Pharmaceutical formulation
阅读说明：本技术 药物调配物 (Pharmaceutical formulation ) 是由 J·徐 W·琼斯 F·弗利克 B·贝尔纳 于 2019-02-01 设计创作，主要内容包括：本公开尤其提供了包括腺苷A2A受体拮抗剂的微粉化药物颗粒的药物组合物以及使用所述药物组合物治疗癌症的方法。(The present disclosure provides, inter alia, pharmaceutical compositions comprising micronized drug particles of an adenosine A2A receptor antagonist and methods of using the pharmaceutical compositions for the treatment of cancer.)
1. A pharmaceutical composition comprising a drug particle and a pharmaceutically acceptable excipient; wherein the drug particles comprise a compound of formula (III) or a pharmaceutically acceptable salt thereof, having a particle size distribution with D90 of about 30 microns or less, as measured by laser diffraction spectroscopy; wherein the compound of formula (III) is:
2. the composition of claim 1, wherein the drug particles have a particle size distribution with a D90 of about 25 microns or less as measured by laser diffraction spectroscopy.
3. The composition of claim 1, wherein the drug particles have a particle size distribution with a D90 of about 20 microns or less as measured by laser diffraction spectroscopy.
4. The composition of claim 1, wherein the drug particles have a particle size distribution with a D90 of about 15 microns or less as measured by laser diffraction spectroscopy.
5. The composition of claim 1, wherein the drug particles have a particle size distribution with a D90 of about 10 microns or less as measured by laser diffraction spectroscopy.
6. The composition of claim 1, wherein the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, a surfactant, a glidant, or a combination of two or more thereof.
7. The composition of claim 1, wherein the pharmaceutically acceptable excipient comprises: (i) a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or combinations of two or more thereof; (ii) carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) hydroxyalkyl cellulose, alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, or a combination of two or more thereof; (iv) (iii) a compound from (i) and a compound from (ii); (v) (iv) a compound from (i) and a compound from (iii); (vi) (iv) a compound from (ii) and a compound from (iii); or (vii) a compound from (i), a compound from (ii) and a compound from (iii).
8. The composition of claim 7, comprising a compound from (i), a compound from (ii), and a compound from (iii).
9. The composition of claim 8, comprising from about 40 wt% to about 80 wt% of the compound from (i), from about 1 wt% to about 20 wt% of the compound from (ii), and from about 1 wt% to about 20 wt% of the compound from (iii).
10. The composition of claim 8, comprising from about 50 wt% to about 70 wt% of the compound from (i), from about 1 wt% to about 15 wt% of the compound from (ii), and from about 1 wt% to about 10 wt% of the compound from (iii).
11. The composition of claim 8, comprising from about 55 wt% to about 65 wt% of the compound from (i), from about 2 wt% to about 12 wt% of the compound from (iii), and from about 1 wt% to about 8 wt% of the compound from (iii).
12. The composition of claim 8, comprising from about 58 wt% to about 63 wt% of the compound from (i), from about 2 wt% to about 10 wt% of the compound from (iii), and from about 2 wt% to about 8 wt% of the compound from (iii).
13. The composition of claim 8, comprising about 61 wt% of the compound from (i); (iii) about 8 wt% of the compound from (ii); and about 4 wt% of the compound from (iii).
14. The composition of claim 1, wherein the pharmaceutically acceptable excipient comprises: (i) a polyol; (ii) microcrystalline cellulose; (ii) a carboxymethyl cellulose; and (iii) hydroxyalkyl cellulose.
15. The composition of claim 1, wherein the pharmaceutically acceptable excipient comprises (i) a polyol, (ii) microcrystalline cellulose, (iii) maltodextrin, (iv) carboxymethylcellulose, (v) hydroxyalkyl cellulose, (vi) alkyl cellulose, or (vii) a combination of two or more thereof.
16. The composition of claim 15, wherein the hydroxyalkyl cellulose is hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or a combination of two or more thereof.
17. The composition of claim 16, wherein the hydroxyalkyl cellulose is hydroxypropyl cellulose.
18. The composition of claim 15, wherein the polyol is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof.
19. The composition of claim 18, wherein the polyol is mannitol.
20. The composition of claim 1, comprising about 1 wt% to about 50 wt% of the compound of formula (III).
21. The composition of claim 20, comprising about 5 wt% to about 45 wt% of the compound of formula (III).
22. The composition of claim 21, comprising about 10 wt% to about 40 wt% of the compound of formula (III).
23. The composition of claim 22, comprising about 15 wt% to about 35 wt% of the compound of formula (III).
24. The composition of claim 23, comprising about 20 wt% to about 30 wt% of the compound of formula (III).
25. The composition of claim 24, comprising about 24 wt% to about 26 wt% of the compound of formula (III).
26. The composition of claim 25, comprising about 25 wt% of the compound of formula (III).
27. The composition of claim 1, further comprising from about 0.5 wt% to about 4 wt% of a lubricant.
28. The composition of claim 27, comprising from about 0.5 wt% to about 2.3 wt% of a lubricant.
29. The composition of claim 28, comprising about 2.25 wt% lubricant.
30. The composition of claim 1, comprising from about 1mg to about 1,000mg of the compound of formula (III).
31. The composition of claim 30, comprising about 50mg to about 600mg of the compound of formula (III).
32. The composition of claim 31, comprising about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, or about 600mg of the compound of formula (III).
33. The composition of claim 1, wherein the compound of formula (III) is a compound of formula (IIIA):
34. the composition of claim 1, wherein the compound of formula (III) is a compound of formula (IIIB):
35. the composition of claim 1, having a disintegration time of about 15 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopeia (USP).
36. The composition of claim 35, having a disintegration time of about 10 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopoeia (USP).
37. The composition of claim 1, having a dissolution rate of at least 75% in 60 minutes as measured by the dissolution apparatus method type II & lt711 & gt Chapter US pharmacopoeia (USP).
38. The composition of claim 37, having a dissolution rate of at least 90% in 60 minutes as measured by the dissolution apparatus type II (paddle) method in chapter < 711 in the United States Pharmacopeia (USP).
39. The composition of claim 1, having a dissolution rate of at least 70% in 10 minutes as measured by the dissolution apparatus method type II (paddle) of chapter < 711 in the United States Pharmacopeia (USP).
40. The composition of claim 1, wherein the composition is an oral formulation.
41. The composition of claim 1, wherein the composition is a tablet.
42. The composition of claim 1, wherein the composition is a powder.
43. The composition of claim 1, wherein the composition is a capsule.
44. The composition of claim 1, wherein the composition is encapsulated within a capsule shell.
45. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 1 to treat the cancer.
46. The method of claim 45, wherein the cancer is non-small cell lung cancer, melanoma, renal cell carcinoma, breast cancer, colorectal cancer, bladder cancer, prostate cancer, or head and neck cancer.
47. The method of claim 45, wherein the therapeutically effective amount is from about 1mg to about 1,000mg per day.
48. The method of claim 47, wherein the therapeutically effective amount is from about 10mg to about 600mg per day.
49. The method of claim 48, wherein the therapeutically effective amount is from about 100mg to about 400mg per day.
50. A granule comprising a drug particle and a pharmaceutically acceptable excipient; wherein the drug particles comprise a compound of formula (III) or a pharmaceutically acceptable salt thereof, having a particle size distribution with D90 of about 30 microns or less, as measured by laser diffraction spectroscopy; wherein the compound of formula (III) is:
51. the granules of claim 50, wherein the drug particles have a particle size distribution with a D90 of about 25 microns or less as measured by laser diffraction spectroscopy.
52. The granules of claim 51, wherein the drug particles have a particle size distribution with a D90 of about 20 microns or less as measured by laser diffraction spectroscopy.
53. The granules of claim 52, wherein the drug particles have a particle size distribution with a D90 of about 15 microns or less as measured by laser diffraction spectroscopy.
54. The granules of claim 53, wherein the drug particles have a particle size distribution with a D90 of about 10 microns or less as measured by laser diffraction spectroscopy.
55. The granule of claim 50, wherein the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, a lubricant, a surfactant, a glidant, or a combination of two or more thereof.
56. The granule of claim 50, wherein the pharmaceutically acceptable excipients comprise: (i) a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or combinations of two or more thereof; (ii) carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) hydroxyalkyl cellulose, alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, or a combination of two or more thereof; (iv) (iii) a compound from (i) and a compound from (ii); (v) (iv) a compound from (i) and a compound from (iii); (vi) (iv) a compound from (ii) and a compound from (iii); or (vii) a compound from (i), a compound from (ii) and a compound from (iii).
57. A granulate according to claim 56, comprising a compound from (i), a compound from (ii) and a compound from (iii).
58. The granule of claim 57, comprising from about 40 wt% to about 80 wt% of the compound from (i), from about 1 wt% to about 20 wt% of the compound from (ii), and from about 1 wt% to about 20 wt% of the compound from (iii).
59. The granule of claim 57, comprising from about 50 wt% to about 70 wt% of the compound from (i), from about 1 wt% to about 15 wt% of the compound from (ii), and from about 1 wt% to about 10 wt% of the compound from (iii).
60. The granule of claim 57, comprising about 55 wt% to about 65 wt% of the compound from (i), about 2 wt% to about 12 wt% of the compound from (iii), and about 1 wt% to about 8 wt% of the compound from (iii).
61. The granule of claim 57, comprising from about 58 wt% to about 63 wt% of the compound from (i), from about 2 wt% to about 10 wt% of the compound from (iii), and from about 2 wt% to about 8 wt% of the compound from (iii).
62. A granulate according to claim 57, comprising about 61 wt% of the compound from (i); (iii) about 8 wt% of the compound from (ii); and about 4 wt% of the compound from (iii).
63. The granule of claim 50, wherein the pharmaceutically acceptable excipients comprise: (i) a polyol; (ii) microcrystalline cellulose; (ii) a carboxymethyl cellulose; and (iii) hydroxyalkyl cellulose.
64. The granule of claim 50, wherein the pharmaceutically acceptable excipient comprises (i) a polyol, (ii) microcrystalline cellulose, (iii) maltodextrin, (iv) carboxymethylcellulose, (v) hydroxyalkyl cellulose, (vi) alkyl cellulose, or (vii) a combination of two or more thereof.
65. The granule of claim 64, wherein the hydroxyalkyl cellulose is hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or a combination of two or more thereof.
66. The granule of claim 65, wherein the hydroxyalkyl cellulose is hydroxypropyl cellulose.
67. The granule of claim 64, wherein the polyol is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof.
68. The granule of claim 67, wherein the polyol is mannitol.
69. The granule of claim 50, comprising about 1 wt% to about 50 wt% of the compound of formula (III).
70. The granule of claim 69, comprising about 5 wt% to about 45 wt% of the compound of formula (III).
71. The granule of claim 70, comprising about 10 wt% to about 40 wt% of the compound of formula (III).
72. The granule of claim 71, comprising about 15 wt% to about 35 wt% of the compound of formula (III).
73. The granule of claim 72, comprising about 20 wt% to about 30 wt% of the compound of formula (III).
74. The granule of claim 73, comprising about 24 wt% to about 26 wt% of the compound of formula (III).
75. The granule of claim 74, comprising about 25 wt% of the compound of formula (III).
76. The granule of claim 50, further comprising from about 0.5 wt% to about 4 wt% of a lubricant.
77. The granule of claim 76, comprising about 0.5 wt% to about 2.3 wt% lubricant.
78. The granule of claim 77, comprising about 2.25 wt% lubricant.
79. The granule of claim 52, wherein the compound of formula (III) is a compound of formula (IIIA):
80. the granule of claim 52, wherein the compound of formula (III) is a compound of formula (IIIB):
81. a pharmaceutical composition comprising the granule of claim 50 and a pharmaceutically acceptable excipient.
82. A tablet comprising the granule of claim 50.
83. The tablet of claim 82, which is encapsulated within a coating.
84. A capsule comprising the granule of claim 50 encapsulated within a capsule shell.
85. The capsule of claim 84, which is encapsulated within a coating.
86. A sachet or stick pack comprising the granule of claim 50.
87. The pharmaceutical composition of claim 81, comprising from about 1mg to about 1,000mg of the compound of formula (III).
88. The pharmaceutical composition of claim 87, comprising about 50mg to about 500mg of the compound of formula (III).
89. The pharmaceutical composition of claim 88, comprising about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, or about 600mg of the compound of formula (III).
90. The pharmaceutical composition of claim 81, having a disintegration time of about 15 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopoeia (USP).
91. The pharmaceutical composition of claim 90, having a disintegration time of about 10 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopoeia (USP).
92. The pharmaceutical composition of claim 81, having a dissolution rate of at least 75% in 60 minutes as measured by the dissolution apparatus method type II < 711 > Chapter United States Pharmacopeia (USP).
93. The pharmaceutical composition of claim 92, having a dissolution rate of at least 90% in 60 minutes as measured by the dissolution apparatus type II (paddle) method in Chapter < 711 in United States Pharmacopoeia (USP).
94. The pharmaceutical composition of claim 81, having a dissolution rate of at least 70% in 10 minutes as measured by the dissolution apparatus method type II < 711 > Chapter United States Pharmacopeia (USP).
95. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the granule of claim 50 to treat the cancer.
96. The method of claim 95, wherein the cancer is lung cancer, melanoma, renal cell carcinoma, breast cancer, colorectal cancer, bladder cancer, prostate cancer, or head and neck cancer.
97. The method of claim 95, wherein the therapeutically effective amount is from about 1mg to about 1,000mg per day.
98. The method of claim 97, wherein the therapeutically effective amount is from about 10mg to about 600mg per day.
99. The method of claim 98, wherein the therapeutically effective amount is from about 100mg to about 400mg per day.
100. A bead comprising an inert core and a drug layer; wherein the drug layer comprises drug particles and pharmaceutically acceptable excipients; wherein the drug particles comprise a compound of formula (III), or a pharmaceutically acceptable salt thereof, having a particle size distribution with D90 of about 30 microns or less, as measured by laser diffraction spectroscopy:
101. the bead of claim 100, wherein said core has a particle size greater than 50 microns.
102. The bead of claim 101, wherein said core has a particle size of from about 100 microns to about 2.5 mm.
103. The bead of claim 100, wherein said drug particles have a particle size distribution with a D90 of about 25 microns or less as measured by laser diffraction spectroscopy.
104. The bead of claim 103, wherein said drug particles have a particle size distribution with a D90 of about 20 microns or less as measured by laser diffraction spectroscopy.
105. The bead of claim 104, wherein said drug particles have a particle size distribution with a D90 of about 15 microns or less as measured by laser diffraction spectroscopy.
106. The bead of claim 105, wherein said drug particles have a particle size distribution with a D90 of about 10 microns or less as measured by laser diffraction spectroscopy.
107. The bead of claim 100, wherein said pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, a lubricant, a surfactant, a glidant, or a combination of two or more thereof.
108. The bead of claim 100, wherein said pharmaceutically acceptable excipients comprise: (i) a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or combinations of two or more thereof; (ii) carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) hydroxyalkyl cellulose, alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, or a combination of two or more thereof; (iv) (iii) a compound from (i) and a compound from (ii); (v) (iv) a compound from (i) and a compound from (iii); (vi) (iv) a compound from (ii) and a compound from (iii); or (vii) a compound from (i), a compound from (ii) and a compound from (iii).
109. The bead of claim 108, comprising a compound from (i), a compound from (ii), and a compound from (iii).
110. The bead of claim 109, comprising about 40 wt% to about 80 wt% of the compound from (i), about 1 wt% to about 20 wt% of the compound from (ii), and about 1 wt% to about 20 wt% of the compound from (iii).
111. The bead of claim 109, comprising about 50 wt% to about 70 wt% of the compound from (i), about 1 wt% to about 15 wt% of the compound from (ii), and about 1 wt% to about 10 wt% of the compound from (iii).
112. The bead of claim 109, comprising about 55 wt% to about 65 wt% of the compound from (i), about 2 wt% to about 12 wt% of the compound from (iii), and about 1 wt% to about 8 wt% of the compound from (iii).
113. The bead of claim 109, comprising about 58 wt% to about 63 wt% of the compound from (i), about 2 wt% to about 10 wt% of the compound from (iii), and about 2 wt% to about 8 wt% of the compound from (iii).
114. The bead of claim 109, comprising about 61 wt% of the compound from (i); (iii) about 8 wt% of the compound from (ii); and about 4 wt% of the compound from (iii).
115. The bead of claim 100, wherein said pharmaceutically acceptable excipients comprise: (i) a polyol; (ii) microcrystalline cellulose; (ii) a carboxymethyl cellulose; and (iii) hydroxyalkyl cellulose.
116. The bead of claim 100, wherein said pharmaceutically acceptable excipient comprises (i) a polyol, (ii) microcrystalline cellulose, (iii) maltodextrin, (iv) carboxymethylcellulose, (v) hydroxyalkyl cellulose, (vi) alkyl cellulose, or (vii) a combination of two or more thereof.
117. The bead of claim 116, wherein said hydroxyalkyl cellulose is hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, or a combination of two or more thereof.
118. The bead of claim 117, wherein said hydroxyalkyl cellulose is hydroxypropyl cellulose.
119. The bead of claim 116, wherein the polyol is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof.
120. The bead of claim 119, wherein said polyol is mannitol.
121. The bead of claim 100, comprising about 1 wt% to about 50 wt% of said compound of formula (III).
122. The bead of claim 121, comprising about 5 wt% to about 45 wt% of said compound of formula (III).
123. The bead of claim 122, comprising about 10 wt% to about 40 wt% of said compound of formula (III).
124. The bead of claim 123, comprising about 15 wt% to about 35 wt% of said compound of formula (III).
125. The bead of claim 124, comprising about 20 wt% to about 30 wt% of said compound of formula (III).
126. The bead of claim 125, comprising about 24 wt% to about 26 wt% of said compound of formula (III).
127. The bead of claim 126, comprising about 25 wt% of said compound of formula (III).
128. The bead of claim 100, further comprising from about 0.5 wt% to about 4 wt% of a lubricant.
129. The bead of claim 128, comprising about 0.5% to about 2.3% by weight lubricant.
130. The bead of claim 129, comprising about 2.25 wt.% lubricant.
131. The bead of claim 100, wherein said compound of formula (III) is a compound of formula (IIIA):
132. the bead of claim 100, wherein said compound of formula (III) is a compound of formula (IIIB):
133. a pharmaceutical composition comprising the bead of claim 100.
