid oral dosage forms should also have a size and weight suitable for oral administration to humans (e.g., these solid oral dosage forms should have a total weight of less than about 1.5 g). To facilitate ingestion of such dosage forms by a mammal, the dosage forms may be shaped into a suitable shape, such as a circular or elongated shape.
(8) Exemplary formulations (tables) for example, as shown in table 1, the disclosed pharmaceutical compositions may comprise one or more fillers, disintegrants, glidants, and/or lubricants in combination with an active agent and an anti-gelling agent.
Compound a mentioned in table 1 below is compound a sodium salt and the corresponding weight percentages are provided in the salt form.
Table 1.
a is the percentage provided based on the weight of the coated tablet. The total percentage may not be 100% by rounding.
The amount of compound a or a pharmaceutically acceptable salt thereof (mg) mentioned in the following table refers to the amount of compound a in free form (mg) (i.e., in the case of a pharmaceutically acceptable salt, the equivalent of the free form).
In certain embodiments, the pharmaceutical composition comprises:
composition (I)
Amount (mg)
Compound A or pharmaceutically acceptable salt thereof
125-175
Mannitol
125-175
Pregelatinized starch
35-55
Povidone
13-15
Sodium carbonate
66-90
Magnesium stearate
7-10
Optional film coating
16-20
In certain embodiments, the pharmaceutical composition comprises:
composition (I)
Amount (mg)
Compound A or pharmaceutically acceptable salt thereof
170-230
Mannitol
170-230
Pregelatinized starch
47-71
Povidone
17-20
Sodium carbonate
88-120
Magnesium stearate
9-13
Optional film coating
21-27
In certain embodiments, the pharmaceutical composition comprises:
composition (I)
Amount (mg)
Compound A or pharmaceutically acceptable salt thereof
255-345
Mannitol
255-345
Pregelatinized starch
70-107
Povidone
25-30
Sodium carbonate
132-180
Magnesium stearate
14-20
Optional film coating
24-30
In certain embodiments, the pharmaceutical composition comprises:
in certain embodiments, the pharmaceutical composition comprises:
composition (I)
Amount (mg)
Compound A or pharmaceutically acceptable salt thereof
200
200
Pregelatinized starch
59.1
Povidone
18.4
Sodium carbonate
104
Magnesium stearate
11.2
Optional film coating
24
In certain embodiments, the pharmaceutical composition comprises:
composition (I)
Amount (mg)
Compound A or pharmaceutically acceptable salt thereof
300
Mannitol
300
Pregelatinized starch
88.7
Povidone
27.7
Sodium carbonate
156
Magnesium stearate
16.8
Optional film coating
27
D. Manufacturing method
The disclosed pharmaceutical compositions can be prepared by any suitable method. Compound a or a pharmaceutically acceptable salt thereof can be co-mixed with an anti-gelling agent and any other excipients of the pharmaceutical composition, including water-soluble or water-insoluble fillers and surfactants, using methods such as direct compression, fluid bed granulation, roller compaction or dry granulation, and wet granulation.
In certain embodiments, the disclosed pharmaceutical compositions are prepared using a wet granulation process and by compressing the final blend into tablets.
In certain embodiments, the disclosed pharmaceutical compositions are prepared using a roll-on process. The rolling process may comprise any suitable step. For example, as shown in fig. 1, rolling may comprise the steps of: co-mixing the active agent with one or more intragranular excipients sized for co-mixing; feeding the blend into a roller press to compact the loose powder into a ribbon; grinding the resulting ribbon into particles; optionally, co-mixing the granules with an extra-granular excipient such as a lubricant; compressing the granules into tablets; and optionally, coating the tablet with a film coating.
Each of the methods, compositions, or uses described herein optionally includes the following limitations: "wherein the pharmaceutical composition is not an immediate release tablet comprising 155.2mg of compound a sodium salt (equivalent to 150mg of compound a) in combination with mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and high tone carmine".
Each method, composition, or use described herein also optionally includes the following limitations: "wherein the pharmaceutical composition is not an immediate release tablet comprising 207.0mg of compound a sodium salt (equivalent to 200mg of compound a) in combination with mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide".
In some embodiments, the one or more pharmaceutically acceptable carriers are selected from the group consisting of binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, and flavoring agents.
Suitable binders or granulating agents include, but are not limited to, starches, such as corn STARCH, potato STARCH, and pregelatinized STARCH (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss (Irish moss) extract, panwal gum (Panwar gum), ghatti gum (ghatti gum), mucilage of psyllium husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum (Veegum), larch arabinogalactan, powdered tragacanth and guar gum; cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMCCorp, Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein in about 50 to about 99 weight percent.
Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose such as methyl cellulose and carboxymethyl cellulose; wood products; a natural sponge; a cation exchange resin; alginic acid; gums, such as guar gum and Vigrem HV; citrus pulp; crosslinked celluloses, such as crosslinked carboxymethylcellulose; crosslinked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium (polacrilin potassium); starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; align; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible by one of ordinary skill in the art. The pharmaceutical compositions provided herein can contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerol; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; pulverizing herba Lycopodii; silica or silica gels, e.g.200 (Baltimore, Md.) W.R.Grace Co.) and
Pharmaceutical compositions may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carrier excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants.
E. Application method
In at least one aspect, the invention encompasses a method of treating endometriosis comprising administering to a patient a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating endometriosis comprises administering a pharmaceutical composition comprising a dose of compound a, or a pharmaceutically acceptable salt thereof, of about 150 mg. In some such embodiments, the composition is administered once daily ("QD"). In certain embodiments, the method of treating endometriosis comprises administering a pharmaceutical composition comprising a dose of compound a, or a pharmaceutically acceptable salt thereof, of about 200 mg. In some such embodiments, the composition is administered twice daily ("BID"). In certain embodiments, the method of treating endometriosis comprises administering a pharmaceutical composition comprising a dose of compound a, or a pharmaceutically acceptable salt thereof, of about 300 mg. In some such embodiments, the composition is administered twice daily ("BID"). In certain embodiments, the method of treating endometriosis comprises administering a pharmaceutical composition comprising a dose of compound a, or a pharmaceutically acceptable salt thereof, of about 600 mg. In some such embodiments, the composition is administered once daily ("QD").
In at least one aspect, the invention encompasses a method of treating uterine fibroids comprising administering to a patient a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating uterine fibroids comprises administering a pharmaceutical composition comprising a dose of compound a, or a pharmaceutically acceptable salt thereof, of about 150 mg. In some such embodiments, the composition is a QD administration. In certain embodiments, the method of treating uterine fibroids comprises administering a pharmaceutical composition comprising a dose of about 200mg of compound a or a pharmaceutically acceptable salt thereof. In some such embodiments, the composition is a BID administration. In certain embodiments, the method of treating uterine fibroids comprises administering a pharmaceutical composition comprising a dose of about 300mg of compound a or a pharmaceutically acceptable salt thereof. In some such embodiments, the composition is a BID administration. In certain embodiments, the method of treating uterine fibroids comprises administering a pharmaceutical composition comprising a dose of about 600mg of compound a or a pharmaceutically acceptable salt thereof. In some such embodiments, the composition is a QD administration.