134. A tablet comprising the bead of claim 100.
135. The tablet of claim 134, which is encapsulated within a coating.
136. A capsule comprising the bead of claim 100 encapsulated within a capsule shell.
137. The capsule of claim 136, being encapsulated within a coating.
138. The pharmaceutical composition of claim 133 comprising from about 1mg to about 1,000mg of the compound of formula (III).
139. The pharmaceutical composition of claim 138, comprising about 50mg to about 600mg of the compound of formula (III).
140. The pharmaceutical composition of claim 139, comprising about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, or about 600mg of the compound of formula (III).
141. The pharmaceutical composition of claim 100, having a disintegration time of about 15 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopeia (USP).
142. The pharmaceutical composition of claim 141, having a disintegration time of about 10 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopeia (USP).
143. The pharmaceutical composition of claim 100, having a dissolution rate of at least 75% in 60 minutes as measured by the dissolution apparatus type II (paddle) method in chapter < 711 in the United States Pharmacopeia (USP).
144. The pharmaceutical composition of claim 143, having a dissolution rate of at least 90% in 60 minutes as measured by the dissolution apparatus type II (paddle) method in chapter < 711 in the United States Pharmacopeia (USP).
145. The pharmaceutical composition of claim 100, having a dissolution rate of at least 70% in 10 minutes as measured by the dissolution apparatus method type II (paddle) of chapter < 711 in the United States Pharmacopeia (USP).
146. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the beads of claim 100 to treat the cancer.
147. The method of claim 146, wherein the cancer is non-small cell lung cancer, melanoma, renal cell carcinoma, breast cancer, colorectal cancer, bladder cancer, prostate cancer, or head and neck cancer.
148. The method of claim 146, wherein the therapeutically effective amount is from about 1mg to about 1,000mg per day.
149. The method of claim 148, wherein the therapeutically effective amount is from about 50mg to about 600mg per day.
150. The method of claim 149, wherein the therapeutically effective amount is about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, or about 600mg of the compound of formula (III) per day.
151. A composition or bioequivalent formulation thereof comprising: (i) about 20 wt% to about 30 wt% of a compound of formula (III) or a pharmaceutically acceptable salt thereof, having a particle size distribution with D90 of about 10 microns or less, as measured by laser diffraction spectroscopy; (ii) about 35 wt% to about 40 wt% mannitol; (iii) about 15 wt% to about 30 wt% microcrystalline cellulose; (iv) from about 4 wt% to about 12 wt% croscarmellose sodium; and (v) about 1 wt% to about 8 wt% hydroxypropyl cellulose.
152. The composition of claim 151, wherein the mannitol comprises spray dried mannitol and crystalline mannitol in a weight ratio of about 1: 1 to about 1: 3.
153. A composition or bioequivalent formulation thereof comprising: (i) about 24 wt% to about 26 wt% of a compound of formula (III), or a pharmaceutically acceptable salt thereof, having a particle size distribution with D90 of about 10 microns or less, as measured by laser diffraction spectroscopy; (ii) about 37 wt% to about 40 wt% mannitol; (iii) about 20 wt% to about 25 wt% microcrystalline cellulose; (iv) from about 4 wt% to about 12 wt% croscarmellose sodium; and (v) about 2 wt% to about 6 wt% hydroxypropyl cellulose.
154. The composition of claim 153, wherein the mannitol comprises spray dried mannitol and crystalline mannitol in a weight ratio of about 1: 1.5 to about 1: 2.5.
155. A pharmaceutical composition No. 1 or a bioequivalent formulation thereof.
156. A pharmaceutical composition No. 2 or a bioequivalent formulation thereof.
157. A pharmaceutical composition No. 3 or a bioequivalent formulation thereof.
158. A pharmaceutical composition No. 4 or a bioequivalent formulation thereof.
159. A pharmaceutical composition No. 5 or a bioequivalent formulation thereof.
160. A pharmaceutical composition No. 6 or a bioequivalent formulation thereof.
161. The composition of claim 151, comprising from about 1mg to about 1,000mg of the compound of formula (III).
162. The composition of claim 161, comprising about 10mg to about 600mg of the compound of formula (III).
163. The composition of claim 162 comprising from about 100mg to about 400mg of the compound of formula (III).
164. The composition of claim 162 comprising about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, or about 600mg of the compound of formula (III).
165. The composition of claim 151, having a disintegration time of about 15 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopeia (USP).
166. The composition of claim 165, having a disintegration time of about 10 minutes or less as measured by the disintegration test method of chapter < 701 in the United States Pharmacopoeia (USP).
167. The composition of claim 151, having a dissolution rate of at least 75% in 60 minutes as measured by the dissolution apparatus type II (paddle) method in chapter < 711 in the United States Pharmacopeia (USP).
168. The composition of claim 167, having a dissolution rate of at least 90% in 60 minutes as measured by the dissolution apparatus type II (paddle) method in chapter < 711 in the United States Pharmacopeia (USP).
169. A tablet comprising the pharmaceutical composition of claim 151.
170. The tablet of claim 169, which is encapsulated within a coating.
171. A capsule comprising the composition of claim 151 encapsulated within a capsule shell.
172. The capsule of claim 171, which is encapsulated within a coating.
173. A powder comprising the composition of claim 151.
174. A sachet or stick pack comprising the powder of claim 151.
175. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 151 to treat the cancer.
176. The method of claim 175, wherein the cancer is non-small cell lung cancer, melanoma, renal cell carcinoma, breast cancer, colorectal cancer, bladder cancer, prostate cancer, or head and neck cancer.
177. The method of claim 175, wherein the therapeutically effective amount is from about 1mg to about 1,000mg per day.
178. The method of claim 177, wherein the therapeutically effective amount is from about 10mg to about 600mg per day.
179. The method of claim 178, wherein the therapeutically effective amount is from about 100mg to about 400mg per day.
180. The method of claim 178, wherein the therapeutically effective amount is about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, or about 600mg of the compound of formula (III) per day.
Background
The goal of immunotherapy is to drive cytotoxic T cell responses to eradicate cancer. To prevent a response to self-antigens, there are multiple inhibitory checkpoint signals. Extracellular adenosine is produced during acute inflammatory processes by adenosine triphosphate conversion by exonucleases CD73 and CD39 expressed on the cell surface of various tissue types. Adenosine is generally upregulated in response to stimuli such as infection or ischemia by binding to its extracellular G protein-coupled receptor on target cells to protect the host from excessive damage and to begin healing. However, various tumor types can actively maintain extracellular adenosine levels far beyond the acute phase response to suppress the host immune response by a variety of mechanisms. The increase of adenosine in the microenvironment by malignant cells recruits regulatory T cells to this region and further increases adenosine levels.
Cancer cells appear to utilize adenosine directly. Because adenosine causes less efficient presentation of tumor antigens to the adaptive system and enhances tumor growth. Therefore, adenosine A2A receptor antagonists have been designed and are in clinical development to treat cancer. Thus, there is a need in the art for formulations of adenosine A2A receptor antagonists that can provide the desired combination of exposure, safety, and/or stability necessary for commercial pharmaceutical products. To this end, as described herein, studies have been conducted to develop such formulations that, for example, have improved bioavailability, are stable at room temperature, and minimize the potential for gastric irritation. The present disclosure is directed to these and other important ends.
Disclosure of Invention
Provided herein are pharmaceutical compositions comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an adenosine receptor antagonist. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 30 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 20 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IIIA), a compound of formula (IIIB), or a pharmaceutically acceptable salt of one of the foregoing. In some aspects, the micronized drug particles are crystalline. In some aspects, the pharmaceutically acceptable excipient comprises (i) a filler, such as a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or a combination of two or more thereof; (ii) a disintegrant such as carboxymethyl cellulose, sodium starch glycolate, a cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) a binder, such as a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, or a combination of two or more thereof; or (iv) a combination of two or more of a filler, a disintegrant and a binder. In some aspects, the pharmaceutical composition is in the form of a tablet, capsule, or powder. In some aspects, the pharmaceutical composition comprises about 10 wt% to about 40 wt% adenosine A2A receptor antagonist, about 40 wt% to about 80 wt% filler, about 1 wt% to about 20 wt% disintegrant, and about 1 wt% to about 20 wt% binder. In some aspects, the composition comprises from about 1mg to about 1,000mg of the adenosine A2A receptor antagonist. In some aspects, the composition has an outer coating.
Provided herein are granules comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an adenosine receptor antagonist. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 30 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 20 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IIIA), a compound of formula (IIIB), or a pharmaceutically acceptable salt of one of the foregoing. In some aspects, the micronized drug particles are crystalline. In some aspects, the pharmaceutically acceptable excipient comprises (i) a filler, such as a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or a combination of two or more thereof; (ii) a disintegrant such as carboxymethyl cellulose, sodium starch glycolate, a cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) a binder, such as a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, or a combination of two or more thereof; or (iv) a combination of two or more of a filler, a disintegrant and a binder. In some aspects, the granule comprises about 10 wt% to about 40 wt% adenosine A2A receptor antagonist, about 40 wt% to about 80 wt% filler, about 1 wt% to about 20 wt% disintegrant, and about 1 wt% to about 20 wt% binder. In some aspects, a lubricant, glidant, or surfactant may be included inside or outside the granule. In some aspects, the granules have an outer coating. In some aspects, the granules, optionally with an outer coating, are compressed into tablets, placed in capsule shells or placed in sachets or stick packs.
Provided herein are tablets comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an adenosine receptor antagonist. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 30 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 20 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IIIA), a compound of formula (IIIB), or a pharmaceutically acceptable salt of one of the foregoing. In some aspects, the micronized drug particles are crystalline. In some aspects, the pharmaceutically acceptable excipient comprises (i) a filler, such as a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or a combination of two or more thereof; (ii) a disintegrant such as carboxymethyl cellulose, sodium starch glycolate, a cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) a binder, such as a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, or a combination of two or more thereof; or (iv) a combination of two or more of a filler, a disintegrant and a binder. In some aspects, the tablet comprises about 10 wt% to about 40 wt% adenosine A2A receptor antagonist, about 40 wt% to about 80 wt% filler, about 1 wt% to about 20 wt% disintegrant, and about 1 wt% to about 20 wt% binder. In some aspects, the tablet comprises from about 1mg to about 600mg of the adenosine A2A receptor antagonist. In some aspects, the tablet comprises a surfactant, a glidant, a lubricant, or a combination thereof. In some aspects, the tablet has an outer coating.
Provided herein are powders comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an adenosine receptor antagonist. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 30 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 20 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IIIA), a compound of formula (IIIB), or a pharmaceutically acceptable salt of one of the foregoing. In some aspects, the micronized drug particles are crystalline. In some aspects, the pharmaceutically acceptable excipient comprises (i) a filler, such as a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or a combination of two or more thereof; (ii) a disintegrant such as carboxymethyl cellulose, sodium starch glycolate, a cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) a binder, such as a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, or a combination of two or more thereof; or (iv) a combination of two or more of a filler, a disintegrant and a binder. In some aspects, the powder comprises about 10 wt% to about 40 wt% adenosine A2A receptor antagonist, about 40 wt% to about 80 wt% filler, about 1 wt% to about 20 wt% disintegrant, and about 1 wt% to about 20 wt% binder. In some aspects, the powder comprises from about 1mg to about 1,000mg of the adenosine A2A receptor antagonist. The powder may be used in single or multiple doses, more commonly it may be multiplied by the desired number of doses or dosage forms. In some aspects, the powder further comprises a surfactant, a glidant, a lubricant, or a combination of two or more thereof. In some aspects, the powder is compressed into a tablet, placed in a capsule shell or placed in a sachet or stick pack. In some aspects, the powder is measured and applied directly or mixed with food or liquid.
Provided herein are oral formulations comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an adenosine receptor antagonist. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 30 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 20 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IIIA), a compound of formula (IIIB), or a pharmaceutically acceptable salt of one of the foregoing. In some aspects, the micronized drug particles are crystalline. In some aspects, the pharmaceutically acceptable excipient comprises (i) a filler, such as a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or a combination of two or more thereof; (ii) a disintegrant such as carboxymethyl cellulose, sodium starch glycolate, a cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) a binder, such as a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, or a combination of two or more thereof; or (iv) a combination of two or more of a filler, a disintegrant and a binder. In some aspects, the oral formulation is in the form of a tablet, capsule, or powder. In some aspects, the oral formulation comprises about 10 wt% to about 40 wt% adenosine A2A receptor antagonist, about 40 wt% to about 80 wt% filler, about 1 wt% to about 20 wt% disintegrant, and about 1 wt% to about 20 wt% binder. In some aspects, the oral formulation comprises from about 1mg to about 1,000mg of the adenosine A2A receptor antagonist. In some aspects, the oral formulation further comprises a surfactant, a glidant, a lubricant, or a combination of two or more thereof. In some aspects, the oral formulation has an outer coating.
Provided herein are beads comprising an inert core and a drug layer; wherein the outer layer comprises micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an adenosine receptor antagonist. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 30 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 20 microns or less, as measured by laser diffraction spectroscopy. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IIIA), a compound of formula (IIIB), or a pharmaceutically acceptable salt of one of the foregoing. In some aspects, the micronized drug particles are crystalline. In some aspects, the pharmaceutically acceptable excipient comprises (i) a filler, such as a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or a combination of two or more thereof; (ii) a disintegrant such as carboxymethyl cellulose, sodium starch glycolate, a cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; (iii) a binder, such as a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, or a combination of two or more thereof; or (iv) a combination of two or more of a filler, a disintegrant and a binder. In some aspects, the bead comprises about 10 wt% to about 40 wt% adenosine A2A receptor antagonist, about 40 wt% to about 80 wt% filler, about 1 wt% to about 20 wt% disintegrant, and about 1 wt% to about 20 wt% binder. In some aspects, the bead further comprises a surfactant, a glidant, a lubricant, or a combination of two or more thereof. In some aspects, the bead has an outer coating. In some aspects, the beads, optionally with an outer coating, are compressed into tablets, placed in capsule shells or placed in sachets or stick packs.
Provided herein are capsules encapsulating a pharmaceutical composition, granule, powder, or bead described herein within a capsule shell, such as a hypromellose capsule shell. In some aspects, the capsule shell comprises an enteric polymer. In some aspects, the capsule has an outer coating. In some aspects, the capsule comprises from about 1mg to about 600mg of the adenosine A2A receptor antagonist.
Provided herein are pharmaceutical compositions comprising an adenosine A2A receptor antagonist (e.g., a compound of formula (III)), wherein the dissolution rate of the adenosine A2A receptor antagonist in the composition is at least 70% in 60 minutes as measured according to a type II (paddle) dissolution apparatus, chapter < 711, of the united states Pharmacopeia (US Pharmacopeia (USP)). In some aspects, the dissolution rate is at least 75% within 60 minutes. In some aspects, the dissolution rate is at least 80% within 60 minutes. In some aspects, the dissolution rate is at least 85% in 60 minutes. In some aspects, the dissolution rate is at least 90% within 60 minutes. In some aspects, the dissolution rate is at least 70% within 10 minutes. In some aspects, the dissolution rate is at least 60% within 10 minutes.
Provided herein are pharmaceutical compositions comprising an adenosine A2A receptor antagonist (e.g., a compound of formula (III)) having a disintegration time of 15 minutes or less as measured by laser diffraction spectroscopy, by the United States Pharmacopeia (USP) chapter < 701 > disintegration test. In some aspects, the pharmaceutical composition has a disintegration time of about 15 minutes or less as measured by laser diffraction spectroscopy. In some aspects, the pharmaceutical composition has a disintegration time of about 10 minutes or less as measured by laser diffraction spectroscopy. In some aspects, the pharmaceutical composition has a disintegration time of about 5 minutes or less as measured by laser diffraction spectroscopy.
Provided herein are methods of treating cancer in a patient by administering a therapeutically effective amount of a pharmaceutical composition, oral formulation, tablet, capsule, granule, powder, or bead described herein for treating cancer. In some aspects, the cancer is lung cancer (e.g., non-small cell lung cancer), melanoma (e.g., malignant melanoma), renal cell carcinoma, breast cancer (e.g., triple negative breast cancer), colorectal cancer, bladder cancer, prostate cancer, or head and neck cancer. In some aspects, the pharmaceutical composition, oral formulation, tablet, capsule, granule, powder, or bead described herein is administered once daily (QD) to a patient. In some aspects, once daily administration can include administration of 1, 2, or 3 oral formulations (e.g., 1, 2, or 3 formulations or capsules). In some aspects, the pharmaceutical composition, oral formulation, tablet, capsule, granule, powder, or bead described herein is administered to a patient twice daily (BID). In some aspects, twice daily administration can include administering 1, 2, or 3 oral formulations (e.g., 1, 2, or 3 tablets or capsules) twice daily. In some aspects, the therapeutically effective amount for cancer treatment is from about 1mg per day to about 1,000mg per day. In some aspects, a therapeutically effective amount for adult cancer treatment is from about 50mg to about 600mg per day. In some aspects, a therapeutically effective amount for the treatment of cancer in human pediatric or veterinary applications may be from about 5mg to about 400mg per day.
The present disclosure provides processes for preparing the pharmaceutical compositions, oral formulations, and granules described herein by mixing the micronized adenosine A2A receptor antagonist with at least one pharmaceutically acceptable excipient to form granules; drying and grinding or sieving the granules; and encapsulating the granules or compressing the granules into tablets; and optionally coating the capsule or tablet with a coating.
The pharmaceutical compositions and oral formulations (e.g., tablets, capsules, granules, powders, beads) described herein have unexpectedly superior properties. In some aspects, the pharmaceutical compositions and oral formulations (e.g., tablets, capsules, granules, powders, beads) described herein have unexpectedly superior bioavailability. In some aspects, the pharmaceutical compositions and oral formulations (e.g., tablets, capsules, granules, powders, beads) described herein have unexpectedly superior stability. In some aspects, the pharmaceutical compositions and oral formulations described herein (e.g.Tablets, capsules, granules, powders, beads) have unexpectedly superior dissolution profiles. In some aspects, the pharmaceutical compositions and oral formulations (e.g., tablets, capsules, granules, powders, beads) described herein have unexpectedly superior disintegration profiles. In some aspects, the pharmaceutical compositions and oral formulations (e.g., tablets, capsules, granules, powders, beads) described herein have unexpectedly superior pharmacokinetic properties. In some aspects, the pharmaceutical compositions and oral formulations (e.g., tablets, capsules, granules, powders, beads) described herein have unexpectedly superior Cmin、Cmax、Cmax/CminRatio, TmaxOr AUC.
These and other embodiments and aspects of the disclosure are set forth herein.
Drawings
Figure 1 shows dissolution in the United States Pharmacopeia (USP) < 711 > Chapter dissolution test for pharmaceutical composition # 5, wherein the composition is placed in 900mL of 0.1N HCl dissolution media at about 37 ℃ in
Figure 2 is a graph showing dissolution rates of pharmaceutical compositions No. 1-3 according to USP < 711 > chapter dissolution test in 900mL of 0.1N HCl dissolution medium at about 37 ℃ placed in
Figures 3A-3C are graphs showing dissolution of pharmaceutical compositions nos. 1-3 in 900mL of 0.1N HCl dissolution medium at about 37 ℃ as a function of storage time at 40 ℃ and 75% relative humidity according to the dissolution test of USP < 711 > chapter, in which the compositions are placed in
Figure 4 shows dissolution of pharmaceutical composition No. 1 as a function of storage time under accelerated conditions (ACC) or controlled room temperature Conditions (CRT) in 900mL of 0.1N HCl dissolution medium at about 37 ℃ and pH 1.0 according to USP < 711 > chapter dissolution test in which the composition is placed in
Figure 5 shows dissolution of pharmaceutical composition No. 5 as a function of storage time under accelerated conditions (ACC) or controlled room temperature Conditions (CRT) in 900mL of 0.1N HCl dissolution medium at about 37 ℃ and pH 1.0 according to USP < 711 > chapter dissolution test in which the composition is placed in
Detailed Description
Definition of
The term "drug particles" or "drug particles" as used herein means one or more particles comprised of an A2A receptor antagonist or a pharmaceutically acceptable salt thereof. In some aspects, the drug particles are solid. In some aspects, the drug particles are semi-solid. In some aspects, the drug particles do not comprise other active pharmaceutical ingredients than the one or more A2A receptor antagonists. In some aspects, the drug particles comprise only a single type of A2A receptor antagonist. In some aspects, the drug particles comprise only a single type of A2A receptor antagonist and no other active pharmaceutical ingredient. In some aspects, the drug particles comprise only a single type of A2A receptor antagonist and no pharmaceutical excipients or other active pharmaceutical ingredients. In some aspects, the drug particles comprise only a single type of A2A receptor antagonist, optionally comprising water molecules, and no pharmaceutical excipients or other active pharmaceutical ingredients. In some aspects, the drug particles are crystalline. In some aspects, the drug particles are amorphous. In some aspects, the drug particle or the plurality of drug particles refers to all of the drug particles in the composition.
By "micronized drug particles" is meant drug particles having a particle size distribution with a D90 of about 50 microns or less as measured by laser diffraction spectroscopy. In some aspects, the drug particles have a particle size distribution with a D90 of about 40 microns or less as measured by laser diffraction spectroscopy. In some aspects, the drug particles have a particle size distribution with a D90 of about 30 microns or less as measured by laser diffraction spectroscopy. In some aspects, the drug particles have a particle size distribution with a D90 of about 25 microns or less as measured by laser diffraction spectroscopy. In some aspects, the drug particles have a particle size distribution with a D90 of about 20 microns or less as measured by laser diffraction spectroscopy. In some aspects, the drug particles have a particle size distribution with a D90 of about 15 microns or less as measured by laser diffraction spectroscopy. In some aspects, the drug particles have a particle size distribution with a D90 of about 10 microns or less as measured by laser diffraction spectroscopy. In some aspects, the micronized drug particles refer to all of the drug particles in the composition.
"particle size distribution" or "PSD" or "particle size distribution" refers to the particle size of the particles present in relative proportions in a sample as measured by laser diffraction spectroscopy. In some aspects, the particle size distribution refers to the particle size distribution of all drug particles in the composition. The particle size distribution of the sample was measured by laser diffraction spectroscopy. The laser diffraction spectrometer may be, for example, of Malvern Instruments Ltd3000 and of HORIBA Instruments, Inc. (Irvine CA), of Lvwang, CalifLA-950 is commercially available. For laser diffraction spectroscopy, the particle size distribution is typically described in terms of a D value, such as D90. In some aspects, laser diffraction spectroscopy can be analyzed using Fraunhofer theory (Fraunhofer spectroscopy). In some aspects, the laser diffraction spectra can be analyzed using mie scattering theory (miescatting theory). In some aspects, laser diffraction spectroscopy can be analyzed by combining fraunhofer theory and mie scattering theory.
"D90" is as measured by laser diffraction spectroscopyIn an amount such that 90% of the total volume of material (e.g., drug particles) in the sample is below the particle size distribution point at the specified particle size. That is, D90 refers to the particle size distribution where 90% of the total volume of drug particle material in the sample is below the specified particle size. For example, if D90 is 20 microns, this means that 90% of the material in the sample has a particle size of 20 microns or less. "D90" is also referred to as Dv (90) or D90. The particle size distribution of the sample was measured by laser diffraction spectroscopy. The laser diffraction spectrometer may be, for example, of Malvern instruments Inc3000 and HORIBA instruments, Inc. of Lwan, CalifLA-950 is commercially available.
"D50" is the point of particle size distribution at which 50% of the total volume of material (e.g., drug particles) in the sample is below a specified particle size. That is, D50 refers to a particle size distribution in which 50% of the total volume of drug particle material in the sample is below a specified particle size. For example, if D50 is 6 microns, this means that 50% of the material in the sample has a particle size of 6 microns or less. "D50" is also referred to as Dv (50) or D50. The particle size distribution of the sample was measured by laser diffraction spectroscopy. The laser diffraction spectrometer may be, for example, of Malvern instruments Inc
"D10" is the point of particle size distribution where 10% of the total volume of material (e.g., drug particles) in the sample is below a specified particle size. That is, D10 refers to the particle size distribution where 10% of the total volume of drug particle material in the sample is below the specified particle size. For example, if D10 is 1.8 microns, this means that 10% of the material in the sample has a particle size of 1.8 microns or less. "D10" is also referred to as Dv (10) or D10. Pellets of the sampleThe degree distribution was measured by laser diffraction spectroscopy. The laser diffraction spectrometer may be, for example, of Malvern instruments Inc3000 and HORIBA instruments, Inc. of Lwan, Calif
"crystalline" refers to a compound having an ordered three-dimensional lattice of atoms and/or molecules as determined by methods known in the art (e.g., X-ray powder diffraction, IR spectroscopy, raman spectroscopy, Differential Scanning Calorimetry (DSC), solid state NMR, polarized light microscopy, or by its melting point). See, e.g., remington: pharmaceutical science and Practice (Remington: The science and Practice of Pharmacy, 21 st edition, Lippincott Williams and Wilkins publishing Co., Lippincott, Williams and Wilkins, Baltimore, Maryland (2005); U.S. pharmacopoeia, 23 rd edition (1995); specifically, when a compound is disclosed herein as crystalline, one of ordinary skill in The art will immediately recognize that The compound forms part of a crystalline solid that comprises a plurality of The compound.
"amorphous" refers to a solid compound (i.e., a solid comprising multiple compounds) or solid composition that does not have long-range crystalline order. In some aspects, amorphous refers to a compound or composition that is substantially free of crystalline forms. That is, amorphous refers to a solid comprising a compound (e.g., a plurality of pharmaceutically active agents or drugs), wherein the solid is substantially free of crystalline forms. In some aspects, an amorphous compound (i.e., a solid comprising multiple compounds) or composition has less than 10% of the compound (i.e., a solid comprising multiple compounds) or composition in a crystalline form; or less than 5%; or less than 2% of the compound (i.e., a solid comprising multiple compounds) or composition in crystalline form. In some aspects, an amorphous compound or composition has less than 1% of the compound (i.e., a solid comprising multiple compounds) or composition in a crystalline form. In some aspects, an amorphous compound (i.e., a solid comprising a plurality of compounds) or composition has no crystallinity as determined by X-ray powder diffraction, IR spectroscopy, raman spectroscopy, Differential Scanning Calorimetry (DSC), solid state NMR, polarized light microscopy, or melting point thereof. In some aspects, an amorphous compound (i.e., a solid comprising a plurality of compounds), an amorphous solid dispersion, an amorphous composition (i.e., a solid comprising a plurality of compositions), or an amorphous extrudate as described herein remains in the amorphous state for a period of time of more than 18 months; for more than 2 years; more than 3 years; for more than 4 years; or more than 5 years. In particular, when a compound (e.g., a drug or active agent) is disclosed herein as being amorphous, one of ordinary skill in the art will immediately recognize that the compound forms part of an amorphous solid comprising a plurality of such compounds. Likewise, when a compound is disclosed herein as a solid (e.g., "solid compound"), one of ordinary skill in the art will immediately recognize that the compound forms part of a solid that comprises a plurality of the compound.
"pharmaceutically acceptable excipient" refers to a substance that facilitates administration of the adenosine A2A receptor antagonist to and absorption by a patient, or facilitates manufacture of the granules, beads, powders, tablets, compositions, and formulations described herein. The pharmaceutically acceptable excipients are inert. Non-limiting examples of pharmaceutically acceptable excipients include pharmaceutically acceptable polymers, water, NaCl, physiological saline solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavors, salt solutions, alcohols, oils, gelatins, carbohydrates, pigments, and the like. This can be sterilized and, if desired, the preparations can be mixed with auxiliaries, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers, colorants and/or aromatic substances. Pharmaceutically acceptable Excipients are described in Handbook of Pharmaceutical Excipients (8 th edition) and the United States Food and Drug Administration Inactive Ingredient Database (7.2017), published by Pharmaceutical Press (2017), the disclosure of which is incorporated herein by reference. The pharmaceutical compositions described herein (including granules, beads, powders, tablets, capsules, and oral formulations) may include one or more pharmaceutically acceptable excipients. One skilled in the art will recognize that other pharmaceutically acceptable excipients will be useful in the compositions described herein.
"fillers" are pharmaceutically acceptable excipients used in pharmaceutical compositions to increase the volume of low dose active ingredients. Exemplary fillers include polyols, maltodextrins, microcrystalline cellulose, and the like. Other fillers are known to those skilled in the art.
A "disintegrant" is a pharmaceutically acceptable excipient that swells and/or dissolves when exposed to water or body fluids (e.g., gastric acid, saliva) that causes the pharmaceutical composition to rupture (typically in the digestive tract, such as the stomach, small intestine or large intestine) and release the active ingredient. In some aspects, the disintegrant is a super disintegrant. Exemplary disintegrants include carboxyalkyl celluloses (e.g., carboxymethyl cellulose or cross-linked carboxymethyl cellulose), sodium starch glycolate, cross-linked polyvinylpyrrolidone polymers, and the like. Other disintegrants and superdisintegrants are known to those skilled in the art.
A "binder" is a pharmaceutically acceptable excipient that binds one or more other compounds or active ingredients together. The binder can provide mechanical strength to the tablet, granule, bead or capsule. Exemplary binders include hydroxyalkyl cellulose, alkyl cellulose, corn starch, gelatin, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, and the like. Other binders are known to those skilled in the art.
A "lubricant" is a pharmaceutically acceptable excipient that prevents other compounds or active ingredients from aggregating and/or from adhering to a device or equipment during manufacture. Exemplary lubricants include magnesium stearate, calcium stearate, sodium stearate, stearic acid, talc, sodium stearyl fumarate, boric acid, sodium benzoate, sodium oleate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl behenate, and the like. Other lubricants are known to those skilled in the art.
A "glidant" is a pharmaceutically acceptable excipient used to improve the flow of a compound or composition. Exemplary glidants include calcium phosphate, cellulose, colloidal silicon dioxide, hydrophobic colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, silicon dioxide, talc and the like.
A "polyol" is an organic alcohol having two or more hydroxyl groups. In some aspects, the polyol is a monomeric polyol. Exemplary polyols include mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, and the like.
"mannitol" refers to the compound HO-CH2-(CH(OH))4-CH2-OH. In some aspects, the mannitol is D-mannitol. Mannitol is commercially available, for example, as
"cellulose" or "cellulosic compound" or "cellulosic polymer" is meant to encompass polymers having the formula (C)6H10O5)nβ (1 → 4) linked to a chain of D-glucose units.
"microcrystalline cellulose" refers to refined wood pulp that meets USP standards. Microcrystalline cellulose may be natural or synthetic and is available from a number of suppliers, such as Sigma Aldrich (Sigma-Aldrich), Miles Scientific (Miles Scientific), JRS pharmaceutical (JRS Pharma), and FMC.
"hydroxyalkyl cellulose" refers to ether derivatives of cellulose compounds having hydroxyalkyl groups. Examples of hydroxyalkyl celluloses include hydroxypropyl cellulose, hydroxyethyl methyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and the like.
"alkyl cellulose" refers to ether derivatives of cellulose compounds having an alkyl group. Examples of alkyl celluloses include methyl cellulose, ethyl methyl cellulose, and the like.
"carboxyalkyl cellulose" refers to ether derivatives of cellulose compounds having carboxyalkyl groups. Examples of carboxyalkyl celluloses include carboxymethyl cellulose, cross-linked carboxymethyl cellulose, and the like.
"HPC" refers to hydroxypropyl cellulose. HPC is a cellulose ether in which some of the hydroxyl groups in the repeating glucose units are hydroxypropylated with propylene oxide. HPC is an exemplary pharmaceutically acceptable polymer.
"HPMC" refers to hydroxypropyl methylcellulose or hypromellose. HPMC is a propylene glycol ether of methylcellulose, hydroxypropyl and methyl, which is bound to the anhydroglucose ring by an ether bond. The percentage of each component (e.g., methoxy, hydroxypropyl) and molecular weight may vary.
By "pharmaceutically acceptable polymer" is meant any polymer known in the art that can be used as a pharmaceutically acceptable excipient. Exemplary pharmaceutically acceptable polymers comprise: polyvinyl pyrrolidine polymers, polyvinyl pyrrolidine copolymers, cellulosic compounds, poly (lactide), poly (glycolide), poly (lactide-co-glycolide) copolymers, poloxamers, polysorbates (e.g.,
"PVP" refers to polyvinylpyrrolidone or a polymer of vinylpyrrolidone. PVP is a class of polymers having an average molecular weight of about 1,000 daltons to about 1,500,000 daltons. In some aspects, the PVP can be crosslinked PVP. In some aspects, the polyvinylpyrrolidone polymer has an average molecular weight of about 1,000 daltons to about 1,000,000 daltons; or from about 1,000 daltons to about 500,000 daltons; or from about 1,000 daltons to about 200,000 daltons. In some aspects, the polyvinylpyrrolidone polymer has an average molecular weight of about 1,000 daltons to about 150,000 daltons. In some aspects, the polyvinylpyrrolidone polymer has an average molecular weight of about 10,000 daltons to about 150,000 daltons. In some aspects, the polyvinylpyrrolidone polymer has an average molecular weight of about 50,000 daltons to about 150,000 daltons. In some aspects, the polyvinylpyrrolidone polymer has an average molecular weight of about 60,000 daltons to about 120,000 daltons. PVP is commercially available from a variety of sources, such as sigma aldrich, BASF, and Ashland (Ashland).
"polyvinylpyrrolidone copolymer" or "vinylpyrrolidone copolymer" refers to a copolymer comprising vinylpyrrolidone and one or more other monomers (e.g., acrylic monomers, styrene, vinyl acetate, etc.). Polyvinylpyrrolidone vinyl acetate copolymer and PVP-VA are exemplary polyvinylpyrrolidone copolymers. In some aspects, the polyvinylpyrrolidone copolymer has an average molecular weight of about 1,000 daltons to about 1,000,000 daltons; or from about 1,000 daltons to about 500,000 daltons; or from about 1,000 daltons to about 200,000 daltons. In some aspects, the polyvinylpyrrolidone copolymer has an average molecular weight of about 1,000 daltons to about 150,000 daltons. In some aspects, the polyvinylpyrrolidone copolymer has an average molecular weight of about 10,000 daltons to about 150,000 daltons. In some aspects, the polyvinylpyrrolidone copolymer has an average molecular weight of about 50,000 daltons to about 150,000 daltons.
"polyvinylpyrrolidone-vinyl acetate copolymer" or "copolymer of polyvinylpyrrolidone and vinyl acetate" or "copolymer of vinylpyrrolidone and vinyl acetate" all refer to a class of copolymers of vinylpyrrolidone and vinyl acetate having different wt% ratios of vinylpyrrolidone to vinyl acetate, for example from about 30: 70 to about 70: 30, including 30: 70, 35: 65, 50: 50, 60: 40 and 70: 30. The wt% ratio of vinyl pyrrolidone to vinyl acetate can determine different properties of the copolymer, including the glass transition temperature. Polyvinylpyrrolidone vinyl acetate copolymers are commercially available from a variety of sources, such as BASF and ashland corporation.
"Copovidone" refers to a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of 1-vinyl-2-pyrrolidone to vinyl acetate of about 3: 2. The "copovidone" may be prepared fromVA64 is available from BASF Corporation of Frollem park, N.J..
"polyethylene oxide" or "polyoxyethylene" or "polyethylene glycol" or "PEO" means having the chemical structure H- (OCH)2CH2)n-OH. The average molecular weight of the polyethylene oxide can be from 100 daltons to about 10,000,000 daltons. In some aspects, the polyethylene oxide has an average molecular weight of about 1,000 daltons to about 2,000,000 daltons. In some aspects of the compositions, granules, and beads described herein, two or more polyoxyethylene compounds having different average molecular weights may be used. Polyethylene oxides are available from, for example, Dow Chemical.
"surfactant" refers to a wetting agent that reduces the surface or interfacial tension between two liquids. The surfactant may be anionic, cationic, nonionic or zwitterionic.