In at least one aspect, the invention encompasses a method of treating adenomyosis comprising administering to a patient a pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating adenomyosis comprises administering a pharmaceutical composition comprising a dose of compound a or a pharmaceutically acceptable salt thereof of about 150 mg. In some such embodiments, the composition is administered once daily ("QD"). In certain embodiments, the method of treating adenomyosis comprises administering a pharmaceutical composition comprising a dose of about 200mg of compound a or a pharmaceutically acceptable salt thereof. In some such embodiments, the composition is administered twice daily ("BID"). In certain embodiments, the method of treating adenomyosis comprises administering a pharmaceutical composition comprising a dose of about 300mg of compound a or a pharmaceutically acceptable salt thereof. In some such embodiments, the composition is administered twice daily ("BID"). In certain embodiments, the method of treating adenomyosis comprises administering a pharmaceutical composition comprising a dose of about 600mg of compound a or a pharmaceutically acceptable salt thereof. In some such embodiments, the composition is administered once daily ("QD").
In certain embodiments, any of the above methods further comprises administering a hormone to the subject to reduce or alleviate a potential side effect of compound a or a pharmaceutically acceptable salt thereof. For example, the method may comprise administering an estrogen, a gestagen, or a combination thereof. Such treatment is commonly referred to as "reverse-additive" therapy. The estrogen is selected from the group consisting of: estradiol, ethinyl estradiol, and conjugated estrogens. The progestogen is selected from the group consisting of: progesterone, norethindrone acetate, norgestimate (norgestimate), drospirenone, and medroxyprogesterone.
In one embodiment, the estrogen is estradiol and the progestin is norethindrone acetate.
In some such embodiments, the reverse-addition therapy includes a progestin, such as a gestagen. In some such embodiments, the back-up therapy comprises estrogen. In some such embodiments, the reverse-addition therapy comprises a progestogen and an estrogen.
The estrogen and/or progestin can be administered orally, transdermally, or intravaginally. Progestins suitable for use in the reverse-addition therapy include, for example, progesterone, norethindrone acetate, norgestimate, drospirenone, and medroxyprogesterone. Estrogens suitable for use in the counter-additive therapy include, for example, estradiol, ethinyl estradiol, and conjugated estrogens. Combined oral formulations containing an estrogen and a progestin are known in the art and include, for example
in certain embodiments, the estrogen is estradiol, ethinyl estradiol, or a conjugated estrogen. In some such embodiments, the estrogen is estradiol. In some such embodiments, the estradiol is administered once a day. In some such embodiments, the dose of estradiol is 0.5 mg. In other such embodiments, the dose of estradiol is 1.0 mg. In some such embodiments, the estrogen is ethinyl estradiol. In some such embodiments, ethinyl estradiol is administered once a day. In some such embodiments, the dose of ethinyl estradiol is 2.5 meg. In other such embodiments, the dose of ethinyl estradiol is 5.0 meg. In some such embodiments, the estrogen is a conjugated estrogen. In some such embodiments, the conjugated estrogen is administered once a day. In some such embodiments, the dose of conjugated estrogen is 0.3 mg. In other such embodiments, the dose of conjugated estrogen is 0.45mg or 0.625 mg.
In certain embodiments, the progestin is progesterone, norethindrone acetate, norgestimate, medroxyprogesterone, or drospirenone. In some such embodiments, the progestin is oral progesterone. In some such embodiments, the oral progesterone is administered periodically (the last 12 days of a 28-30 day cycle). In some such embodiments, the dosage of oral progesterone is 100 or 200 mg. In some such embodiments, the progestin is norethindrone or norethindrone acetate. In some such embodiments, norethindrone or norethindrone acetate is administered once a day. In some such embodiments, the dose of norethindrone or norethindrone acetate is 0.1 mg. In some such embodiments, the dose of norethindrone or norethindrone acetate is 0.5 mg. In some such embodiments, the dose of norethindrone or norethindrone acetate is 1.0 mg. In some such embodiments, the progestin is norgestimate. In some such embodiments, the norgestimate is administered once a day. In some such embodiments, the dose of norgestimate is 0.09 mg. In some such embodiments, the progestin is medroxyprogesterone. In some such embodiments, medroxyprogesterone is administered once a day. In some such embodiments, the dosage of medroxyprogesterone is 1.5 mg. In some such embodiments, the dosage of medroxyprogesterone is 2.5mg or 5 mg. In some such embodiments, the progestin is drospirenone. In some such embodiments, drospirenone is administered once a day. In some such embodiments, the dose of drospirenone is 0.25 mg. In some such embodiments, the dose of drospirenone is 0.5 mg.
In certain embodiments, the reverse addition therapy includes an norethindrone prodrug, such as norethindrone acetate. In some such embodiments, the reverse addition therapy further comprises estradiol. Thus, in some such embodiments, the counter-addition therapy comprises estradiol and norethindrone acetate. In some such embodiments, the estradiol and norethindrone acetate are administered orally once daily. In some such embodiments, the amount of estradiol administered is about 0.5mg per day and the amount of norethindrone acetate administered is about 0.1mg per day. In other such embodiments, the amount of estradiol administered is about 1.0mg per day and the amount of norethindrone acetate administered is about 0.5mg per day. Alternatively, in certain embodiments, estradiol is administered continuously and norethindrone acetate is administered once daily during the last 12-14 days of the menstrual cycle.
In certain embodiments, the dose of compound a or a pharmaceutically acceptable salt thereof is administered twice a day. In some such embodiments, the reverse addition therapy is administered once a day. Compound a or a pharmaceutically acceptable salt thereof can be administered prior to, immediately prior to, during, immediately after, or after administration of the reverse-addition therapy.
In certain embodiments, a dose (e.g., 300mg) of compound a or a pharmaceutically acceptable salt thereof is administered in the morning with a counter-addition therapy such as a combination of an estrogen and a progestin (e.g., estradiol and norethindrone acetate), and in the evening, a dose (e.g., 300mg) of compound a or a pharmaceutically acceptable salt thereof is administered, but no counter-addition therapy is administered.
In certain embodiments, compound a or a pharmaceutically acceptable salt thereof is co-packaged with a counter-additive therapy. For example, a blister pack may contain a dose of compound a or a pharmaceutically acceptable salt thereof and a dose of a counter-additive therapy.
The pharmaceutical compositions, methods and uses described herein will be better understood with reference to the following illustrative examples and examples, which are included as illustrations and do not limit the scope of the invention.
F. Examples of the invention
The following examples demonstrate certain challenges encountered during formulation development and describe formulations that address these challenges.
Example 1: compound A monosodium salt gel formation
To estimate the solubility of compound a in water, various amounts of compound a sodium salt were added to a fixed volume of 1.5mL and equilibrated at 37 ℃; the solution was analyzed for the concentration of compound a.
Table 2 lists the raw data and observations of the experiment and figure 2 shows the concentration as a function of the amount of compound a solid added. The dashed line in fig. 2 is the theoretical concentration based on the weight of added solids and the volume of water. As shown in FIG. 2, the concentration of Compound A is consistent with a simple calculation to 100mg solids/1.5 mL. The deviation of concentration from the theoretical line is caused by the volume expansion when a large amount of solute is dissolved. In addition, although the concentration deviates from the theoretical line, the solution is still clear and no significant gelation is observed. When more than 500mg of compound a solid was added, significant gelation was observed and therefore, the concentration could not be determined.
Table 2: raw data for solubility experiments of Compound A in Water at 37 ℃
Amount added to 1.5mL (mg)
Concentration measurement (mg/mL)
Observation results
0
0
N/A
About 6
12.2
7.45
Clear solution
9.66
28.7
17.3
Clear solution
9.96
49.8
28.0
Clear solution
10.10
100.4
60.8
Clear solution
10.16
202.5
111
Clear solution
10.18
295.6
149
Clear solution
10.20
503.2
170
Clear solution
10.17
700.9
N/A
Gel formation
N/A
990.0
N/A
Gel formation
N/A
Further experiments revealed that if the percentage of compound a or a salt thereof in the tablet formulation is greater than 10% (and in the absence of sufficient antigelling agent), incomplete dissolution occurs, i.e. compound a is present as an insoluble precipitate. Thus, formulations of compound a sodium salt were evaluated at about 10% drug loading, in which case minimal gelling was observed.
Example 2: in vitro release profile in the absence of antigelling agent
An immediate release formulation was prepared without an anti-gelling agent. All components except magnesium stearate were co-mixed in a high shear granulator and granulated with pure deionized water. The granules were pan dried at 40 ℃ and passed through a #20 U.S. standard sieve and lubricated with magnesium stearate. Compound a mentioned in the table below is compound a sodium salt.
Composition of formulation without antigelling agent
Composition (I)
Quantity (mg/tablet)
Compound A, sodium salt
207.3
Mannitol
304.0
Pregelatinized starch
59.1
Povidone K29/32
18.4
Magnesium stearate
11.2
The dissolution profile of the uncoated tablets in pH 1.2 medium is shown in table 3.
Table 3: (RC2 i; 200 mg; batch No. 170123A-01(GLIMS #39746))
Time (minutes)
Mean value% (standard deviation)
15
15(0.5)
30
31(0.5)
45
45(0.6)
60
57(0.7)
Example 3: formulations with anti-gelling agents
Table 4 provides additional non-limiting examples of the components of the disclosed formulations and the weight percentages (w/w) of these components in the final coated tablets. Compound a mentioned in the table below is compound a sodium salt and the corresponding amounts (mg/tablet) and weight percentages are provided in the salt form.
Table 4. composition of exemplary formulations.
aPercentages provided based on the weight of the coated tablets. The total percentage may not be 100% by rounding.
TABLE 4 composition of exemplary formulations (continuation)
aPercentages provided based on the weight of the coated tablets. The total percentage may not be 100% by rounding.
TABLE 4 composition of exemplary formulations (continuation)
aPercentages provided based on the weight of the coated tablets. The total percentage may not be 100% by rounding.
bMannitol (12.3%) was added outside the granules.
TABLE 4 composition of exemplary formulations (continuation)
aPercentages provided based on the weight of the coated tablets. The total percentage may not be 100% by rounding.
3.1. And (4) preparation.
F1 was prepared using a two-step granulation process. A flow chart of the manufacturing method is provided in fig. 3. In this method, the binder and a portion of the filler are added to a single pot processor tank. Sodium carbonate, the remaining filler, compound a and colloidal silica were co-mixed in IBC. In the first granulation step, the filler/binder blend in the SPP tank is granulated with water. In the second granulation step, compound a blend is added to the SPP tank and granulated by short mixing. Next, in the SPP tank, the particles were dried using vacuum and oscillating modes. The dried granules were milled in another IBC using Comil. The lubricant magnesium stearate was added to the granules and blended together. For a 150mg dose specification, the granules were compressed into 600mg tablets.
Formulations F2 and F3 were prepared using co-mixing, fluid bed granulation, milling, tableting, and tablet coating.
Formulations F4-F11 were prepared using co-mixing, roller compaction and grinding, tableting, and tablet enrobing, as generally shown in figure 1. Formulations F4 and F5 were developed with a target drug loading of about 35% compound a, thereby yielding uncoated tablet weights of 300 and 450mg for 100 and 150mg dose specifications, respectively.
A small group of immediate release tablets was coated with an enteric coating to provide delayed release tablets (F7DR) (DR 1). The tablets were coated with an enteric coating comprising Eudragit L30D-55, Plasacryl T20 and triethyl citrate. Typical cladding parameters were maintained during this process.
3.2. In vitro dissolution characteristics of formulations F1 and F5 in pH 1.2 buffer
Batches of formulations were made with 25% drug loading. The dissolution characteristics of the F1 tablets in pH 1.2 medium are shown in table 5.
Table 5.
The dissolution characteristics of the F5 tablets in pH 1.2 medium are shown in table 6.
Table 6:
time (minutes)
Average elution amount%
15
20
30
54
45
80
60
95
3.3. In vitro dissolution characteristics after storage for up to 24 months
Formulations F5, F6, and F10 were tested for dissolution in 900mL of pH6.8 sodium phosphate using USP apparatus II at 37 ℃ and 50rpm paddle speed. Formulations F5, F6, and F10 all showed similar dissolution profiles at the start of the test and after up to 24 months of storage. The dissolution profiles of formulation F5 tablet at 18 months and 24 months are shown in figure 4. The stability dissolution profile of formulation F7 tablet is shown in figure 5. The dissolution profiles of uncoated and film coated formulation F10 tablets are shown in figure 6.
Pharmacokinetic profiles of 3.4.150 mg, 200mg, and 300 doses.
Pharmacokinetics of F3 and F5(150mg)
A study was conducted to investigate the bioavailability of a single dose of 2 150mg IR tablet formulations (F3 and F5) under fasting conditions. Pharmacokinetic parameters are shown in table 7. Data for pharmacokinetic parameters are presented as mean ± SD.
Table 7:
pharmacokinetics of F4 and F7(200mg)
A study was conducted to compare the relative bioavailability of a single dose of one IR tablet of 200mg formulation F7 with a single dose of two IR tablets of 100mg formulation F4 under fasting conditions. Pharmacokinetic evaluation showed that the maximum concentration (Cmax) and area under the curve (AUC) of formulation F7(200mg IR tablet) was bioequivalent to formulation F4(2 × 100mg IR), with 90% CI within the limits of 0.80 to 1.25. Pharmacokinetic parameters are shown in table 8. Data for pharmacokinetic parameters are presented as mean ± SD.
Table 8:
pharmacokinetics of F4 and F10(200mg)
Another study was conducted to compare the relative bioavailability of a single dose of one IR tablet of 200mg formulation F10 with a single dose of two IR tablets of 100mg formulation F4 under fasting conditions. Pharmacokinetic parameters are shown in table 9. Data for pharmacokinetic parameters are presented as mean ± SD.
Table 9:
pharmacokinetics of F5(300mg)
A study was conducted to explore the bioavailability of a single dose of two IR tablets of 150mg formulation F5 under fasting conditions. Pharmacokinetic parameters are shown in table 10. Data for pharmacokinetic parameters are presented as mean ± SD.
Table 10:
pharmacokinetics of F7 and F7DR (200mg)
Clinical studies were performed to compare the in vivo performance of F7 with F7 DR. In addition, the study also evaluated the potential impact of a high fat diet on the pharmacokinetics of F7 DR. An adult pre-menopausal healthy female subject was administered a single dose of F7DR in fasting conditions, a single dose of
The high fat diet reduced the concentration of the F7DR tablet formulation. Delayed absorption was observed for the F7DR tablet formulation regardless of dietary conditions. Food reduced Cmax and AUC of F7 DR. Absorption is delayed longer under fed conditions.