By "anionic surfactant" is meant a surfactant having a negatively charged head group moiety (e.g., a carboxylate group, a sulfate group, a sulfonate group, a phosphate group, or a combination of two or more thereof). In some aspects, the anionic surfactant comprises an alkyl sulfate, an acyl sulfate, a bile acid salt, and a fatty acid. In some aspects, the anionic surfactant comprises sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, sodium myristyl polyether sulfate, sodium stearate, diisooctyl succinate sulfonic acidSodium, and the like. In some aspects, the anionic surfactant comprises cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, oleic acid, and the like. In some aspects, the anionic surfactant comprises an aliphatic sulfonate, a primary alkane (e.g., C)5-C25) Sulfonates, primary alkanes (e.g. C)5-C25) Disulfonate, (C)5-C25) Olefin sulfonates, C5-C25Hydroxyalkane sulfonates, alkyl glyceryl ether sulfonates, aromatic sulfonates (e.g. alkylbenzene sulfonates), C10-C20Sodium olefin sulfonates (e.g. C)14-C16Sodium olefin sulfonates); phosphonic acids (e.g., octylphosphonic acid, laurylphosphonic acid, salts of octylphosphonic acid, salts of laurylphosphonic acid), and the like.
By "cationic surfactant" is meant a surfactant having a positively charged head group moiety. Exemplary cationic surfactants include cetylpyridinium chloride and cetyltrimethylammonium bromide.
"nonionic surfactant" refers to a surfactant having covalently bonded oxygen-containing hydrophilic groups. Exemplary nonionic surfactants include long chain alcohols; fatty acid esters (e.g., monolaurate, monooleate, monopalmitate, monostearate); sorbitan (e.g., polyoxyethylene (20) sorbitan monooleate, monostearate, monolaurate); ethoxylated fatty acids (e.g., polyoxyethylene (40) stearate, ethoxylated lauric acid); ethoxylated alcohols (e.g., polyoxyethylene lauryl ether); ethoxylated alkylphenols (e.g., nonylphenoxypoly (ethoxy) ethanol); and polyglycolyzed glycerides.
"zwitterionic surfactant" refers to a surfactant having both a cationic portion and an anionic portion. Typically, zwitterionic surfactants have cationic moieties based on primary, secondary, tertiary or quaternary ammonium cations. The anionic moiety may include a phosphate anion with an amine or ammonium (e.g., phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, sphingomyelin, etc.).
By "capsule" is meant a shell that encapsulates the composition. The shell can be a hard or soft shell and typically comprises gelatin, a polymer (such as a hydroxyalkyl cellulose, an alkyl cellulose, a carboxyalkyl cellulose, or a combination of two or more thereof), or a combination thereof. In some aspects, the capsule shell comprises a hydroxyalkyl cellulose. In some aspects, the capsule shell comprises hydroxypropyl methylcellulose. In some aspects, the capsule shell comprises an enteric polymer.
"outer layer" means a layer that completely surrounds the composition, tablet, capsule, bead or granule. In some aspects, the outer layer is a polymer, such as a hydroxyalkyl cellulose, an alkyl cellulose, a carboxyalkyl cellulose, a polyvinyl alcohol, or a combination of two or more thereof. In some aspects, the outer layer is a protective coating or an aesthetic coating. In some aspects, the outer layer is an enteric coating. In some aspects, the outer layer is a protective coating, an aesthetic coating, an enteric coating, or a combination of two or more thereof.
By "enteric coating" is meant a coating containing one or more substances that dissolve or disintegrate in the small intestine but not in the stomach or stomach environment. Exemplary enteric coating materials comprise enteric polymers.
By "enteric polymer" is meant a polymer that dissolves or disintegrates at a pH of about 5 to about 7.4 but does not dissolve or disintegrate at a pH of about 1 to about 4.5. An exemplary enteric polymer comprises: polymeric gelatins, shellac, methacrylic acid copolymers, cellulose phthalate butyrate, cellulose hydrogen phthalate, cellulose phthalate propionate, polyacetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, and acrylic acid polymers and copolymers, typically formed from copolymers of methyl acrylate, ethyl acrylate, methyl methacrylate, and/or ethyl methacrylate with acrylic acid esters and methacrylic acid esters (e.g., manufactured by Evonik Roehm GMBH)
By "inert core" is meant a pharmacologically inactive particle of any shape. The inert core may be soluble, insoluble, or a combination thereof. In some aspects, the inert core is spherical. In some aspects, the inert core comprises sugar, microcrystalline cellulose, carnauba wax, mannitol, or a combination of two or more thereof. The inert core has a particle size greater than 25 microns; or from about 50 microns to about 3 mm; or from about 1mm to about 2.5 mm. Inert cores are commercially available, for example from Pharmatrans Sanaq, Switzerland (Pharmatrans Sanaq AG). When used in reference to beads, the "inert core" is surrounded by a "drug layer" which is a layer of any thickness including the adenosine A2A receptor antagonist described herein and a pharmaceutically acceptable excipient. The drug layer may be a single layer or multiple layers.
"therapeutically effective amount" or "effective amount" refers to an amount sufficient to treat or prevent a disease or condition (e.g., to achieve the effect of administration, treat a disease, reduce enzyme activity, increase enzyme activity, reduce protein function, reduce one or more symptoms of a disease or condition). In some aspects, a therapeutically effective amount is an amount sufficient to treat cancer. The exact amount will depend on the purpose of the treatment, whether the adenosine A2A receptor antagonist is used as the sole therapeutic agent for the treatment of cancer, or whether it is used in combination with other chemotherapeutic or immunomodulatory compounds. If the adenosine A2A receptor antagonist is used as a sole therapeutic agent or in combination therapy, the dosage may vary, and those skilled in the art will appreciate that the amount of adenosine A2A receptor antagonist may be adjusted higher or lower depending on the patient, other chemotherapeutic or immunomodulatory compounds used, and the type of cancer being treated.
By "patient" or "subject" is meant a mammal suffering from or susceptible to a disease (e.g., cancer) that can be treated by administration of a compound or pharmaceutical composition or by methods provided herein. Non-limiting examples of patients include humans, cows, rats, mice, dogs, cats, monkeys, goats, sheep, and the like. In some aspects, the patient is a human. In some aspects, the patient is a dog or cat. In some aspects, the patient is an adult. In some aspects, the patient is a child of a human.
"month" refers to a period of about 28 days to about 31 days. In some aspects, one month is 28 days. In some aspects, one month is 29 days. In some aspects, one month is 30 days. In some aspects, one month is 31 days.
The term "rapidly disintegrating" refers to a pharmaceutical composition described herein (e.g., oral formulation, granules, beads, tablets, capsules) that is capable of disintegrating in a relatively short period of time. Disintegration is measured by the disintegration test in United States Pharmacopeia (USP) < 701. Briefly, the composition was placed in 1000mL of deionized water in a basket-rack assembly at about 37 ℃ at a rate of 30 cycles/minute. In some aspects, the shorter period of time is about 30 minutes or less.
The term "rapid dissolution" refers to a pharmaceutical composition (e.g., oral formulation, granules, beads, tablets, capsules) described herein that provides dissolution of the adenosine A2A receptor antagonist from the pharmaceutical composition over a shorter period of time. Dissolution was measured by the dissolution test in Chapter < 701 in United States Pharmacopeia (USP). Briefly, the composition was placed in 900mL of 0.1N HCl dissolution medium at about 37 ℃ in
"Total impurities" in the common drug nomenclature refers to the sum of all measured impurities and degradation products in the drug, also referred to as total related species. The total impurities were obtained from the HPLC method indicating stability by integrating all peaks except solvent or peaks associated with excipients. A gradient method was used with 0.1% (V/V) aqueous methanesulfonic acid as the first mobile phase and acetonitrile as the second mobile phase. A C18 column was used, with a UV detection of 225 nm. The sample was diluted with an acetonitrile-water mixture.
The term "bioequivalent" or "bioequivalent formulation" or "bioequivalent product" is a formulation that is pharmaceutically equivalent to the drug listed with reference thereto (e.g., pharmaceutical composition No. 5; pharmaceutical composition No. 6), i.e., having the same active ingredient, dosage form, strength, and route of administration under the same conditions of use. The bioequivalent formulations did not differ significantly in the rate and extent of absorption of the active pharmaceutical ingredient; also, since there is no significant difference in the rate and extent of absorption of the active pharmaceutical ingredient, it is therapeutically equivalent, i.e., it can replace the drug of reference to the market, and the bioequivalent product is expected to have the same safety and efficacy as the drug listed in its reference (e.g., pharmaceutical composition No. 5; pharmaceutical composition No. 6).
The term "disease" or "condition" refers to a state or health condition of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein. In some aspects, the disease is a cancer, such as lung cancer (e.g., non-small cell lung cancer), melanoma (e.g., malignant melanoma), renal cell carcinoma, breast cancer (e.g., triple negative breast cancer), colorectal cancer (e.g., microsatellite unstable colorectal cancer), bladder cancer, prostate cancer (e.g., metastatic castration-resistant prostate cancer, castration-resistant prostate cancer), or head and neck cancer. In some aspects, the disease is a metastatic cancer.
"QD" refers to the administration of the compounds and compositions described herein once per day.
"BID" refers to the administration of the compounds and compositions described herein (BID) twice daily. In some aspects, the twice daily administration is after the patient wakes and before going to bed. In some aspects, the administration is about 8 hours apart to about 16 hours apart twice daily. In some aspects, the administration is about 9 hours apart to about 15 hours apart twice daily. In some aspects, the administration is about 10 hours apart to about 14 hours apart twice daily. In some aspects, the twice daily administration is about 11 hours apart to about 13 hours apart. In some aspects, the administration is twice daily about 12 hours apart.
"cancer" refers to all types of cancer, tumors or malignancies found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include: lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistance, herceptin resistance, HER2 positive, doxorubicin resistance, tamoxifen resistance, ductal cancer, lobular cancer, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck or esophagus), Colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma. Additional examples include thyroid cancer, cancer of the endocrine system, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, Non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer or medulloblastoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, cancer, malignant islet cell tumor, malignant carcinoid cancer, bladder cancer, precancerous skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, liver cancer, kidney cancer, lung cancer, Non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, glioblastoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, endocrine or exocrine pancreatic tumors, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's Disease of the Nipple Disease, phyllodes tumor, lobular carcinoma, ductal carcinoma, stellate pancreatic carcinoma, hepatic stellate cell carcinoma, or prostate cancer.
As used herein, the terms "metastasis," "metastatic tumor," and "metastatic cancer" are used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., cancer) from one organ or another non-adjacent organ or body part. Cancer occurs at a starting site (e.g., breast), which is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells at the primary tumor or initiation site acquire the ability to penetrate and infiltrate normal tissue surrounding the local area and/or penetrate the lymphatic or vascular system walls that circulate through the system to other sites and tissues in the body. The second clinically detectable tumor formed by the cancer cells of the primary tumor is called a metastatic or secondary tumor.
The "adenosine A2A receptor" or "A2A receptor" refers to and encompasses any recombinant or native form of the adenosine A2A receptor (also known as ADORA2A or an isoform or variant or homolog thereof) that retains adenosine A2A receptor activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the activity range as compared to the adenosine A2A receptor). In some aspects, an isoform, variant, or homologue has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 contiguous amino acid portions) as compared to the naturally occurring adenosine A2A receptor. In some aspects, the adenosine A2A receptor is substantially identical to the protein identified by UniProt reference P29274, or an isoform, variant, or homolog that has substantial identity to the protein. In some aspects, the adenosine A2A receptor is substantially identical to a protein recognized by UniProt reference Q60613 or an isoform, variant, or homolog that has substantial identity to the protein.
An "adenosine A2A receptor antagonist" is a compound that inhibits the adenosine A2A receptor, for example, by binding, partially or completely blocking, reducing, preventing, delaying, inactivating, desensitizing, or down-regulating the activity of the adenosine A2A receptor. "inhibit/inhibiting" or the like with respect to adenosine A2A receptor interaction means negatively affecting (e.g., decreasing) the activity or functional production of the protein (e.g., decreasing the activity of the A2A receptor) relative to the activity or function of the protein in the absence of an inhibitor (e.g., an A2A receptor antagonist). In some aspects, inhibition refers to a reduction in a disease or disease symptom (e.g., cancer). Thus, inhibiting comprises at least partially or fully blocking the stimulation of, reducing, preventing or delaying activation of, or inactivating, desensitizing or down-regulating the signal transduction or enzymatic activity of the adenosine A2A receptor. In some aspects, the adenosine A2A receptor antagonist is a pharmaceutically acceptable salt of an adenosine A2A receptor antagonist.
In an embodiment, the adenosine A2A receptor antagonist is a compound of formula (I):
in formula (I): r1Independently hydrogen, halogen, -CXa 3、-CN、-SO2Cl、-SOn1R9、-SOv1NR9R10、-NHNH2、-ONR9R10、-NHC＝(O)NHNH2、-NHC＝(O)NR9R10、-N(O)m1、-NR9R10、-NH-O-R9、-C(O)R9、-C(O)-OR9、-C(O)NR9R10、-OR9A substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
In formula (I): r2Independently hydrogen, halogen, -CXb 3、-CN、-SO2Cl、-SOn2R11、-SOv2NR11R12、-NHNH2、-ONR11R12、-NHC＝(O)NHNH2、-NHC＝(O)NR11R12、-N(O)m2、-NR11R12、-NH-O-R11、-C(O)R11、-C(O)-OR11、-C(O)NR11R12、-OR11A substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
In formula (I): r3Independently hydrogen, halogen, -CXc 3、-CN、-SO2Cl、-SOn3R13、-SOv3NR13R14、-NHNH2、-ONR13R14、-NHC＝(O)NHNH2、-NHC＝(O)NR13R14、-N(O)m3、-NR13R14、-NH-O-R13、-C(O)R13、-C(O)-OR13、-C(O)NR13R14、-OR13A substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
In formula (I): r9、R10、R11、R12、R13And R14Independently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2A substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In some aspects, R9、R10、R11、R12、R13And R14Independently is hydrogen, substituted orUnsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
In formula (I): xa、XbAnd XcIndependently F, Cl, Br or-I.
In formula (I): symbol n1、n2And n3Independently an integer from 0 to 4. In some aspects, n1Is 0. In some aspects, n1Is 1. In some aspects, n1Is 3. In some aspects, n1Is 4. In some aspects, n2Is 0. In some aspects, n2Is 1. In some aspects, n2Is 3. In some aspects, n2Is 4. In some aspects, n3Is 0. In some aspects, n3Is 1. In some aspects, n3Is 3. In some aspects, n3Is 4.
In formula (I): symbol m1、m2And m3Independently an integer from 1 to 2. In some aspects, m1Is 0. In some aspects, m1Is 1. In some aspects, m1Is 2. In some aspects, m2Is 0. In some aspects, m2Is 1. In some aspects, m2Is 2. In some aspects, m3Is 0. In some aspects, m3Is 1. In some aspects, m2Is 2.
In formula (I): symbol v1、v2And v3Independently an integer from 1 to 2. In some aspects, v1Is 0. In some aspects, v1Is 1. In some aspects, v1Is 2. In some aspects, v2Is 0. In some aspects, v2Is 1. In some aspects, v2Is 2. In some aspects, v3Is 0. In some aspects, v3Is 1. In some aspects, v3Is 2.
In embodiments, R1 is independently hydrogen, halogen, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R1ASubstituted or unsubstituted alkyl, R1ASubstituted or unsubstituted heteroalkyl, R1ASubstituted or unsubstituted cycloalkyl, R1ASubstituted or unsubstituted heterocycloalkyl, R1ASubstituted or unsubstituted aryl, or R1ASubstituted or unsubstituted heteroaryl. R1May be R1ASubstituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R1ASubstituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R1ASubstituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R1ASubstituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R1ASubstituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R1ASubstituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R1AIndependently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R1BSubstituted or unsubstituted alkyl, R1BSubstituted or unsubstituted heteroalkyl, R1BSubstituted or unsubstituted cycloalkyl, R1BSubstituted or unsubstituted heterocycloalkyl, R1BSubstituted or unsubstituted aryl or R1BSubstituted or unsubstituted heteroaryl. R1AMay be R1BSubstituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R1BSubstituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R1BSubstituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R1BSubstituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R1BSubstituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R1BSubstituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R1BIndependently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R1CSubstituted or unsubstituted alkyl, R1CSubstituted or unsubstituted heteroalkyl, R1CSubstituted or unsubstituted cycloalkyl, R1CSubstituted or unsubstituted heterocycloalkyl, R1CSubstituted or unsubstituted aryl, or R1CSubstituted or unsubstituted heteroaryl. R1BMay be R1CSubstituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R1CSubstituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R1CSubstituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R1CSubstituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R1CSubstituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R1CSubstituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R1CIndependently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R1CMay independently be unsubstituted (e.g., C)1-C20Or C1-C6) Alkyl, unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, unsubstituted (e.g., C)3-C8Or C5-C7) Cycloalkyl, unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, unsubstituted (e.g., C)5-C10Or C5-C6) Aryl or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R1Independently is R1ASubstituted or unsubstituted alkyl, R1ASubstituted or unsubstituted heteroalkyl, R1ASubstituted or unsubstituted cycloalkyl, R1ASubstituted or unsubstituted heterocycloalkyl, R1ASubstituted or unsubstituted aryl, or R1ASubstituted or unsubstituted heteroaryl. In some aspects, R1Is R1ASubstituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl. In some aspects, R1Is unsubstituted 5-to 6-membered heteroaryl. In some aspects, R1Is R1ASubstituted 5-to 6-membered heteroaryl. In some aspects, R1Is an unsubstituted 5 membered heteroaryl. In some aspects, R1Is R1AA substituted 5-membered heteroaryl. In some aspects, R1Is R1AA substituted furyl group.
In the examples, R1AIs R1BSubstituted or unsubstituted (e.g. C)1-C20Or C1-C6) An alkyl group. In some aspects, R1AIs R1BSubstituted C1-C6An alkyl group. In some aspects, R1AIs unsubstituted C1-C6An alkyl group. In some aspects, R1AIs R1BSubstituted C1-C4An alkyl group. In some aspects, R1AIs unsubstituted C1-C4An alkyl group. In some aspects, R1AIs R1BSubstituted C1-C3An alkyl group.In some aspects, R1AIs unsubstituted C1-C3An alkyl group. In some aspects, R1AIs methyl.
In the examples, R2Independently hydrogen, halogen, -CXb 3、-CN、-SO2Cl、-SOn2R11、-SOv2NR11R12、-NHNH2、-ONR11R12、-NHC＝(O)NHNH2、-NHC＝(O)NR11R12、-N(O)m2、-NR11R12、-NH-O-R11、-C(O)R11、-C(O)-OR11、-C(O)NR11R12OR-OR11. In some aspects of the methods provided herein, R2Independently hydrogen, halogen, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some aspects, R2is-NR11R12. In some aspects, R11And R12Independently hydrogen or substituted or unsubstituted (e.g., C)1-C20Or C1-C6) An alkyl group. In some aspects, R11And R12Independently is substituted or unsubstituted C1-C6An alkyl group. In some aspects, R11And R12Independently is substituted or unsubstituted C1-C4An alkyl group. In some aspects, R11And R12Independently is substituted or unsubstituted C1-C3An alkyl group. In some aspects, R11And R12Independently is unsubstituted C1-C6An alkyl group. In some aspects, R11And R12Independently is substituted or unsubstituted C1-C4An alkyl group. In some aspects, R11And R12Independently is unsubstituted C1-C3An alkyl group. In some aspects, R11And R12Independently hydrogen.
In the examples, R3Independently hydrogen, halogen, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R4Substituted or unsubstituted alkyl, R4Substituted or unsubstituted heteroalkyl, R4Substituted or unsubstituted cycloalkyl, R4Substituted or unsubstituted heterocycloalkyl, R4Substituted or unsubstituted aryl, or R4Substituted or unsubstituted heteroaryl. R3May be R4Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R4Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R4Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R4Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R4Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R4Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R4Independently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R5Substituted or unsubstituted alkyl, R5Substituted or unsubstituted heteroalkyl, R5Substituted or unsubstituted cycloalkyl, R5Substituted or unsubstituted heterocycloalkyl, R5Substituted or unsubstituted aryl, or R5Substituted or unsubstitutedA heteroaryl group. R4May be R5Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R5Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R5Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R5Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R5Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R5Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R5Independently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R6Substituted or unsubstituted alkyl, R6Substituted or unsubstituted heteroalkyl, R6Substituted or unsubstituted cycloalkyl, R6Substituted or unsubstituted heterocycloalkyl, R6Substituted or unsubstituted aryl, or R6Substituted or unsubstituted heteroaryl. R5May be R6Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R6Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R6Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R6Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R6Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R6Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R6Independently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R7Substituted or unsubstituted alkyl, R7Substituted or unsubstituted heteroalkyl, R7Substituted or unsubstituted cycloalkyl, R7Substituted or unsubstituted heterocycloalkyl, R7Substituted or unsubstituted aryl, or R7Substituted or unsubstituted heteroaryl. R6May be R7Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R7Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R7Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R7Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R7Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R7Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In the examples, R3Independently of one another is hydrogen, halogen, R4Substituted or unsubstituted alkyl, R4Substituted or unsubstituted heteroalkyl, R4Substituted or unsubstituted cycloalkyl, R4Substituted or unsubstituted heterocycloalkyl, R4Substituted or unsubstituted aryl, or R4Substituted or unsubstituted heteroaryl. In some aspects, R3Independently is R4Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) An alkyl group. In some aspects, R3Independently is R4Substituted or unsubstituted C1-C6An alkyl group. In some aspects, R3Independently is R4Substituted or unsubstituted C1-C5An alkyl group. In some aspects, R3Independently R4 substituted or unsubstituted C1-C4An alkyl group. In some aspects, R3Independently is a R4 substitutionOr unsubstituted C1-C3An alkyl group. In some aspects, R3Independently is unsubstituted C1-C6An alkyl group. In some aspects, R3Independently is unsubstituted C1-C5An alkyl group. In some aspects, R3Independently is R4Unsubstituted C1-C4An alkyl group. In some aspects, R3Independently is unsubstituted C1-C3An alkyl group. In some aspects, R3Independently is R4Substituted C1-C6An alkyl group. In some aspects, R3Independently is R4Substituted C1-C5An alkyl group. In some aspects, R3Independently is R4Substituted C1-C4An alkyl group. In some aspects, R3Independently is R4Substituted C1-C3An alkyl group. In some aspects, R3Independently is R4Substituted C1An alkyl group.
In the examples, R4May be R5Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R5Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R5Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R5Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R5Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R5Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl. In some aspects, R4Is R5A substituted or unsubstituted 5-to 6-membered heteroaryl. In some aspects, R4Is R5A substituted or unsubstituted 6 membered heteroaryl. In some aspects, R4Is an unsubstituted 6 membered heteroaryl. In some aspects, R4Is R5Substituted 6-membered heteroaryl. In some aspects, R4Is R5A substituted pyridyl group.
In the examples, R5May be R6Substituted or unsubstituted(e.g., C)1-C20Or C1-C6) Alkyl radical, R6Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R6Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R6Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R6Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R6Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl. In some aspects, R5Is R6Substituted or unsubstituted 2-to 6-membered heteroalkyl. In some aspects, R5Is R6Substituted or unsubstituted 2-to 5-membered heteroalkyl. In some aspects, R5Is R6Substituted or unsubstituted 2-to 4-membered heteroalkyl. In some aspects, R5Is R6Substituted or unsubstituted 2-to 3-membered heteroalkyl. In some aspects, R5Is R6Substituted or unsubstituted 2-membered heteroalkyl. In some aspects, R5Is unsubstituted 2-to 6-membered heteroalkyl. In some aspects, R5Is unsubstituted 2-to 5-membered heteroalkyl. In some aspects, R5Is unsubstituted 2-to 4-membered heteroalkyl. In some aspects, R5Is unsubstituted 2-to 3-membered heteroalkyl. In some aspects, R5Is unsubstituted 2 membered heteroalkyl. In some aspects, R5Is R6Substituted 2-to 6-membered heteroalkyl. In some aspects, R5Is R6Substituted 2-to 5-membered heteroalkyl. In some aspects, R5Is R6Substituted 2-to 4-membered heteroalkyl. In some aspects, R5Is R6Substituted 2-to 3-membered heteroalkyl. In some aspects, R5Is R6Substituted 2-membered heteroalkyl.
In the examples, R6May be R7Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R7Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R7Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R7Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R7Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R7Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl. In some aspects, R6Is R7A substituted or unsubstituted 3-to 6-membered heterocycloalkyl. In some aspects, R6Is R7Substituted or unsubstituted 5-membered heterocycloalkyl. In some aspects, R6Is R7Substituted 5-membered heterocycloalkyl. In some aspects, R6Is unsubstituted 5-membered heterocycloalkyl. In some aspects, R6Is unsubstituted tetrahydrofuranyl.
In the examples, R9、R10、R11、R12、R13And R14Independently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
In the examples, R1Is R1AA substituted furyl group. In some aspects, R1AIs methyl. In some aspects, R2is-NR11R12. In some aspects, R11And R12Independently hydrogen. In some aspects, R3Independently is R4Substituted C1An alkyl group. In some aspects, R4Is R5A substituted pyridyl group. In some aspects, R5Is R6Substituted 2-membered heteroalkyl. In some aspects, R6Is unsubstituted tetrahydrofuranyl.
In an embodiment, the adenosine A2A receptor antagonist is a compound of formula (II):
in formula (II): r6、R6.1And R6.2Independently hydrogen, halogen, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2A substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In some aspects, R6、R6.1And R6.2Independently is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some aspects, R6.1And R6.2Is hydrogen, and R6Is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some aspects, R6.1And R6.2Is hydrogen, and R6Is a substituted or unsubstituted heterocycloalkyl. In some aspects, R6.1And R6.2Is hydrogen, and R6Is unsubstituted heterocycloalkyl. In some aspects, R1Is substituted (e.g. by unsubstituted C)1-C5Alkyl substituted) or unsubstituted heteroaryl. In some aspects, R1Is substituted (e.g. by unsubstituted C)1-C5Alkyl substituted) or unsubstituted furyl. In some aspects, R1Is a methyl substituted furyl group.
In formula (II): r1And R6As described above (e.g., R)6May be R7Substituted or unsubstituted 3-to 6-membered heterocycloalkylAnd R is1May be R1ASubstituted 5-to 6-membered heteroaryl). In some aspects, R6Is unsubstituted tetrahydrofuranyl, and R1Is R1AA substituted furyl group.
In formula (II): r6.1May independently be hydrogen, halogen, ═ O, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R7.1Substituted or unsubstituted alkyl, R7.1Substituted or unsubstituted heteroalkyl, R7.1Substituted or unsubstituted cycloalkyl, R7.1Substituted or unsubstituted heterocycloalkyl, R7.1Substituted or unsubstituted aryl, or R7.1Substituted or unsubstituted heteroaryl. R6.1May be R7.1Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R7.1Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R7.1Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R7.1Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R7.1Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R7.1Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl. In some aspects, R6.1Is R7.1Substituted or unsubstituted C1-C6An alkyl group. In some aspects, R6.1Is R7.1Substituted or unsubstituted C1-C5An alkyl group. In some aspects, R6.1Is R7.1Substituted or unsubstituted C1-C4An alkyl group. In some aspects, R6.1Is R7.1Substituted or unsubstituted C1-C3An alkyl group. In some aspects, R6.1Independently is R7.1Substituted C1-C6An alkyl group.In some aspects, R6.1Is R7.1Substituted C1-C5An alkyl group. In some aspects, R6.1Is R7.1Substituted C1-C4An alkyl group. In some aspects, R6.1Is R7.1Substituted C1-C3An alkyl group. In some aspects, R6.1Is unsubstituted C1-C6An alkyl group. In some aspects, R6.1Is unsubstituted C1-C5An alkyl group. In some aspects, R6.1Is unsubstituted C1-C4An alkyl group. In some aspects, R6.1Is unsubstituted C1-C3An alkyl group. In some aspects, R6.1Is unsubstituted methyl.
In formula (II): r6.2Independently hydrogen, halogen, ═ O, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、R7.2Substituted or unsubstituted alkyl, R7.2Substituted or unsubstituted heteroalkyl, R7.2Substituted or unsubstituted cycloalkyl, R7.2Substituted or unsubstituted heterocycloalkyl, R7.2Substituted or unsubstituted aryl, or R7.2Substituted or unsubstituted heteroaryl. R6.2May be R7.2Substituted or unsubstituted (e.g. C)1-C20Or C1-C6) Alkyl radical, R7.2Substituted or unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, R7.2Substituted or unsubstituted (e.g. C)3-C8Or C5-C7) Cycloalkyl radical, R7.2Substituted or unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, R7.2Substituted or unsubstituted (e.g. C)5-C10Or C5-C6) Aryl or R7.2Substituted or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl. In some aspects, R6.2Is R7.2Substituted or unsubstitutedC1-C6An alkyl group. In some aspects, R6.2Is R7.2Substituted or unsubstituted C1-C5An alkyl group. In some aspects, R6.2Is R7.2Substituted or unsubstituted C1-C4An alkyl group. In some aspects, R6.2Is R7.2Substituted or unsubstituted C1-C3An alkyl group. In some aspects, R6.2Is R7.2Substituted C1-C6An alkyl group. In some aspects, R6.2Is R7.2Substituted C1-C5An alkyl group. In some aspects, R6.2Is R7.2Substituted C1-C4An alkyl group. In some aspects, R6.2Is R7.2Substituted C1-C3An alkyl group. In some aspects, R6.2Is unsubstituted C1-C6An alkyl group. In some aspects, R6.2Is unsubstituted C1-C5An alkyl group. In some aspects, R6.2Is unsubstituted C1-C4An alkyl group. In some aspects, R6.2Is unsubstituted C1-C3An alkyl group. In some aspects, R6.2Is unsubstituted methyl.
In formula (II): r7、R7.1And R7.2Independently hydrogen, halogen, ═ O, ═ S, -CF3、-CN、-CCl3、-COOH、-CH2COOH、-CONH2、-OH、-SH、-SO2Cl、-SO3H、-SO4H、-SO2NH2、-NO2、-NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R7、R7.1And R7.2May independently be unsubstituted (e.g., C)1-C20Or C1-C6) Alkyl, unsubstituted (e.g., 2-to 20-or 2-to 6-membered) heteroalkyl, unsubstituted (e.g., C)3-C8Or C5-C7) Cycloalkyl, unsubstituted (e.g., 3-to 8-or 3-to 6-membered) heterocycloalkyl, unsubstitutedGeneration (e.g., C)5-C10Or C5-C6) Aryl or unsubstituted (e.g., 5-to 10-or 5-to 6-membered) heteroaryl.
In embodiments, the A2A receptor antagonist is a compound of formula (III):
the "compound of formula (III)" may also be referred to herein as "formula (III)" or CPI-444. In some aspects, the compound of formula (III) is a compound of formula (IIIA). In some aspects, the compound of formula (III) is a compound of formula (IIIB). In some aspects, the compound of formula (III) is a mixture of compounds of formula (IIIA) and (IIIB). In some aspects, the compound of formula (III) is a racemic mixture of the compounds of formula (IIIA) and formula (IIIB).
In embodiments, the compound of formula (III) is a compound of formula (IIIA):
in embodiments, the compound of formula (III) is a compound of formula (IIIB):
methods for preparing adenosine A2A receptor antagonists, including adenosine A2A receptor antagonists of formula (I), formula (II), formula (III), formula (IIIA), and formula (IIIB), are known in the art and are described, for example, in WO 2017/112917, U.S. patent No. 8,450,328, U.S. patent No. 8,987,279, U.S. patent No. 9,376,443, and U.S. patent No. 9,765,080, the disclosures of which are incorporated herein by reference in their entirety.
The abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and chemical formulas set forth herein are according to standard chemical valency rules known in the chemical artsIt is constructed. When substituents are illustrated by conventional formulas written from left to right, the substituents are intended to equally encompass chemically identical substituents resulting from writing the structure from right to left, e.g., -CH2O-is equivalent to-OCH2-。
"alkyl" by itself or as part of another substituent means a straight (i.e., unbranched) or branched acyclic carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may contain divalent and polyvalent radicals (i.e., C) having the indicated number of carbon atoms1-C10Meaning one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, (cyclohexyl) methyl, and the like; such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl is a group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy group is an alkyl group attached to the rest of the molecule through an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. In addition to one or more double bonds, an alkenyl group may contain more than one double bond and/or one or more triple bonds. In addition to one or more triple bonds, an alkynyl group may contain more than one triple bond and/or one or more double bonds.
"alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkyl group, such as, but not limited to, CH2CH2CH2CH2-. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, preferably these groups have 10 or fewer carbon atoms, and more preferably "lower alkyl" or "lower alkylene" having 6 or fewer carbon atoms or 4 or fewer carbon atoms is a short chain alkyl or alkylene, usually eight or moreA few carbon atoms. Unless otherwise indicated, the term "alkenylene" by itself or as part of another substituent refers to a divalent radical derived from an alkene.
"heteroalkyl," by itself or in combination with another term, refers to a stable straight or branched non-cyclic chain, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si and S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteroatoms (e.g., O, N, P, S and Si) can be placed at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-Si(CH3)3、-CH2-CH＝N-OCH3、-CH＝CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3and-CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and-CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise two optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise three optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise four optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise five optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may contain up to 8 optionally different heteroatoms (e.g., O, N, S, Si or P). Unless otherwise specified, the term "heteroalkenyl" by itself or in combination with another term denotes a heteroalkyl group containing at least one double bond. The heteroalkenyl group may optionally contain, in addition to one or more double bondsMore than one double bond and/or one or more triple bonds. Unless otherwise indicated, the term "heteroalkylalkynyl" by itself or in combination with another term means a heteroalkyl group containing at least one triple bond. In addition to one or more triple bonds, a heteroalkynyl group can optionally contain more than one triple bond and/or one or more double bonds.
By "heteroalkylene" alone or as part of another substituent is meant derived from a heteroalkyl group (such as, but not limited to, -CH)2-CH2-S-CH2-CH2-and-CH2-S-CH2-CH2-NH-CH2-) of a divalent radical. For heteroalkylene groups, heteroatoms can also occupy one or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Furthermore, for alkylene and heteroalkylene linking groups, the written direction of the structural formula of the linking group does not imply orientation of the linking group. For example, of the formula-C (O)2R' represents-C (O)2R 'and-R' C (O)2-both. As noted above, heteroalkyl groups, as used herein, include those groups attached to the remainder of the molecule through a heteroatom, such as-C (O) R ', -C (O) NR', -NR 'R', -OR ', -SR', and/OR-SO2R' is provided. When a particular heteroalkyl group (e.g., "-NR 'R'", etc.) is recited after the recitation of "heteroalkyl," it is to be understood that the terms "heteroalkyl" and "-NR 'R'" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are recited for added clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude a particular heteroalkyl, such as — NR' R ", and the like.
"cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms mean the non-aromatic cyclic forms of "alkyl" and "heteroalkyl," respectively, wherein the carbons making up one or more rings do not necessarily need to be bonded to hydrogen, as all carbon valences participate in bonding with non-hydrogen atoms. Further, for heterocycloalkyl, a heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobut-3-enyl-1, 2, diketones, 1H-1, 2, 4-triazolyl-5 (4H) -one, 4H-1, 2, 4-triazolyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1, 2, 5, 6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent refer to divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively. The heterocycloalkyl moiety may contain one ring heteroatom (e.g., O, N, S, Si or P). The heterocycloalkyl moiety may comprise two optionally different ring heteroatoms (e.g., O, N, S, Si or P). The heterocycloalkyl moiety can comprise three optionally different ring heteroatoms (e.g., O, N, S, Si or P). The heterocycloalkyl moiety can contain four optionally different ring heteroatoms (e.g., O, N, S, Si or P). The heterocycloalkyl moiety can contain five optionally different heteroatoms (e.g., O, N, S, Si or P). The heterocycloalkyl moiety may contain up to 8 optionally different heteroatoms (e.g., O, N, S, Si or P).