Pharmacokinetic parameters are shown in table 11. Data for Cmax and AUC are expressed as mean (% CV); tmax is expressed as median (min-max); and the data at t1/2 is expressed as harmonic mean (pseudo CV).
Table 11: (study M14-313)
Example 4: estradiol concentrations following treatment with F4 or F5
Another study was conducted on premenopausal women with moderate to severe pain associated with endometriosis. Women enrolled in this study represent the general female population with moderate to severe endometriosis-associated pain. The baseline characteristics of each treatment group, including the subject's endometriosis-related pain at study enrollment, were comparable.
The treatment groups were: (a) one F5 tablet once a day (i.e., 150mg QD) and (b) two F4 tablets twice a day (i.e., 200mg BID). During the monthly outpatient visit, blood samples were collected to measure hormone concentrations. In this study, more than 800 female subjects from 151 sites in north america were randomized into placebo, 150mg QD, or 200mg BID groups at a 3:2:2 ratio, respectively.
During the treatment period, a dose-dependent inhibition of estradiol in the treated groups was observed compared to placebo. For the placebo group, the median estradiol level at the subjects visit monthly was between 70.0 and 91.6pg/mL, with estradiol concentrations <20pg/mL for 2% to 4% of women. For the 150mg QD group, the median estradiol level at the subjects visit per month was between 36.8 and 45.7pg/mL, with estradiol concentrations <20pg/mL for 15% to 24% of women. For the 200mg BID group, the median estradiol level at the subjects visit per month was at the limit of quantitation (12.4pg/mL), with estradiol concentrations <20pg/mL for 71% to 81% of women.
Table 12: serum concentration of estradiol
Example 5: estradiol concentrations following treatment with F4 or F5
Another study was conducted on premenopausal women with moderate to severe pain associated with endometriosis. Women enrolled in this study represent the general female population with moderate to severe endometriosis-associated pain. The baseline characteristics of each treatment group, including the subject's endometriosis-related pain at study enrollment, were comparable.
The treatment groups were: (a) one F5 tablet once a day (i.e., 150mg QD) and (b) two F4 tablets twice a day (i.e., 200mg BID). During the monthly outpatient visit, blood samples were collected to measure hormone concentrations. In this study, more than 800 female subjects from 187 sites in north america, south america, europe, africa and australia were randomized to the placebo, 150mg QD or 200mg BID groups at a 3:2:2 ratio, respectively.
During the treatment period, a dose-dependent inhibition of estradiol in the treated groups was observed compared to placebo. For the placebo group, the median estradiol level at the subjects visit monthly was between 70.7 and 105pg/mL, with estradiol concentrations <20pg/mL for 4% to 6% of women. For the 150mg QD dose, the median estradiol level at the subjects visit per month was between 37.2 and 55.8pg/mL, with estradiol concentrations <20pg/mL for 14% to 22% of women. For a 200mg BID dose, the median estradiol level at the subjects visit per month was between 8.43 and 13.1pg/mL, with estradiol concentrations <20pg/mL for 62% to 77% of women.
Table 13: serum concentration of estradiol
Example 6: effect of Water-insoluble Filler and surfactant
An immediate release formulation containing sodium carbonate was prepared. All components except magnesium stearate were co-mixed in a high shear granulator and granulated with pure deionized water. The granules were pan dried at 40 ℃ and passed through a #20 U.S. standard sieve and lubricated with magnesium stearate. Compound a mentioned in table 14 below is compound a sodium salt.
Table 14: composition of formulation F12
Formulation F12A was prepared by combining 6.3g of formulation F12 and 97.3mg of sodium lauryl sulfate (1.5% w/w) in a bottle and blending by rolling the bottle with the hand.
In vitro dissolution studies were performed. Release of Compound A was monitored in 900mL of pH6.8 buffer using USP apparatus II at 37 ℃ and 50rpm paddle speed. Dissolution results are provided in table 15:
table 15: percent Compound A released in pH6.8 buffer
Example 7: effect of sodium carbonate on dissolution
The effect of sodium carbonate monohydrate level on dissolution was examined. The amount of sodium carbonate monohydrate was varied within ± 20% of the nominal level to investigate the effect on dissolution. Mannitol levels in the formulation were adjusted to maintain overall tablet weight. Tablets with a target percent solids of 0.88 and a hardness of 125N were made using a tableting method. The dissolution profiles of the tablets from the respective batches are presented in fig. 7. All results pass the proposed dissolution index at t-30 minutes. The results indicate that a ± 20% change in sodium carbonate monohydrate level does not affect dissolution.
Example 8: effect of sodium carbonate on degradation products including Compound B
One degradation product of compound a is compound B, which has a lactam moiety. The lactam moiety can be determined using a variety of techniques. In one embodiment, the lactam moiety is determined using reverse phase High Performance Liquid Chromatography (HPLC) and detection with ultraviolet light (UV) at 275 nm. The HPLC system consisted of a C8 column with a flow rate of 1.1 mL/min. The column temperature was maintained at 50 ℃ throughout the analysis. Both mobile phases a and B were used, wherein mobile phase a was a triethylamine/acetic acid buffer solution at pH 5.3 and the ratio of water to triethylamine: acetic acid was 100:0.1:0.06(v/v) and mobile phase B was acetonitrile. The diluent was triethylamine/acetic acid buffer and acetonitrile in a 50:50(v/v) ratio. Limit of detection standards were prepared in a diluent having an accurately known concentration of about 0.06 μ g of the free form of loragolide per ml. The typical Relative Retention Time (RRT) of the lactam fraction is about 1.48 and the Normalization Factor (NF) is 1.08.
Excipient compatibility studies were performed using mixtures of excipients and compound a, in the presence and absence of sodium carbonate. The results are shown in fig. 8. All excipients showed significantly more lactam formation in the absence of sodium carbonate. In the presence of sodium carbonate, the excipient showed a significantly lower lactam content, very close to the detectable limit of about 0.03%.
Formulations were prepared using compound a to sodium carbonate monohydrate ratios of 2:1, 3:1 and 4:1 w/w. These formulations contained about 35% of compound a, sodium carbonate monohydrate, mannitol, pregelatinized starch, povidone, and magnesium stearate. The tablets were coated with film and tested under the following accelerated stability protocol conditions: 50 ℃/75% RH, 60 ℃/5% RH, 60 ℃/40% RH, 70 ℃/5% RH, 70 ℃/75% RH, 80 ℃/40% RH over a period of time ranging from 2 to 25 days. The results are shown in fig. 9. Formulations prepared with 3:1 and 4:1w/w ratios of compound a to sodium carbonate showed more lactam degradation, while formulations prepared with 2:1w/w ratios showed relatively less lactam degradation.
Additional stability tests were performed on formulations F5 and F7. Tablets were prepared, placed in transparent blister packs with aluminium foil and stored under the following conditions: 25 ℃/60% RH or 40 ℃/75% RH. The tablets were evaluated for the presence of degradation products comprising compound B at 0 (initial), 1, 3,6, 9, 12, 18 and 24 months for 25 ℃/60% RH conditions, and at 0 (initial), 1, 3 and 6 months for 40 ℃/75% RH conditions. The results are presented in table 16.
Table 16: stability of F5 and F7 for up to 24 months storage
ND is not detected; NT ═ untested
Example 9: preparation of 200mg tablets of oxaagolide sodium with different pH adjusting Agents for stability and dissolution testing
Formulations
Formulations of 200mg tablets of oxagorskili sodium were prepared with different types and amounts of pH adjusting agents such as buffering agents. The pH adjusting agents used in this study are presented in table C1. The formulation compositions are presented in table C2.
Table c1 list of ph adjusters
pH regulator
Suppliers of goods
Sodium carbonate
Jost Chemical
N-methyl-D-reduced glucamine
Sigma
Calcium hydroxide
Sigma-Aldrich
Anhydrous trisodium phosphate
Combi-Blocks
L-arginine
Sigma-Aldrich
Eudragit EPO
EVONIK
Piperazine derivatives
Combi-Block
TABLE C2. formulation compositions
TABLE C2. formulation compositions (continuation)
Preparation of Stable tablets
A 200mg round tablet for stability studies was prepared using a direct co-mixing and compression method, with the target tablet weight shown in table C3. The target tablet percent solids were consistent for all formulations.
Preparation of dissolution tablets
A 200mg oval tablet for dissolution studies was prepared using a co-mixing → compression → milling → compression method. The formulation blend was tableted and then ground through a 1.0mm screen. The target tablet percent solids were consistent for all formulations.
TABLE C3. target tablet weights
Formulation ID
Target tablet weight (mg)
1
496.8
2
548.6
3
531.3
4
517.5
5
507.2
6
600.0
7
600.0
8
600.0
9
600.0
10
600.0
11
600.0
TABLE C4 lactam moiety in accelerated stability studies (Compound B)
Formulation number
Lactam fraction% (w/w) maintained at 60 ℃/40% RH for 13
1
0.77
2
0.23
3
0.32
4
0.32
5
0.35
6
0.10
7
0.10
8
0.09
9
0.09
10
0.27
11
0.16
Table C5. The% release of the selected formulations of sodium agoraphobium at pH 1.2
Figure 10 provides dissolution profiles of the
Example A-1: efficacy and safety of falagolide in a small group of women with uterine fibroids and non-dominant adenomyosis
Adenomyosis is an estrogen-dependent disease of benign endometrial tissue growth in uterine musculature and is associated with severe menstrual bleeding (HMB) and dysmenorrhea. Adenomyosis occurs when endometrial tissue, typically the lining of the uterus, is present within and grows into the myometrium wall. During each menstrual cycle, displaced endometrial tissue continues to behave in the usual way, i.e., thickening, rupturing and bleeding. This results in enlarged and painful uterus and increased menstrual flow. Symptoms most often begin late in the reproductive years after birth. The cause of adenomyosis is not clear, but the disease typically disappears after menopause. For women who experience severe discomfort due to adenomyosis, some treatments may be helpful, but hysterectomy is the only cure. Sometimes, adenomyosis is asymptomatic, i.e., does not cause signs or symptoms, or is only mildly uncomfortable. In other cases, adenomyosis may cause: severe menstrual bleeding or extended menstrual period, severe cramping or sharp, incisional pelvic pain (dysmenorrhea); menstrual pain that persists throughout the menstrual period and worsens with age; pain during sexual intercourse; and menstrual clot shedding.
The efficacy and safety of the falagolide was analyzed in a small group of women with UF and adenomyosis.
Patients and methods: a randomized, double-blind, placebo-controlled phase 2b clinical trial with 6 months of age was conducted in pre-menopausal women with HMB (. gtoreq.80 ml/month) and UF to evaluate the safety and efficacy of ropingolide (
All subjects were evaluated with ultrasound, some of which also received voluntary MRI evaluations. Women were excluded from the study if they had evidence of diffuse or segmental adenomyosis as the major condition (> 50% of the myometrium as determined by ultrasound/MRI). Efficacy and safety was assessed post-hoc in a small group of women with non-dominant adenomyosis (ultrasound/MRI) determined at baseline. Menstrual Blood Loss (MBL) was quantified from hygiene products (basic haem). The primary endpoint of the combination was the proportion of women with ≧ 50% reduction of HMB from baseline and MBL <80mL for 28-day treatment. Adverse Events (AE) were recorded.
As a result: of the 567 women treated in the study, 86 (15%;
Example A-2: safety and efficacy of loragolide in women with symptomatic adenomyosis
The safety, efficacy and tolerability of the combination of 300mg BID and E2/NETA (
The 300mg BID equivalent to reverse plus treatment is expected to reduce severe menstrual bleeding (HMB) and pelvic pain in women with symptomatic adenomyosis. Symptomatic adenomyosis may also be treated with other doses of reverse-additive and ropinirole as previously described.
Various aspects of the evaluation that can be found to be effective and safe for loragolide may include the following:
(a) at
(b) at
(c) at
(d) at 12 months, heavy menstrual bleeding decreased to <80ml/mo and MBL decreased > 50% from baseline;
(e) at
(f) MBL volume mean relative to placebo changed from baseline;
(g) bleeding inhibition as defined by drop/drop bleeding;
(h) suppression of menstrual pain for extended periods;
(i) reduced pain during intercourse; or
(j) The blood clot shed during menstruation is reduced.
Safety assessments may include physical examination, vital signs, endometrial assessment (endometrial thickness and biopsy), pelvic ultrasound [ TAU (transabdominal ultrasound)/TVU (transvaginal ultrasound) ], clinical laboratory tests, and adverse event monitoring.
Example A-3: safety and efficacy of loragolide in endometriosis-related conditions
(I) Agolide is a short-acting, selective, non-peptidic, small molecule GnRH receptor antagonist administered orally that blocks endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland. Administration of ropinirole causes dose-dependent suppression of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) levels, resulting in a decrease in blood levels of the ovarian sex hormones estradiol and progesterone. LH and FSH inhibition began within hours of administration and was readily reversed after discontinuation of the oxaagolide.
(a) Pharmacodynamics: effects on ovulation and estradiol
Over the course of a 3 month menstrual cycle study on healthy women, about 50% and 32% ovulation rates were induced by falagolide 150mg QD and 200mg bid, respectively. In a
(b) Effect of Oxagolide on QT Interval
The QTc interval is not prolonged by the oxaagolide. The effect of falagolide (up to 1200mg) on QTc intervals was evaluated in an active control (moxifloxacin)400mg) full QT study. At therapeutic concentrations of oxaagolide ranging from 17 to 23 fold (relative to 200mg BID and 150mg QD regimens, respectively), oxaagolide does not prolong the QTc interval.
(II) the pharmacokinetic profile of oxaagolide in healthy subjects is provided in Table A-1. The steady state pharmacokinetic parameters are presented in table a-2.
TABLE A-1 pharmacokinetic Properties of Oxagolide in healthy subjects
TABLE A-2 mean (% CV) steady state pharmacokinetic parameters of Oxagolide
(III) pharmacokinetics of a specific population
(a) Kidney damage
The amount of exposure to roping (Cmax and AUC) was not altered by kidney damage. The average exposure of women with moderate to severe or end-stage renal disease (including women receiving dialysis) is similar to women with normal renal function.