"halogen" alone or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Further, the terms "haloalkyl" and the like are intended to encompass monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)1-C4) Alkyl "includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
Unless otherwise indicated, "acyl" refers to — c (o) R, wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
"aryl" means a polyunsaturated aromatic hydrocarbon substituent which can be fused together (i.e., a fused cyclic aryl) or covalently linked monocyclic or polycyclic rings (preferably 1 to 3 rings). Fused ring aryl refers to multiple rings fused together, wherein at least one fused ring is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom (e.g., N, O or S), wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one fused ring is a heteroaromatic ring). A 5, 6-fused ring heteroaryl refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a6, 6-fused ring heteroaryl refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And 6, 5-fused ring heteroaryl refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. The heteroaryl group may be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinolyl, 5-quinolyl, 3-quinolyl and 6-quinolyl. The substituents for each of the above-indicated aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. By "arylene" and "heteroarylene", alone or as part of another substituent, is meant a divalent radical derived from an aryl and heteroaryl group, respectively. Non-limiting examples of aryl and heteroaryl groups include: pyridyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzodiazepine, benzodioxazolyl, benzodioxanyl, thenoyl, pyrrolopyridyl, indazolyl, quinolinyl, quinoxalinyl, benzopyrazolyl, quinazolinyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanylthienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazo, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidyl, benzotriazolyl, benzoxazolyl or quinolinyl. The above examples may be substituted or unsubstituted, and the divalent radical of each of the above heteroaryl examples is a non-limiting example of a heteroaryl group. The heteroaryl moiety may contain one ring heteroatom (e.g., O, N or S). The heteroaryl moiety may comprise two optionally different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may comprise three optionally different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may comprise four optionally different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may comprise five optionally different ring heteroatoms (e.g., O, N or S). The aryl moiety may have a single ring. The aryl moiety may have two optionally different rings. The aryl moiety may have three optionally different rings. The aryl moiety may have four optionally different rings. The heteroaryl moiety may have a ring. The heteroaryl moiety may have two optionally different rings. The heteroaryl moiety may have three optionally different rings. The heteroaryl moiety may have four optionally different rings. The heteroaryl moiety may have five optionally different rings.
Fused-ring heterocycloalkyl-aryl is aryl fused to a heterocycloalkyl. Fused-ring heterocycloalkyl-heteroaryl is heteroaryl fused to heterocycloalkyl. Fused-ring heterocycloalkyl-cycloalkyl is heterocycloalkyl fused to cycloalkyl. Fused-ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl group fused to another heterocycloalkyl group. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more substituents described herein.
"oxo" refers to an oxygen double bonded to a carbon atom.
"alkylsulfonyl" means a compound having the formula-S (O)2) A moiety of-R ', wherein R' is a substituted or unsubstituted alkyl group as defined above. R' may have a particular number of carbons (e.g., "C1-C4Alkylsulfonyl ").
Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") encompasses both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are as follows.
The substituents of the alkyl and heteroalkyl radicals (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more of a variety of groups selected from, but not limited to: -OR ', - (O), - (NR '), - (N-OR ', - (NR ' R ',), - (SR ',), - (si ' R ' R ', - (oc) (O) R ', - (c) (O) R ', - (CO) CO2R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-NR″C(O)2R′、-NR-C(NR′R″R″′)＝NR″″、-NR-C(NR′R″)＝NR″′、-S(O)R′、-S(O)2R′、-S(O)2NR′R″、-NRSO2R′、-NR′NR″R″′、-ONR′R″、-NR′C＝(O)NR″NR″′R″″、-CN、-NO2The number is in the range of zero to (2m '+ 1), where m' is the total number of carbon atoms in such radicals. R, R ', R ' and R ' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl. When the compound comprises more than one R group, for example, each R', R is independently selected as when more than one of these groups is presentEach of the R groups is independently selected as is the group of ", R'", and R "" groups. When R 'and R' are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 4-, 5-, 6-or 7-membered ring. For example, -NR' R "includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to encompass groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF)3and-CH2CF3) And acyl (e.g., -C (O) CH)3、-C(O)CF3、-C(O)CH2OCH3Etc.).
Similar to the substituents described for the alkyl radicals, the substituents for the aryl and heteroaryl radicals vary and are selected, for example, from the following: -OR ', -NR ' R ', -SR ', -halogen, -SiR ' R ' R ', -OC (O) R ', -C (O) R ', -CO2R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-NR″C(O)2R′、-NR-C(NR′R″R″′)＝NR″″、-NR-C(NR′R″)＝NR″′、-S(O)R′、-S(O)2R′、-S(O)2NR′R″、-NRSO2R′、-NR′NR″R″′、-ONR′R″、-NR′C(O)NR″NR″′R″″、-CN、-NO2、-R′、-N3、-CH(Ph)2Fluorine (C)1-C4) Alkoxy and fluorine (C)1-C4) Alkyl in an amount ranging from zero to the total number of open valences on the aromatic ring system and wherein R ', R ", R'" and R "" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound comprises more than one R group, for example, each of the R groups is independently selected as are each R 'group, R "group, R'" group, and R "" group when more than one of these groups is present.
Two or more substituents may be optionally joined to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically (although not necessarily) attached to the cyclic base structure. In one aspect, the ring-forming substituent is attached to an adjacent member of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another aspect, the ring-forming substituent is attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spiro ring structure. In yet another aspect, the ring-forming substituent is attached to a non-adjacent member of the base structure.
Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula-T-C (O) - (CRR')q-U-, wherein T and U are independently-NR-, -O-, -CRR' -or a single bond, and q is an integer of 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted by a group of formula-A- (CH)2)r-B-wherein A and B are independently-CRR' -, -O-, -NR-, -S (O)2-、-S(O)2NR' -or a single bond, and r is an integer of 1 to 4. One of the single bonds of the new ring so formed may be optionally substituted by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted by a compound of formula- (CRR')s-X′-(C″R″R″′)d-wherein S and d are independently integers from 0 to 3, and X 'is-O-, -NR' -, -S (O)2-or-S (O)2NR' -. The substituents R ', R ", R'" and R "" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
"heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
As used herein, "substituent" refers to a group selected from the following moieties: (A) oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from the group consisting of: (i) oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the group consisting of: (a) oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH，-OCF3、-OCHF2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the group consisting of: oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.
As used herein, "size-limited substituent group" means a group selected from all substituents described above for "substituent group", wherein each substituted or unsubstituted alkyl group is substituted or unsubstituted C1-C20Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 10-membered heteroaryl.
As used herein, "lower substituent" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl group is substituted or unsubstituted C1-C8Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 9-membered heteroaryl.
In embodiments, each substituted group described in the compounds herein is substituted with at least one substituent. More specifically, in some aspects, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other aspects, at least one or all of these groups are substituted with at least one size-limited substituent. In other aspects, at least one or all of these groups are substituted with at least one lower substituent.
In embodiments of the compounds herein, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C20Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 10-membered heteroaryl. In some aspects, each substituted or unsubstituted alkylene is substituted or unsubstituted C1-C20Alkylene, each substituted or unsubstituted heteroalkylene being a substituted or unsubstituted 2-to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene being a substituted or unsubstituted C3-C8Cycloalkylene, each substituted or unsubstituted heterocycloalkylene being a substituted or unsubstituted 3-to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene being a substituted or unsubstituted C6-C10The arylene group, and/or the substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5-to 10-membered heteroarylene group.
In embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7Cycloalkyl, each substituted or unsubstituted heterocycloalkyl being a substituted or unsubstituted 3-to 7-membered heterocycloalkyl, each substituted or unsubstitutedUnsubstituted aryl is substituted or unsubstituted C6-C10Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 9-membered heteroaryl. In some aspects, each substituted or unsubstituted alkylene is substituted or unsubstituted C1-C8Alkylene, each substituted or unsubstituted heteroalkylene being a substituted or unsubstituted 2-to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene being a substituted or unsubstituted C3-C7Cycloalkylene, each substituted or unsubstituted heterocycloalkylene being a substituted or unsubstituted 3-to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene being a substituted or unsubstituted C6-C10The arylene group, and/or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5-to 9-membered heteroarylene group.
The term "pharmaceutically acceptable salts" is intended to encompass salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds described herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired base, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonium or magnesium salts or the like. When the compounds described herein contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include acid addition salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid (monohydrogencarbonic acid), phosphoric acid, monohydrogenphosphoric acid (monohydrogenphosphoric acid), dihydrogenphosphoric acid (dihydrogenphosphoric acid), sulfuric acid, monohydrogensulfuric acid (monohydrogensulfuric acid), hydroiodic acid, or phosphorous acid, and the like; as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids (e.g., arginine salts, etc.), and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds described herein contain both basic and acidic functional groups, such that the compounds can be converted to base addition salts or acid addition salts.
The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as dissolution in polar solvents.
The compounds described herein may exist in both undissociated and solvated forms, including hydrated forms. In general, the solvated forms correspond to unsolvated forms.
The compounds described herein have asymmetric carbon atoms (optical centers or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, as well as individual isomers of amino acids that may be defined as (R) -or (S) -or (D) -or (L) -are included within the scope of the present disclosure, in terms of absolute stereochemistry. The present disclosure is intended to encompass compounds in racemic and optically pure forms. Optically active (R) -and (S) -, or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless otherwise indicated, the structures described herein are also intended to encompass all stereochemical forms of the structures; i.e., the R configuration and S configuration of each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the present invention are within the scope of the disclosure. When the compounds described herein contain an olefinic bond or other geometrically asymmetric center, and unless otherwise specified, it is intended that the compounds include both the E and Z geometric isomers.
As used herein, "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It will be apparent to those skilled in the art that certain compounds may exist in tautomeric forms.
Unless otherwise indicated, structures described herein are also intended to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, other than replacement of hydrogen by deuterium or tritium, or by13C-or14In addition to the C-rich carbon instead of carbon, the compounds may have the structure of the present invention. The compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (A), (B), (C), (D3H) Iodine-125 (125I) Or carbon-14 (14C)。
The symbol "-" represents the point of attachment of a chemical moiety to the remainder of a molecule or formula.
In embodiments, a compound described herein may comprise R2And/or multiple instances of other variables. In some aspects, each variable may optionally be different, and for greater clarity, may be appropriately labeled to distinguish each group. For example, at each R2In different cases, they may be referred to as R, for example2.1、R2.2、R2.3And/or R2.4Wherein R is2Is defined by R2.1、R2.2、R2.3And/or R2.4It is assumed. For greater clarity, at R2The variables used in the definition of (a) and/or other variables that occur in multiple instances and that are different may be similarly appropriately labeled to distinguish each group. In some aspects, the compound is a compound described herein (e.g., in one aspect, embodiment, example, claim, table, scheme, figure, or figure).
The terms "a" and "an" as used herein mean one or more. Furthermore, the phrase "substituted with one" as used herein means that a particular group may be substituted with one or more of any or all of the specified substituents. For example, when alkyl orHeteroaryl and the like radicals being "unsubstituted C1-C20When an alkyl group or unsubstituted 2-to 20-membered heteroalkyl group is substituted ", the group may contain one or more unsubstituted C1-C20Alkyl and/or one or more unsubstituted 2-to 20-membered heteroalkyl.
Where a moiety is substituted with an R substituent, the group may be referred to as "R substituted". Where a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. For example, moieties herein are R12In the case of substituted or unsubstituted alkyl, a plurality of R12Substituents may be attached to the alkyl moiety, wherein each R12The substituents are optionally different. When the R-substituted moiety is substituted with multiple R substituents, each R substituent may be distinguished herein by a prime symbol ('), e.g., R', etc. For example, when a moiety is R12Substituted or unsubstituted alkyl, and the moiety is substituted with multiple R12When substituted by a substituent, the plurality of R12The substituents can be distinguished as R12′、R12″、R12"and the like. In some aspects, the plurality of R substituents is 3. In some aspects, the plurality of R substituents is 2.
In embodiments, the compounds described herein may comprise R1、R2、R3、R4、R5、R6、R7、R9、R10、R11、R12、R13、R14And/or multiple instances of other variables. In these aspects, each variable may optionally be different and, for greater clarity, may be appropriately labeled to distinguish each group. For example, at each R1、R2、R3、R4、R5、R6、R7、R9、R10、R11、R12、R13And/or R14In different cases, they may be referred to as, for example, R1.1、R1.2、R1.3、R1.4、R2.1、R2.2、R2.3、R2.4、R3.1、R3.2、R3.3、R3.4、R4.1、R4.2、R4.3、R4.4、R5.1、R5.2、R5.3、R5.4、R6.1、R6.2、R6.3、R6.4、R7.1、R7.2、R7.3、R7.4、R9.1、R9.2、R9.3、R9.4、R10.1、R10.2、R10.3、R10.4、R11.1、R11.2、R11.3、R11.4、R12.1、R12.2、R12.3、R12.4、R13.1、R13.2、R13.3、R13.4、R14.1、R14.2、R14.3And/or R14.4Wherein R is1Is defined by R1.1、R1.2、R1.3And/or R1.4It is assumed that R2 is defined by R2.1、R2.2、R2.3And/or R2.4Let R be3Is defined by R3.1、R3.2、R3.3And/or R3.4Let R be4Is defined by R4.1、R4.2、R4.3And/or R4.4Let R be5Is defined by R5.1、R5.2、R5.3And/or R5.4Let R be6Is defined by R6.1、R6.2、R6.3And/or R6.4Let R be7Is defined by R7.1、R7.2、R7.3And/or R7.4Let R be9Is defined by R9.1、R9.2、R9.3And/or R9.4Let R be10Is defined by R10.1、R10.2、R10.3And/or R10.4Let R be11Is defined by R11.1、R11.2、R11.3And/or R11.4It is assumed that R12 is defined by R12.1、R12.2、R12.3And/or R12.4It is assumed that R13 is defined by R13.1、R13.2、R13.3And/or R13.4Let R be14Is defined by R14.1、R14.2、R14.3And/or R14.4It is assumed. For greater clarity, at R1、R2、R3、R4、R5、R6、R7、R9、R10、R11、R12、R13And/or R14The variables used in the definition of (a) and/or other variables that occur in multiple instances and that are different may be similarly appropriately labeled to distinguish each group.
The description of compounds herein is limited by the chemical bonding principles known to those skilled in the art. Thus, when a group can be substituted with one or more of a number of substituents, such substitutions are selected so as to comply with the principles of chemical bonding and to yield compounds that are not inherently labile and/or that would be known to one of ordinary skill in the art to be potentially labile under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions). For example, a heterocycloalkyl or heteroaryl group is attached to the rest of the molecule through a ring heteroatom, according to chemical bond principles known to those skilled in the art, thereby avoiding intrinsically unstable compounds.
Pharmaceutical formulation
In some aspects, the present disclosure provides a pharmaceutical composition comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an A2A adenosine receptor antagonist. In some aspects, the adenosine A2A receptor antagonist is crystalline. In some aspects, the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, or a combination of two or more thereof. In some aspects, the pharmaceutically acceptable excipient further comprises a surfactant, a lubricant, a glidant, or a combination of two or more thereof.
In some aspects, the present disclosure provides a granule comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an A2A adenosine receptor antagonist. In some aspects, the adenosine A2A receptor antagonist is crystalline. In some aspects, the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, or a combination of two or more thereof. In some aspects, the pharmaceutically acceptable excipient further comprises a surfactant, a lubricant, a glidant, or a combination of two or more thereof.
In some aspects, the present disclosure provides an oral formulation comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an A2A adenosine receptor antagonist. In some aspects, the adenosine A2A receptor antagonist is crystalline. In some aspects, the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, or a combination of two or more thereof. In some aspects, the pharmaceutically acceptable excipient further comprises a surfactant, a lubricant, a glidant, or a combination of two or more thereof.
In some aspects, the present disclosure provides a tablet comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an A2A adenosine receptor antagonist. In some aspects, the adenosine A2A receptor antagonist is crystalline. In some aspects, the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, or a combination of two or more thereof. In some aspects, the pharmaceutically acceptable excipient further comprises a surfactant, a lubricant, a glidant, or a combination of two or more thereof.
In some aspects, the present disclosure provides a powder comprising micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an A2A adenosine receptor antagonist. In some aspects, the adenosine A2A receptor antagonist is crystalline. In some aspects, the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, or a combination of two or more thereof. In some aspects, the pharmaceutically acceptable excipient further comprises a surfactant, a lubricant, a glidant, or a combination of two or more thereof.