(b) Liver damage
The amount of exposure to ragagolide (Cmax and AUC) was similar between women with normal liver function and women with mild liver damage. The exposure of a woman with moderate and severe liver damage to roping was about 3 and 7 times that of a woman with normal liver function, respectively.
(IV) study of drug interactions
Drug interaction studies were performed with oxaagolide and possibly other co-administered drugs as well as with drugs commonly used as probes for pharmacokinetic interactions. Tables A-3 and A-4 summarize the pharmacokinetic effects of oxaagolide when co-administered with other drugs, showing potentially clinically relevant changes.
Table a-3. drug interactions: changes in the pharmacokinetic parameters of oxaagolide in the Presence of Co-administered drug
Table a-4. drug interactions: changes in pharmacokinetic parameters of co-administered drugs in the presence of agolide
(V) drug interaction
(a) Possibility of influence of the oxaagolide on other drugs
Oxaagolide is a weak to moderate inducer of cytochrome P450(CYP)3A enzyme. Co-administration with loragolide can reduce the plasma concentration of the drug that is a substrate for CYP 3A.
Oxragaglide is an inhibitor of the efflux transporter P-glycoprotein (P-gp) at 200mg BID or higher, such as at 300mg BID or 400mg QD or 600mg QD. Co-administration with 200mg BID of oxagolide increases the plasma concentration of the drug as a P-gp substrate.
(b) Possibility of other drugs affecting the agolide
Oxaagolide is a substrate for CYP3A, P-gp and Organic Anion Transport Polypeptide (OATP)
Co-administration of loragolide with a drug that induces CYP3A reduces the plasma concentration of loragolide.
Co-administration of oxalagroline with a drug that inhibits OATP1B1 increases the plasma concentration of oxalagroline. The use of potent OATP1B1 inhibitors is not recommended in the 200mg BID regimen of roping.
(c) Defined and other potential drug interactions
Table a-5 provides the effect of co-administration of oxalagroline on the concentration of concomitant drugs and the effect of concomitant drugs on oxalagroline.
TABLE A-5 drug interactions determined based on drug interaction assays
See clinical pharmacology, tables A-3 and A-4.
The direction of the arrow indicates the direction (↓ ═ increasing and ↓ ═ decreasing) of change in AUC.
(d) No clinically significant interaction with ropinirole was observed
No dose adjustment is required when the following drugs are co-administered with the oxaagolide: ketoconazole (ketoconazole), fluconazole (fluconazole), sertraline (sertraline) and norethindrone (norethindrone) or other pure progestational contraceptives.
(VI) non-clinical toxicology
(a) Carcinogenesis
For 2 year oncogenic studies (in mice and rats) it was disclosed that the tumor in mice did not increase at any dose, but at large doses (13 times the safety margin for 200mg BID in women) the thyroid (male and female) and liver (male only) tumors in rats appeared to increase. Rat tumors were identified as species-specific and of negligible relevance to humans. This conclusion is based on subsequent studies of thyroid and liver effect-related investigations aimed at demonstrating that thyroid and liver tumors may be specific to rats and occur by inducing liver drug metabolizing enzymes at high doses.
(b) Mutagenesis
Mutagenicity studies have been performed with ropinirole using in vitro and in vivo test systems. These studies do not provide evidence of mutagenic or chromosomally disruptive potential.
(c) Impairment of fertility
The effect on fertility and reproductive organs was evaluated in studies performed with rats and monkeys, with plasma concentrations in rats being lower than AUC under MRHD and plasma concentrations in monkeys being lower than about 0.28-fold to 9.9-fold when adjusted for species differences in GnRH receptor binding affinity. In rats, there was no effect in the fertility study (
(VII) clinical Studies
The efficacy of falagolide 150mg QD and 200mg BID in managing endometriosis and associated pain was demonstrated in two international double-blind placebo-controlled studies on 1686 premenopausal women (studies EM-I and EM-II) and in two blinded extended studies (studies EM-III and EM-IV) by the non-controlled participants. Each placebo-controlled study evaluated the reduction of pain associated with endometriosis within 6 months of treatment. More than 75% of women who completed studies EM-I and EM-II were enrolled in the extension study for a 6 month treatment period. Following treatment, subjects were followed up to 12 months. See fig. 11-14
(a) Pain relief
The common primary efficacy endpoint was the proportion of responders who experienced dysmenorrhea and non-menstrual pelvic pain (also known as non-menstrual pelvic pain [ NMPP ]) at
Women are defined as responders if they experience a clinically significant reduction in dysmenorrhea and/or NMPP and there is no increase in analgesics used for endometriosis-related pain.
At
Intercourse pain was assessed using the daily endometriosis pain impact scale as a secondary endpoint.
A higher proportion of women treated with 200mg BID of ropinirole reported a clinically significant reduction in intercourse pain relative to placebo between
TABLE A-6. responders to dysmenorrhea, non-menstrual pelvic pain, and intercourse pain at
Starting from
Women in these studies also provided a self-assessment of their endometriosis pain on a daily basis using a Numerical Rating Scale (NRS), with scores ranging from 0 (no pain) to 10 (most severe pain). At
In both participants blindly extended studies EM-III and EM-IV, patients who initially took loragolide in control studies EM-I and EM-II were maintained at their doses, demonstrating a total of 12 months of persistent improvement in dysmenorrhea, NMPP and dyspareunia, see FIG. 11. In the study EM-IV, efficacy was maintained when the loragolide was taken with and without food.
The results obtained from study EM-II with respect to efficacy endpoints are consistent with those observed in study EM-I.
(b) Reduced use of analgesics
In these studies, women taking 200mg BID of ropinirole used rescue medications of the opioid (hydrocodone) plus acetamidophenol (acetaminophen) or naproxen (naproxen) in reduced amounts relative to the baseline for their endometriosis-related pain. In addition, the percentage of days per month that women taking 200mg bid of lagagolide were using opioid or naproxen first aid medications was also significantly reduced compared to placebo women. These effects were not consistently observed in women taking 150mg QD of pergolide. See fig. 15. The percent change in mean daily opioid pill volume from baseline was significantly reduced in the 200mg BID vs. placebo group between
In EM-1 and EM-2, 59% and 60% of patients were analgesic at baseline using opioid rescue analgesics. The opioid first-aid analgesics used at baseline are mainly
Hydrocodone/acetamidophenol (HC/APAP) and codeine/APAP,
(c) Effect on bleeding patterns
Effect on menstrual bleeding patterns
The effect of deragorib on menstrual bleeding was evaluated using an electronic diary for up to 12 months in which subjects classified their menstrual bleeding flow (if it occurred within the past 24 hours) as drip bleeding, mild bleeding, moderate bleeding or severe bleeding. The mean bleeding and the number of blood drip days and the intensity of bleeding of subjects reporting menstrual bleeding were dose-dependently reduced by the diragolide.
Table B-3: mean bleeding/drip bleeding days at
The loragolide also showed a dose-dependent increase in the percentage of women who stopped menstruation (defined as no bleeding or drip bleeding over a 56 day interval) during the treatment period. During the first six months of treatment, the incidence of menopause ranged from 6-17% for 150mg of falagolide once a day, 13-52% for 200mg of falagolide twice a day and less than 1% for placebo. During the second 6 month treatment period, the incidence of menopause ranged from 11-15% for 150mg of falagolide once a day and 46-57% for 200mg of falagolide twice a day.
After 6 months of treatment with 150mg of pergolide once a day, 59%, 87% and 95% of women reported menstrual recovery within 1,2 and 6 months after cessation of treatment, respectively. After 6 months of treatment with 200mg of pergolide twice daily, 60%, 88% and 97% of women reported a return of menstruation within 1,2 and 6 months, respectively, after cessation of treatment.
After 12 months of treatment with 150mg of pergolide once a day, 77%, 95% and 98% of women reported a return of menstruation within 1,2 and 6 months, respectively, after cessation of treatment. After 12 months of treatment with 200mg of pergolide twice daily, 55%, 91% and 96% of women reported menstrual recovery within 1,2 and 6 months after cessation of treatment, respectively.
(VII) lactation
Risk summary: no human studies have been conducted to assess the effect of loragolide on milk production, its presence or absence in breast milk, or its effect on breast-fed children. It is not clear whether the presence of lagagolide and its metabolites in human milk, affect human milk production or have an effect on breast-fed infants.
(a) In rats, oxaagolide is rarely secreted by milk.
The developmental and health benefits of breast-feeding should be considered in combination with the clinical need for loragolide by the mother and any potential adverse effects of loragolide on breast-fed children.
(b) Data: animal data
The pregnant rats were given a diet containing loragolide throughout the pregnancy and lactation period to achieve a dose of 400 mg/kg/day of loragolide. During lactation, the mother and baby mice were divided into a restricted feeding group and a non-restricted feeding group to determine whether the falagolide is secreted in breast milk. Plasma concentrations of agoraphobia in restricted fed pups could not be measured on
(IX) adverse reactions
(a) Experience of clinical trial
Since clinical trials are conducted under conditions that vary greatly, the adverse reaction rate observed in a clinical trial of a drug cannot be directly compared with the adverse reaction rate observed in a clinical trial of another drug, and may not reflect the adverse reaction rate observed in clinical practice.
The safety of loragolide was evaluated in two six-month placebo-controlled clinical studies (study EM-I and study EM-II) in which a total of 952 women were treated with 150mg QD or 200mg BID. The age range of the population is 18-49 years. Women who completed six months of treatment and met the inclusion criteria continued treatment in two six-month old participants blindly expanded studies with a total treatment duration of up to 12 months.
(b) Adverse reactions (> 1%) leading to discontinuation of the study
In both control studies (EM-I and EM-II), 5.5% of patients treated with 150mg QD oxaagolide and 9.6% of patients treated with 200mg BID oxaagolide discontinued treatment for adverse reactions. Discontinuation of both dosage forms was most commonly attributed to hot flashes (0.8% and 2.5%) and nausea (0.8% and 1.5%). Most cases of discontinuation of treatment due to hot flashes and nausea occurred within the first 2 months of treatment. After receiving 150mg QD of pergolide for 6 months in the control study, no women discontinued the dosage form due to hot flashes during the extended study.
(c) The common adverse reactions are as follows:
in both placebo-controlled studies ≧ 5% of women in either of the falagolide dose groups reported adverse effects, and adverse effects with higher frequency than placebo are provided in tables A-7 below.
TABLE A-7. percentage of patients who developed adverse reactions in study EM-I and EM-II in at least 5% of patients (either of the falagolide dose groups) and greater than the treatment period of placebo
As shown in tables a-7, in the extended study, the adverse reaction profile was similar to that proposed in the placebo-controlled study.
(d) Less common adverse reactions:
in EM-I and EM-II, greater than or equal to 3% and < 5% of women in either of the falagolide dose groups reported adverse effects and greater than placebo included:
a) and (3) investigation: weight gain;
b) psychiatric disorders: depression, irritability, decreased libido, mood swings;
c) gastrointestinal disorders: diarrhea, abdominal pain, constipation;
d) neurological disorders: dizziness; or
e) Disorders of the skin and subcutaneous tissues: night sweat.
Hot flash events were dose-related and most were assessed as mild to moderate. All other adverse events were comparable between the two doses of loragolide. Addition of low-dose hormone reverse-addition therapy can reduce the occurrence of symptoms associated with estrogen deprivation, such as hot flashes.
(e) Change in bone mineral density
BMD was measured by DXA in both placebo-controlled and extended clinical studies. Lumbar BMD data from these studies are presented in table a-8. BMD changes observed at other anatomical sites (femoral neck, total hip) are generally less than lumbar.
TABLE A-8 mean percent change in bone mineral Density from baseline and percent of subjects with lumbar Z-score ≦ -1.5
After 12 months of treatment with ropingolide, none of the patients taking the daily dose of 150mg had a Z-score below the lower normal limit of-2.0 and less than 1% of the patients taking the dose of 200mg BID had said Z-score. In both the groups of falagolide treatment, BMD at three DXA sites gradually recovered at 6 and 12 months post-treatment: lumbar vertebrae, total hip joint and femoral neck.
Additional analysis from the exposure-response model showed that the predicted mean (95% CI) Z scores for the 150mg QD of ragagolide were 0.23(0.01-0.45) and 0.18(-0.04-0.40) at
(f) Laboratory value changes during treatment
(i) Lipid
Although dose-dependent increases in total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglycerides were observed during the treatment of falagolide, these values generally remained within the normal range.
Lipid increase typically occurs within 1 to 2 months after initiation of the therapy with oxaagolide and then remains stable for 12 months. One month after cessation of treatment, the elevated lipid levels returned to baseline.
The mean increase in LDL-C from pre-treatment baseline was 5.25mg/dL for 150mg QD and 13.10mg/dL for 200mg BID. The mean increase in HDL-C from pre-treatment baseline was 2.24mg/dL for 150mg QD and 4.16mg/dL for 200mg BID. After 6 months of treatment with oxaagolide, the mean increase in triglycerides from pre-treatment baseline was 0.42mg/dL for 150mg QD and 11.08mg/dL for 200mg BID.
The changes in lipid ratios are minimal due to the increase in both LDL-C and HDL-C.
Lipid profiles should be evaluated and managed according to current clinical practice guidelines.
(ii) Safety of endometrium
In study EM-I and its extension, endometrial biopsies were performed on subjects at
Based on transvaginal ultrasound, the average endometrial thickness was dose-dependently reduced by roping 150mg QD and 200mg BID over the course of a 3 month menstrual cycle study on healthy women compared to pre-treatment values.
(X) reduction of bone mineral Density
The diragolide reduces serum estradiol levels in a dose-dependent manner, possibly accompanied by a dose-dependent reduction in Bone Mineral Density (BMD). BMD gradually recovers at 6 and 12 months after cessation of treatment [ see adverse reaction (6.1) ].
BMD was assessed by dual energy x-ray absorptiometry (DXA) after 12 months of continuous use. If the BMD Z score is less than-2.0, the Leagolide is discontinued until the BMD is within the age-appropriate range.
If the use of roping is for more than 12 months, it is recommended to evaluate BMD as clinically indicated. The loss of BMD in premenopausal women should be considered in the efficacy/risk assessment for women who continue to use the perusal for a long period of time.
For patients at greater risk of low BMD, earlier assessments are considered than annual BMD assessments. The risk factors include: administering 200mg of oxaagolide twice a day; a Z-score of less than-2.0 after the previous course of treatment with oxaagolide; pre-administration of a GnRH agonist; metabolic bone disease; long term alcohol and/or tobacco use; anorexia nervosa; a strong family history of osteoporosis; or drugs that reduce bone mass such as anticonvulsants or corticosteroids for long term use.