In some aspects, the present disclosure provides a bead comprising an inert core and a drug layer; wherein the drug layer comprises micronized drug particles and a pharmaceutically acceptable excipient; wherein the micronized drug particles comprise an A2A adenosine receptor antagonist. In some aspects, the adenosine A2A receptor antagonist is crystalline. In some aspects, the pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder, or a combination of two or more thereof. In some aspects, the pharmaceutically acceptable excipient further comprises a surfactant, a lubricant, a glidant, or a combination of two or more thereof. The drug layer surrounds the inert core.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the adenosine A2A receptor antagonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some aspects, the compound of formula (I) is in the form of the free base. In some aspects, the compound of formula (I) is in the form of a pharmaceutically acceptable salt. In some aspects, the compound of formula (I) is crystalline. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (II) or a pharmaceutically acceptable salt thereof. In some aspects, the compound of formula (II) is in the form of the free base. In some aspects, the compound of formula (II) is in the form of a pharmaceutically acceptable salt. In some aspects, the compound of formula (II) is crystalline. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some aspects, the compound of formula (III) is in the form of a pharmaceutically acceptable salt. In some aspects, the compound of formula (III) is in the form of the free base. In some aspects, the compound of formula (III) is crystalline. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof. In some aspects, the compound of formula (IIIA) is in the form of the free base. In some aspects, the compound of formula (IIIA) is in the form of a pharmaceutically acceptable salt. In some aspects, the compound of formula (IIIA) is crystalline. In some aspects, the adenosine A2A receptor antagonist is a compound of formula (IIIB) or a pharmaceutically acceptable salt thereof. In some aspects, the compound of formula (IIIB) is in the form of the free base. In some aspects, the compound of formula (IIIB) is in the form of a pharmaceutically acceptable salt. In some aspects, the compound of formula (IIIB) is crystalline. In some aspects, the adenosine A2A receptor antagonist is a mixture of a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof and a compound of formula (IIIB) or a pharmaceutically acceptable salt thereof. In some aspects, the adenosine A2A receptor antagonist is a racemic mixture of a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof and a compound of formula (IIIB) or a pharmaceutically acceptable salt thereof.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the adenosine A2A receptor antagonist is present in an effective amount. In some aspects, the adenosine A2A receptor antagonist is present in an amount from about 1 wt% to about 50 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount from about 1 wt% to about 40 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is from about 1 wt% to about 30 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 1 wt% to about 25 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is from about 1 wt% to about 20 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 1 wt% to about 15 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is from about 1 wt% to about 10 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 2 wt% to about 48 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 3 wt% to about 47 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 4 wt% to about 46 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount from about 5 wt% to about 45 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount from about 6 wt% to about 44 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 7 wt% to about 43 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 8 wt% to about 42 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount from about 9 wt% to about 41 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount from about 10 wt% to about 40 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 11 wt% to about 39 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 12 wt% to about 38 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 13 wt% to about 37 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 14 wt% to about 36 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 15 wt% to about 35 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 16 wt% to about 34 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 17 wt% to about 33 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 18 wt% to about 32 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 19 wt% to about 31 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 20 wt% to about 30 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 21 wt% to about 29 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 22 wt% to about 28 wt%. In some aspects, the amount of adenosine A2A receptor antagonist is about 23 wt% to about 27 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount from about 24 wt% to about 26 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 15 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 16 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 17 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 18 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 19 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 20 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 21 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 22 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 23 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 24 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 25 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 26 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 27 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 28 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 29 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 30 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 31 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 32 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 33 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 34 wt%. In some aspects, the adenosine A2A receptor antagonist is present in an amount of about 35 wt%.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the micronized drug particles have a particle size distribution with a D90 of about 50 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 45 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 40 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 35 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 30 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 29 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 28 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 27 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 26 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 25 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 24 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 23 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 22 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 21 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 20 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 19 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 18 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 17 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 16 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 15 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 14 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 13 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 12 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 11 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 10 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 9 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 8 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 7 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 6 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D90 of about 5 microns or less. The particle size distribution of the micronized drug particles described herein is measured by laser diffraction spectroscopy.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the micronized drug particles have a particle size distribution with a D50 of about 15 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 14 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 13 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 12 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 11 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 10 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 9.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 9 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 8.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 8 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 7.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 7 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 6.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 6 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 5.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 4.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 4 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 3.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 3 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 2.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D50 of about 2 microns or less. The particle size distribution of the micronized drug particles described herein is measured by laser diffraction spectroscopy.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the micronized drug particles have a particle size distribution with a D10 of about 10 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 9 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 8 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 7 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 6 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 4 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 3 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.9 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.8 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.7 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.6 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.4 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.3 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.2 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2.1 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 2 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.9 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.8 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.7 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.6 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.5 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.4 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.3 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.2 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1.1 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 1 micron or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 0.9 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 0.8 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 0.7 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 0.6 microns or less. In some aspects, the micronized drug particles have a particle size distribution with a D10 of about 0.5 microns or less. The particle size distribution of the micronized drug particles described herein is measured by laser diffraction spectroscopy.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the micronized drug particles have a D90 of less than 20 microns; d50 is less than 10 microns; and a particle size distribution of D10 less than 5 microns. In some aspects, the micronized drug particles have a D90 of less than 20 microns; d50 is less than 6 microns; and a particle size distribution of D10 less than 2 microns. In some aspects, the micronized drug particles have a D90 of less than 15 microns; d50 is less than 8 microns; and a particle size distribution of D10 less than 3 microns. In some aspects, the micronized drug particles have a D90 of less than 12 microns; d50 is less than 5 microns; and a particle size distribution of D10 less than 1.5 microns. In some aspects, the micronized drug particles have a D90 of less than 11 microns; d50 is less than 4.5 microns; and a particle size distribution of D10 less than 1.2 microns. In some aspects, the micronized drug particles have a D90 of less than 10 microns; d50 is less than 4 microns; and a particle size distribution of D10 less than 1.1 microns. In some aspects, the micronized drug particles have a D90 of less than 9 microns; d50 is less than 3.5 microns; and a particle size distribution of D10 of less than 1 micron. The particle size distribution of the micronized drug particles described herein is measured by laser diffraction spectroscopy.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, any pharmaceutically acceptable excipient known in the art may be used. In some aspects, the pharmaceutically acceptable excipient comprises a filler. In some aspects, the pharmaceutically acceptable excipient comprises a disintegrant. In some aspects, the pharmaceutically acceptable excipient comprises a binder. In some aspects, the pharmaceutically acceptable excipient comprises a filler and a disintegrant. In some aspects, the pharmaceutically acceptable excipient comprises a filler and a binder. In some aspects, the pharmaceutically acceptable excipient comprises a disintegrant and a binder. In some aspects, the pharmaceutically acceptable excipients include a filler, a disintegrant, and a binder. In some aspects, the pharmaceutically acceptable excipients include a filler and a lubricant. In some aspects, the pharmaceutically acceptable excipients include a disintegrant and a lubricant. In some aspects, the pharmaceutically acceptable excipient comprises a binder and a lubricant. In some aspects, the pharmaceutically acceptable excipients include a filler, a disintegrant, and a lubricant. In some aspects, the pharmaceutically acceptable excipients include fillers, binders, and lubricants. In some aspects, the pharmaceutically acceptable excipients include a disintegrant, a binder, and a lubricant. In some aspects, the pharmaceutically acceptable excipients include fillers, disintegrants, binders, and lubricants. In some aspects, the pharmaceutically acceptable excipient further comprises a surfactant, a glidant, or a combination thereof. In some aspects, the pharmaceutically acceptable excipient may further comprise one or more additional compounds for enhancing the manufacture, powder flowability, chemical properties (e.g., stability), or biological properties (e.g., absorption) of the pharmaceutical compositions, granules, tablets, capsules, powders, and beads described herein.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the filler may be any filler known in the art. In some aspects, the filler comprises a polyol, maltodextrin, microcrystalline cellulose, or a combination of two or more thereof. In some aspects, the filler is a polyol. In some aspects, the filler is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, the filler is mannitol. In some aspects, the filler is maltitol. In some aspects, the filler is lactose. In some aspects, the filler is maltodextrin. In some aspects, the filler is microcrystalline cellulose. In some aspects, the filler is a polyol and maltodextrin. In some aspects, the filler comprises: (i) maltodextrin and (ii) mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, the filler comprises: (i) maltodextrin and (ii) mannitol. In some aspects, the filler comprises: (i) maltodextrin and (ii) lactose. In some aspects, the filler is a polyol and microcrystalline cellulose. In some aspects, the filler comprises: (i) microcrystalline cellulose and (ii) mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, the filler comprises: (i) microcrystalline cellulose and (ii) mannitol. In some aspects, the filler comprises: (i) microcrystalline cellulose and (ii) lactose. In some aspects, the filler is maltodextrin and microcrystalline cellulose. In some aspects, the filler is a polyol, maltodextrin, and microcrystalline cellulose. In some aspects, the filler comprises: (i) maltodextrin, (ii) microcrystalline cellulose, and (iii) mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, the filler comprises: (i) maltodextrin, (ii) microcrystalline cellulose, and (iii) mannitol. In some aspects, the filler comprises: (i) maltodextrin, (ii) microcrystalline cellulose, and (iii) lactose.
When the filler in the compositions, oral formulations, granules, tablets, capsules, powders and beads described herein comprises mannitol, the mannitol is crystalline mannitol, spray dried mannitol, or a combination thereof. In some aspects, the mannitol is crystalline mannitol. In some aspects, the mannitol is spray dried mannitol. In some aspects, the mannitol comprises crystalline mannitol and spray dried mannitol, wherein the ratio of crystalline mannitol to spray dried mannitol is about 25: 1 to about 1: 25; or from about 20: 1 to about 1: 20; or about 15: 1 to about 1: 15; or from about 10: 1 to about 1: 10; or from about 8: 1 to about 1: 8. In some aspects, the ratio of crystalline mannitol to spray dried mannitol is about 5: 1 to about 1: 5. In some aspects, the ratio of crystalline mannitol to spray dried mannitol is about 3: 1 to about 1: 3. In some aspects, the ratio of crystalline mannitol to spray dried mannitol is about 3: 1 to about 1: 1. In some aspects, the ratio of crystalline mannitol to spray dried mannitol is about 2.5: 1 to about 1.5: 1. In some aspects, the ratio of crystalline mannitol to spray dried mannitol is about 2: 1. In some aspects, the mannitol has a particle size (average diameter, measured by laser diffraction) of about 10 microns to about 600 microns. In some aspects, the mannitol has a particle size (average diameter, measured by laser diffraction) of about 25 microns to about 250 microns. In some aspects, the mannitol is crystalline mannitol having a particle size (average diameter, measured by laser diffraction) of about 25 microns to about 160 microns. In some aspects, the mannitol is crystalline mannitol having a particle size (average diameter, measured by laser diffraction) of about 40 microns to about 60 microns. In some aspects, mannitol is crystalline mannitol (which may be of a size (mean diameter, as measured by laser diffraction) of about 50 micronsCommercially available at 50C). In some aspects, sweetThe mannitol is spray dried mannitol having a particle size of about 100 microns to about 500 microns. In some aspects, the mannitol is spray dried mannitol having a particle size of about 100 microns to about 200 microns. In some aspects, the mannitol is spray dried mannitol (which may be about 180 microns in size)Commercially available at 200 SD). In some aspects, the mannitol comprises crystalline mannitol having a particle size of about 25 microns to about 160 microns and spray dried mannitol having a particle size of about 80 microns to about 200 microns, wherein the ratio of crystalline mannitol to spray dried mannitol is about 10: 1 to about 1: 10; or about 5: 1 to about 1: 5; or a ratio of about 3: 1 to about 1: 3, or a ratio of about 3: 1 to about 1: 1; or in a ratio of about 2.5: 1 to about 1.5: 1; or in a ratio of about 2: 1; or in a ratio of about 1.9: 1; or a ratio of about 2: 1 to about 1.9: 1.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders and beads described herein, the filler is present in the pharmaceutical compositions, granules, tablets, capsules, powders and beads in a suitable amount. In some aspects, the filler is present at a weight percent of about 10 wt% to about 95 wt%; or from about 15 wt% to about 90 wt%; or from about 20 wt% to about 80 wt%; or from about 20 wt% to about 75 wt%; or from about 20 wt% to about 70 wt%. In some aspects, the filler is present in an amount of about 30 wt% to about 80 wt%. In some aspects, the filler is present in an amount of about 30 wt% to about 75 wt%. In some aspects, the amount of filler is about 30 wt% to about 70 wt%. In some aspects, the amount of filler is about 30 wt% to about 65 wt%. In some aspects, the amount of filler is about 40 wt% to about 80 wt%. In some aspects, the amount of filler is about 40 wt% to about 75 wt%. In some aspects, the amount of filler is about 40 wt% to about 70 wt%. In some aspects, the amount of filler is about 40 wt% to about 65 wt%. In some aspects, the amount of filler is about 50 wt% to about 80 wt%. In some aspects, the amount of filler is about 50 wt% to about 75 wt%. In some aspects, the amount of filler is about 50 wt% to about 70 wt%. In some aspects, the amount of filler is about 50 wt% to about 65 wt%. In some aspects, the amount of filler is about 55 wt% to about 80 wt%. In some aspects, the amount of filler is about 55 wt% to about 75 wt%. In some aspects, the amount of filler is about 55 wt% to about 70 wt%. In some aspects, the amount of filler is about 51 wt% to about 69 wt%. In some aspects, the amount of filler is about 52 wt% to about 68 wt%. In some aspects, the amount of filler is about 53 wt% to about 67 wt%. In some aspects, the amount of filler is about 54 wt% to about 66 wt%. In some aspects, the amount of filler is about 55 wt% to about 65 wt%. In some aspects, the amount of filler is about 56 wt% to about 64 wt%. In some aspects, the amount of filler is about 57 wt% to about 63 wt%. In some aspects, the amount of filler is about 58 wt% to about 62 wt%. In some aspects, the amount of filler is about 59 wt% to about 61 wt%. In some aspects, the amount of filler is about 60 wt% to about 61 wt%. In some aspects, the amount of filler is about 60 wt% to about 62 wt%. In some aspects, the amount of filler is about 50 wt%. In some aspects, the amount of filler is about 51 wt%. In some aspects, the amount of filler is about 52 wt%. In some aspects, the amount of filler is about 53 wt%. In some aspects, the amount of filler is about 54 wt%. In some aspects, the amount of filler is about 55 wt%. In some aspects, the amount of filler is about 56 wt%. In some aspects, the amount of filler is about 57 wt%. In some aspects, the amount of filler is about 58 wt%. In some aspects, the amount of filler is about 59 wt%. In some aspects, the amount of filler is about 60 wt%. In some aspects, the amount of filler is about 60.25 wt%. In some aspects, the amount of filler is about 60.5 wt%. In some aspects, the amount of filler is about 60.75 wt%. In some aspects, the amount of filler is about 61 wt%. In some aspects, the amount of filler is about 61.25 wt%. In some aspects, the amount of filler is about 61.5 wt%. In some aspects, the amount of filler is about 61.75 wt%. In some aspects, the amount of filler is about 62 wt%. In some aspects, the amount of filler is about 62.25 wt%. In some aspects, the amount of filler is about 62.5 wt%. In some aspects, the amount of filler is about 62.75 wt%. In some aspects, the amount of filler is about 63 wt%. In some aspects, the amount of filler is about 64 wt%. In some aspects, the amount of filler is about 65 wt%. In some aspects, the amount of filler is about 66 wt%. In some aspects, the amount of filler is about 67 wt%. In some aspects, the amount of filler is about 68 wt%. In some aspects, the amount of filler is about 69 wt%. In some aspects, the amount of filler is about 70 wt%.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the disintegrant may be any disintegrant known in the art. In some aspects, the disintegrant is a super disintegrant. In some aspects, the disintegrant is a pharmaceutically acceptable polymer. In some aspects, the disintegrant comprises a carboxyalkyl cellulose (e.g., carboxymethyl cellulose or cross-linked carboxymethyl cellulose), sodium starch glycolate, a cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof. In some aspects, the disintegrant comprises a carboxyalkyl cellulose. In some aspects, the disintegrant comprises carboxymethyl cellulose. In some aspects, the disintegrant comprises crosslinked carboxymethyl cellulose. In some aspects, the disintegrant comprises sodium starch glycolate. In some aspects, the disintegrant comprises a crosslinked polyvinylpyrrolidone polymer. In some aspects, the disintegrant comprises a carboxyalkyl cellulose and sodium starch glycolate. In some aspects, the disintegrant comprises a crosslinked carboxyalkyl cellulose and sodium starch glycolate. In some aspects, the disintegrant comprises a carboxyalkyl cellulose and a cross-linked polyvinylpyrrolidone polymer. In some aspects, the disintegrant comprises a crosslinked carboxyalkyl cellulose and a crosslinked polyvinylpyrrolidone polymer. In some aspects, the disintegrant comprises a carboxyalkyl cellulose, sodium starch glycolate, and a cross-linked polyvinylpyrrolidone polymer. In some aspects, the disintegrant comprises a crosslinked carboxyalkyl cellulose, sodium starch glycolate, and a crosslinked polyvinylpyrrolidone polymer. In some aspects, the disintegrant comprises sodium starch glycolate and a cross-linked polyvinylpyrrolidone polymer.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders and beads described herein, the disintegrant is present in the pharmaceutical composition, granules, tablets, capsules, powders and beads in a suitable amount. In some aspects, the disintegrant is present in an amount from about 0.5 wt% to about 30 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 25 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 20 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 15 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 14 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 13 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 12 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 11 wt%. In some aspects, the amount of disintegrant is from about 1 wt% to about 10 wt%. In some aspects, the amount of disintegrant is from about 2 wt% to about 15 wt%. In some aspects, the amount of disintegrant is from about 2 wt% to about 14 wt%. In some aspects, the amount of disintegrant is from about 2 wt% to about 13 wt%. In some aspects, the amount of disintegrant is from about 2 wt% to about 12 wt%. In some aspects, the amount of disintegrant is from about 2 wt% to about 11 wt%. In some aspects, the amount of disintegrant is from about 2 wt% to about 10 wt%. In some aspects, the amount of disintegrant is from about 3 wt% to about 11 wt%. In some aspects, the amount of disintegrant is from about 4 wt% to about 10 wt%. In some aspects, the amount of disintegrant is from about 5 wt% to about 9 wt%. In some aspects, the amount of disintegrant is from about 6 wt% to about 8 wt%. In some aspects, the amount of disintegrant is about 7 wt%. In some aspects, the amount of disintegrant is about 5 wt%. In some aspects, the amount of disintegrant is about 6 wt%. In some aspects, the amount of disintegrant is from about 4 wt% to about 12 wt%. In some aspects, the amount of disintegrant is from about 5 wt% to about 11 wt%. In some aspects, the amount of disintegrant is from about 6 wt% to about 10 wt%. In some aspects, the amount of disintegrant is from about 7 wt% to about 9 wt%. In some aspects, the amount of disintegrant is about 8 wt%. In some aspects, the amount of disintegrant is from about 5 wt% to about 13 wt%. In some aspects, the amount of disintegrant is from about 6 wt% to about 12 wt%. In some aspects, the amount of disintegrant is from about 7 wt% to about 11 wt%. In some aspects, the amount of disintegrant is from about 8 wt% to about 10 wt%. In some aspects, the amount of disintegrant is about 9 wt%. In some aspects, the amount of disintegrant is about 10 wt%. In some aspects, the amount of disintegrant is about 11 wt%.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein, the binder can be any binder known in the art. In some aspects, the binder is a pharmaceutically acceptable polymer. In some aspects, the binder comprises a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, or a combination of two or more thereof. In some aspects, the binder comprises a hydroxyalkyl cellulose. In some aspects, the binder comprises an alkyl cellulose. In some aspects, the binder comprises corn starch. In some aspects, the binder comprises polyethylene glycol. In some aspects, the binder comprises polyethylene oxide. In some aspects, the binder comprises polyvinylpyrrolidone. In some aspects, the binder comprises a hydroxyalkyl cellulose and an alkyl cellulose. In some aspects, the binder comprises a hydroxyalkyl cellulose, an alkyl cellulose, and a polyethylene glycol. In some aspects, the binder comprises a hydroxyalkyl cellulose and a polyethylene glycol. In some aspects, the binder comprises an alkyl cellulose and polyethylene glycol. In some aspects, the binder comprises hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, or a combination of two or more thereof. In some aspects, the hydroxyalkyl cellulose is hydroxypropyl cellulose. In some aspects, the binder comprises hydroxyethyl cellulose. In some aspects, the binder comprises hydroxypropyl methylcellulose. In some aspects, the binder comprises hydroxypropyl cellulose and hydroxyethyl cellulose. In some aspects, the binder comprises hydroxypropyl cellulose and hydroxypropyl methylcellulose. In some aspects, the binder comprises hydroxyethyl cellulose and hydroxypropyl methylcellulose. In some aspects, the binder comprises hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose. In some aspects, the binder comprises methyl cellulose, ethyl methyl cellulose, or a combination of two or more thereof. In some aspects, the alkyl cellulose is methyl cellulose. In some aspects, the binder comprises ethyl cellulose. In some aspects, the binder comprises ethyl methyl cellulose. In some aspects, the binder comprises methyl cellulose, ethyl cellulose, and ethyl methyl cellulose. In some aspects, the binder comprises methyl cellulose and ethyl methyl cellulose. In some aspects, the binder comprises ethyl cellulose and ethyl methyl cellulose. In some aspects, the binder comprises methyl cellulose and ethyl cellulose.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders and beads described herein, the binder is present in the pharmaceutical compositions, granules, tablets, capsules, powders and beads in a suitable amount. In some aspects, the binder is present at a concentration of about 0.1 wt% to about 50 wt%; or from about 0.1 wt% to about 45 wt%; or from about 0.1 wt% to about 40 wt%; or from about 0.1 wt% to about 35 wt%; or from about 0.1 wt% to about 30 wt%. In some aspects, the amount of binder is about 0.5 wt% to about 25 wt%. In some aspects, the amount of binder is about 0.5 wt% to about 20 wt%. In some aspects, the amount of binder is about 0.5 wt% to about 15 wt%. In some aspects, the amount of binder is about 0.5 wt% to about 10 wt%. In some aspects, the amount of binder is about 1 wt% to about 10 wt%. In some aspects, the amount of binder is about 2 wt% to about 10 wt%. In some aspects, the amount of binder is about 0.1 wt% to about 8 wt%. In some aspects, the amount of binder is about 0.5 wt% to about 7 wt%. In some aspects, the amount of binder is about 1 wt% to about 6 wt%. In some aspects, the amount of binder is about 2 wt% to about 5 wt%. In some aspects, the amount of binder is about 1 wt% to about 9 wt%. In some aspects, the amount of binder is about 2 wt% to about 8 wt%. In some aspects, the amount of binder is about 3 wt% to about 7 wt%. In some aspects, the amount of binder is about 4 wt% to about 6 wt%. In some aspects, the amount of binder is about 0.5 wt% to about 8 wt%. In some aspects, the amount of binder is about 1 wt% to about 7 wt%. In some aspects, the amount of binder is about 2 wt% to about 6 wt%. In some aspects, the amount of binder is about 3 wt% to about 5 wt%. In some aspects, the amount of binder is about 1 wt%. In some aspects, the amount of binder is about 2 wt%. In some aspects, the amount of binder is about 3 wt%. In some aspects, the amount of binder is about 4 wt%. In some aspects, the amount of binder is about 5 wt%. In some aspects, the amount of binder is about 6 wt%. In some aspects, the amount of binder is about 7 wt%. In some aspects, the amount of binder is about 8 wt%.