Although there has been no study on whether calcium and vitamin D could reduce BMD loss in women using ropingolide, all patients should ingest sufficient calcium and vitamin D.
Clinical studies with GnRH analogues or raggolide (among other groups) have shown that the use of low dose hormone reverse-addition therapy (estrogen/gestagen or norethindrone acetate) effectively reduces the bone mineral loss that occurs with these agents alone.
(XI) dosage and administration
(a) Dosage information
The oxaagolide will be used as a 150mg tablet (once daily, QD) or 200mg tablet (twice daily, BID), 150mg BID, 300mg BID or 400mg QD or 600mg QD, with or without food for oral administration.
(b) Dosage advice
The lowest effective dose was used based on the severity of symptoms and therapeutic objectives [ see clinical study (VII) ]. The treatment of the malagolide may be initiated at any time during the patient's menstrual cycle.
TABLE B-1 in one embodiment, recommended dosages and durations of use
Women with mild liver damage (Child-Pugh grade A) did not need to adjust the dose of falagolide.
Compared to women with normal liver function, the exposure to malaagolide is about 3 times higher for women with moderate liver damage and about 7 times higher for women with severe liver damage. Due to these increased exposure and risk of bone loss: women with moderate liver damage (Child-Pugh grade B) are advised to use 150mg of falagolide once a day and the duration of treatment is limited to 6 months. Women with moderate liver damage are not advised to use 200mg of roping twice a day. The use of dolagolide is contraindicated in women with severe liver damage (Child-Pugh grade C).
Each tablet contained 155.2mg of oxaagolide sodium, corresponding to 150mg of oxaagolide. Each tablet contained 207.0mg of oxaagolide sodium, corresponding to 200mg of oxaagolide.
(c) Kidney damage
Women with any degree of kidney damage or end-stage renal disease (including women receiving dialysis) do not need to adjust the dose of ropinirole [ see drug administration and clinical pharmacology for the particular population ].
(d) Liver damage
Women with mild liver damage (Child-Pugh grade A) did not need to adjust the dose of falagolide. Women with moderate liver damage (Child-Pugh grade B) were advised to use the 150mg QD regimen of Dalagolide; the 200mg BID regimen is not recommended.
The use of dolagolide is contraindicated in women with severe liver damage (Child-Pugh grade C).
Elevation of hepatic transaminase
In clinical trials, dose-dependent elevation of serum alanine Aminotransferase (ALT) occurred with ropinirole, reaching at least 3-fold the upper limit of the reference range. It is recommended to use the lowest effective dose of roping. In addition, if symptoms or signs that may reflect liver damage, such as jaundice, occur, the patient should be instructed to seek medical attention immediately. Patients are evaluated immediately for an increase in liver check to determine if the benefit of continuing treatment is at high risk.
In placebo-controlled clinical trials (studies EM-1 and EM-2), there was a dose-dependent asymptomatic elevation of serum ALT during ORILISSA treatment that was at least 3-fold higher than the upper limit of the reference range (150 mg-1/450, 0.2% once a day; 200mg-5/443, 1.1% twice a day; placebo-1/696, 0.1%). Similar increases were observed in extended trials (study EM-3 and EM-4).
(e) Suicidal thoughts, suicidal behavior, and exacerbation of emotional disorders
The incidence of depression and mood changes was higher in subjects using the falagolide than placebo, and the incidence of depression was higher in users of the falagolide with a history of suicide or depression than in users without such history. Patients with depressive symptoms should be evaluated to determine if the risk of continuing treatment is too high for benefit. Patients with emerging or worsening depression, anxiety or other mood changes should consult mental health professionals as appropriate. Patients with suicidal thoughts and behaviors should seek medical advice immediately. If such an event occurs, the benefit and risk of continued use of the falagolide should be reevaluated and, optionally, the use of the falagolide should be discontinued with worsening or severe depression, anxiety, mood changes, or suicidal thoughts.
In placebo-controlled trials (studies EM-1 and EM-2), oxaagolide was associated with adverse mood changes, particularly in patients with a history of depression.
TABLE B-2 study of suicidal thoughts, suicidal behavior, and emotional disturbance in EM-1 and EM-2
Example a-4. malagolide reduces fatigue in moderate to severe endometriosis pain patients:
a phase III study was conducted to evaluate the role of loragolide in clinically meaningful pain and other symptom relief. The data presented examine the effect of roping on fatigue in women with moderate to severe endometriosis-related pain. In three groupsIn the study, the first group included women receiving placebo, the second group included women receiving 150mg of falagolide once a day, and the third group included women receiving 200mg of falagolide twice a day. It is expected that once or twice daily 300mg and once daily 600mg, or similar doses, will similarly exhibit fatigue reduction. Fatigue is measured using patient report information systemFatigue profile (SF)6a evaluation. Six items evaluate a series of self-reported symptoms ranging from mild, subjective fatigue to overwhelming persistent fatigue, which may diminish one's ability to perform daily activities and normal functions. This area is divided into the fatigue experience (frequency, duration and intensity) and the effects of fatigue on physical, psychological and social activities. All items were evaluated for fatigue within the first seven days. The responses to each question were submitted on the 5-item Likert scale: 1- "completely absent"; 2- "one dot"; 3- "somewhat; 4- "quite many"; and 5- "very much". Questionnaires were administered at baseline and at
And (3) analysis: changes in the PROMIS fatigue SF-6a T score from baseline were compared between each effective treatment (150mg QD and 200mg BID) and placebo. One-way covariance analysis (ANCOVA) was used. ANCOVA control treatment as the main effect. The baseline fatigue SF-6a T score is included as a covariate.
The medical need for fatigue in women with pain associated with endometriosis remains to be met. At baseline, women in this study had an average fatigue level of 1SD lower than women in the general population. Compared to placebo, the loragoride improved fatigue in women with moderate to severe endometriosis-related pain in a dose-dependent manner. See fig. 16. Statistically significant reductions in PROMIS fatigue SF-6a T score were observed at
Method for carrying out the invention
In one aspect of the invention, the method is carried out by administering a pharmaceutical composition containing either sodium xagolide (commonly known as oxaagolide) or 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenylethylamino) -butyric acid. For administration purposes, 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenylethylamino) -butyric acid can be formulated into a pharmaceutical composition. A pharmaceutical composition comprises 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenylethylamino) -butyric acid, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier and/or diluent. The 4- ((R) -2- [5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenylethylamino) -butyric acid in the composition is present in an amount effective to treat a particular disorder, that is, in an amount sufficient to achieve receptor antagonist activity and preferably with acceptable toxicity to the patient.
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Unless otherwise indicated herein, ranges of values recited herein are intended merely to serve as shorthand methods of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
It should be understood that the foregoing detailed description and accompanying examples are exemplary only and are not intended to limit the scope of the invention, which is defined only by the appended claims and equivalents thereof. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those related to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations or methods of the invention, or any combination of such changes and modifications, may be practiced without departing from the spirit and scope of the invention.
All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended only to summarize the assertions made by their authors. No admission is made that any reference (or portion thereof) is relevant prior art (or prior art at all). Applicants reserve the right to challenge the accuracy and pertinency of the cited references.
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