In some aspects, the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein further comprise a lubricant. The lubricant may be any lubricant known in the art. In some aspects, the lubricant is magnesium stearate, stearic acid, calcium stearate, sodium stearate, talc, sodium stearyl fumarate, glyceryl behenate, boric acid, sodium benzoate, sodium oleate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, or a combination of two or more thereof. In some aspects, the lubricant comprises magnesium stearate. In some aspects, the lubricant comprises stearic acid. In some aspects, the lubricant comprises magnesium stearate and stearic acid. In some aspects, the lubricant comprises magnesium stearate, calcium stearate, sodium stearate, stearic acid, or a combination of two or more thereof. In some aspects, the lubricant comprises magnesium stearate, calcium stearate, sodium stearate, or a combination of two or more thereof.
In some aspects of the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders and beads described herein, the lubricant is present in the pharmaceutical compositions, granules, tablets, capsules, powders and beads in a suitable amount. In some aspects, the lubricant is present in an amount of about 0.1 wt% to about 5 wt%. In some aspects, the lubricant is present in an amount of about 1 wt% to about 4 wt%. In some aspects, the lubricant is present in an amount of about 1.5 wt% to about 3.5 wt%. In some aspects, the lubricant is present in an amount of about 2 wt% to about 3 wt%. In some aspects, the lubricant is present in an amount of about 2 wt% to about 2.5 wt%. In some aspects, the lubricant is present in an amount of about 0.5 wt%. In some aspects, the lubricant is present in an amount of about 1 wt%. In some aspects, the lubricant is present in an amount of about 1.25 wt%. In some aspects, the lubricant is present in an amount of about 1.5 wt%. In some aspects, the lubricant is present in an amount of about 1.75 wt%. In some aspects, the lubricant is present in an amount of about 2 wt%. In some aspects, the lubricant is present in an amount of about 2.25 wt%. In some aspects, the lubricant is present in an amount of about 2.5 wt%. In some aspects, the lubricant is present in an amount of about 2.75 wt%. In some aspects, the lubricant is present in an amount of about 3 wt%. In some aspects, the lubricant is present in an amount of about 4 wt%. In some aspects, the lubricant is present in an amount of about 5 wt%.
In some aspects, the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein further comprise a surfactant. In some aspects, the surfactant is anionic, such as ammonium lauryl sulfate, sodium lauryl ether sulfate, sodium myristyl polyether sulfate, sodium diisooctyl succinate sulfonate, and the like. In some aspects, the surfactant is zwitterionic, such as a phospholipid, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and the like. In some aspects, the surfactant is cationic, such as quaternary ammonium and pyridinium cationic surfactants. In some aspects, the surfactant is non-ionic, such as sorbitan esters, polysorbates, poloxamers, and the like.
In some aspects, the pharmaceutical compositions, oral formulations, granules, tablets, capsules, powders, and beads described herein further comprise a surface glidant. In some aspects, the glidant is colloidal silicon dioxide, talc, or a combination thereof. In some aspects, the glidant is colloidal silica. In some aspects, the glidant is talc.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) a compound of formula (III), or a pharmaceutically acceptable salt thereof, having a particle size distribution wherein D90 is about 10 microns or less; and (ii) a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or a combination of two or more thereof. In some aspects, (ii) is a polyol. In some aspects, (ii) is maltodextrin. In some aspects, (ii) is microcrystalline cellulose. In some aspects, (ii) is a polyol and maltodextrin. In some aspects, (ii) is a polyol and microcrystalline cellulose. In some aspects, (ii) is maltodextrin and microcrystalline cellulose. In some aspects, (ii) is a polyol, maltodextrin, and microcrystalline cellulose. In some aspects, the polyol is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, (ii) is mannitol. In some aspects, (ii) is mannitol and maltodextrin. In some aspects, (ii) is mannitol and microcrystalline cellulose. In some aspects, (ii) comprises mannitol, maltodextrin, and microcrystalline cellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) a compound of formula (III) or a pharmaceutically acceptable salt thereof, the compound of formula (III) or a pharmaceutically acceptable salt thereof having a particle size distribution with D90 of about 10 microns or less, and (ii) carboxymethylcellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof. In some aspects, (ii) is carboxymethyl cellulose. In some aspects, the carboxymethyl cellulose is a cross-linked carboxymethyl cellulose. In some aspects, the carboxymethyl cellulose is croscarmellose sodium. In some aspects, (ii) is a polyvinylpyrrolidone polymer. In some aspects, (ii) comprises carboxymethyl cellulose and a polyvinylpyrrolidone polymer.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) a compound of formula (III) or a pharmaceutically acceptable salt thereof, having a particle size distribution with D90 of about 10 microns or less, and (ii) a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, or a combination of two or more thereof. In some aspects, (ii) is a hydroxyalkyl cellulose. In some aspects, (ii) is hydroxypropyl cellulose. In some aspects, (ii) is an alkylcellulose. In some aspects, (ii) comprises hydroxyalkyl cellulose and alkyl cellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) a compound of formula (III), or a pharmaceutically acceptable salt thereof, having a particle size distribution wherein D90 is about 10 microns or less; (ii) a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or combinations of two or more thereof; and (iii) carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof. In some aspects, (ii) is a polyol, and (iii) is a carboxymethyl cellulose. In some aspects, (ii) is maltodextrin, and (iii) is carboxymethylcellulose. In some aspects, (ii) is microcrystalline cellulose, and (iii) is carboxymethyl cellulose. In some aspects, (ii) comprises a polyol and maltodextrin, and (iii) is carboxymethylcellulose. In some aspects, (ii) comprises a polyol and microcrystalline cellulose, and (iii) is carboxymethyl cellulose. In some aspects, (ii) comprises maltodextrin and microcrystalline cellulose, and (iii) is carboxymethylcellulose. In some aspects, (ii) comprises a polyol, maltodextrin, and microcrystalline cellulose, and (iii) is carboxymethylcellulose. In some aspects, the polyol is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, (ii) is mannitol, and (iii) is carboxymethylcellulose. In some aspects, (ii) comprises mannitol and maltodextrin, and (iii) is carboxymethylcellulose. In some aspects, (ii) comprises mannitol and microcrystalline cellulose, and (iii) is carboxymethyl cellulose. In some aspects, (ii) comprises mannitol, maltodextrin, and microcrystalline cellulose, and (iii) is carboxymethylcellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) a compound of formula (III), or a pharmaceutically acceptable salt thereof, having a particle size distribution wherein D90 is about 10 microns or less; (ii) a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or combinations of two or more thereof; and (iii) a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, or a combination of two or more thereof. In some aspects, (ii) is a polyol, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) is maltodextrin, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises microcrystalline cellulose, and (iii) is hydroxyalkyl cellulose. In some aspects, (ii) comprises a polyol and maltodextrin, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises a polyol and microcrystalline cellulose, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises maltodextrin and microcrystalline cellulose, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises a polyol, maltodextrin, and microcrystalline cellulose, and (iii) is a hydroxyalkyl cellulose. In some aspects, the polyol is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, (ii) is mannitol, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises mannitol and maltodextrin, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises mannitol and microcrystalline cellulose, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises mannitol, maltodextrin, and microcrystalline cellulose, and (iii) is a hydroxyalkyl cellulose. In some aspects, the hydroxyalkyl cellulose is hydroxypropyl cellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) a compound of formula (III) or a pharmaceutically acceptable salt thereof, the compound of formula (III) or a pharmaceutically acceptable salt thereof having a particle size distribution with D90 of about 10 microns or less, (ii) carboxymethylcellulose, sodium starch glycolate, crosslinked polyvinylpyrrolidone polymer, or a combination of two or more thereof; and (iii) a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, or a combination of two or more thereof. In some aspects, (ii) is carboxymethyl cellulose, and (iii) is hydroxyalkyl cellulose. In some aspects, the carboxymethyl cellulose is a cross-linked carboxymethyl cellulose. In some aspects, the carboxymethyl cellulose is croscarmellose sodium. In some aspects, (ii) is a polyvinylpyrrolidone polymer, and (iii) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises carboxymethyl cellulose and a polyvinylpyrrolidone polymer, and (iii) is a hydroxyalkyl cellulose. In some aspects, the hydroxyalkyl cellulose is hydroxypropyl cellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) a compound of formula (III), or a pharmaceutically acceptable salt thereof, having a particle size distribution wherein D90 is about 10 microns or less; (ii) a polyol, maltodextrin, microcrystalline cellulose, dicalcium phosphate, or combinations of two or more thereof; (iii) carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone polymer, or a combination of two or more thereof; and (iv) a hydroxyalkyl cellulose, an alkyl cellulose, corn starch, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, or a combination of two or more thereof. In some aspects, (ii) is a polyol, (iii) is a carboxymethyl cellulose, and (iv) is a hydroxyalkyl cellulose. In some aspects, (ii) is maltodextrin, (iii) is carboxymethylcellulose, and (iv) is a hydroxyalkyl cellulose. In some aspects, (ii) is microcrystalline cellulose, (iii) is carboxymethyl cellulose, and (iv) is hydroxyalkyl cellulose. In some aspects, (ii) comprises a polyol and maltodextrin, (iii) is a carboxymethyl cellulose, and (iv) is a hydroxyalkyl cellulose. In some aspects, (ii) comprises a polyol and microcrystalline cellulose, (iii) is carboxymethyl cellulose, and (iv) is hydroxyalkyl cellulose. In some aspects, (ii) comprises maltodextrin and microcrystalline cellulose, (iii) is carboxymethyl cellulose, and (iv) is hydroxyalkyl cellulose. In some aspects, (ii) comprises a polyol, maltodextrin, and microcrystalline cellulose, (iii) is carboxymethyl cellulose, and (iv) is hydroxyalkyl cellulose. In some aspects, the polyol is mannitol, sorbitol, isomalt, maltitol, lactose, sucrose, amylose, glucose, dextrose, lactitol, erythritol, arabitol, xylitol, trehalose, ribitol, inositol, or a combination of two or more thereof. In some aspects, the hydroxyalkyl cellulose is hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, or a combination of two or more thereof. In some aspects, (ii) is mannitol, (iii) is cross-linked carboxymethylcellulose, and (iv) is hydroxypropylcellulose. In some aspects, (ii) comprises mannitol and maltodextrin, (iii) is a crosslinked carboxymethyl cellulose, and (iv) is hydroxypropyl cellulose. In some aspects, (ii) comprises mannitol and microcrystalline cellulose, (iii) is a crosslinked carboxymethyl cellulose, and (iv) is hydroxypropyl cellulose. In some aspects, (ii) comprises mannitol, maltodextrin, and microcrystalline cellulose, (iii) is a crosslinked carboxymethyl cellulose, and (iv) is hydroxypropyl cellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) about 25 wt% to about 35 wt% of an adenosine A2A receptor antagonist or a pharmaceutically acceptable salt thereof; (ii) about 50 wt% to about 70 wt% of a filler; and (iii) about 1 wt% to about 10 wt% of a disintegrant. In some aspects, the pharmaceutical composition further comprises about 1 wt% to about 10 wt% of a binder.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) about 25 wt% to about 35 wt% of a compound of formula (III) or a pharmaceutically acceptable salt thereof; (ii) about 40 wt% to about 60 wt% mannitol; (iii) about 5 wt% to about 20 wt% microcrystalline cellulose; and (iv) about 1 wt% to about 10 wt% croscarmellose sodium. In some aspects, the pharmaceutical composition further comprises about 1 wt% to about 10 wt% hydroxypropyl cellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) about 25 wt% to about 35 wt% of a compound of formula (III) or a pharmaceutically acceptable salt thereof; (ii) about 45 wt% to about 55 wt% mannitol; (iii) about 10 wt% to about 15 wt% microcrystalline cellulose; and (iv) about 4 wt% to about 8 wt% croscarmellose sodium. In some aspects, the pharmaceutical composition further comprises about 1 wt% to about 8 wt% hydroxypropyl cellulose.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) about 20 wt% to about 30 wt% of a compound of formula (III) or a pharmaceutically acceptable salt thereof; (ii) about 30 wt% to about 50 wt% mannitol; (iii) about 15 wt% to about 30 wt% microcrystalline cellulose; and (iv) about 1 wt% to about 15 wt% croscarmellose sodium. In some aspects, the pharmaceutical composition further comprises about 1 wt% to about 10 wt% hydroxypropyl cellulose. In some aspects, the mannitol comprises spray dried mannitol and crystalline mannitol in a weight ratio of about 1: 1.5 to about 1: 2.5.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) about 23 wt% to about 27 wt% of a compound of formula (III) or a pharmaceutically acceptable salt thereof; (ii) about 37 wt% to about 40 wt% mannitol; (iii) about 21 wt% to about 24 wt% microcrystalline cellulose; and (iv) from about 5 wt% to about 10 wt% of croscarmellose sodium. In some aspects, the pharmaceutical composition further comprises about 2 wt% to about 6 wt% hydroxypropyl cellulose. In some aspects, the mannitol comprises spray dried mannitol and crystalline mannitol in a weight ratio of about 1: 1.5 to about 1: 2.5.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) about 24 wt% to about 26 wt% of a compound of formula (III) or a pharmaceutically acceptable salt thereof; (ii) about 38 wt% to about 39 wt% mannitol; (iii) about 22 wt% to about 23 wt% microcrystalline cellulose; and (iv) from about 7 wt% to about 9 wt% of croscarmellose sodium. In some aspects, the pharmaceutical composition further comprises about 3 wt% to about 5 wt% hydroxypropyl cellulose. In some aspects, the mannitol comprises spray dried mannitol and crystalline mannitol in a weight ratio of about 1: 1.5 to about 1: 2.5.
In some aspects, the present disclosure provides pharmaceutical compositions, oral formulations, tablets, capsules, granules, powders, and beads comprising: (i) about 25 wt% of a compound of formula (III) or a pharmaceutically acceptable salt thereof; (ii) about 38.25 wt% mannitol; (iii) about 22.5 wt% microcrystalline cellulose; and (iv) about 8 wt% croscarmellose sodium. In some aspects, the pharmaceutical composition further comprises about 4 wt% hydroxypropyl cellulose. In some aspects, the mannitol comprises spray dried mannitol and crystalline mannitol in a weight ratio of about 1: 1.5 to about 1: 2.5.
In some aspects, the present disclosure provides bioequivalent formulations of the pharmaceutical compositions, oral formulations, granules, tablets, powders, oral formulations, and beads described herein. In some aspects, the present disclosure provides pharmaceutical composition No. 6. In some aspects, the present disclosure provides pharmaceutical composition No. 6 as shown in table 11A or a bioequivalent formulation thereof. In some aspects, the present disclosure provides pharmaceutical composition No. 6 as shown in table 11B or a bioequivalent formulation thereof. In some aspects, the present disclosure provides pharmaceutical composition No. 5. In some aspects, the present disclosure provides pharmaceutical composition No. 5 as shown in table 9A or a bioequivalent formulation thereof. In some aspects, the present disclosure provides pharmaceutical composition No. 5 as shown in table 9B or a bioequivalent formulation thereof. In some aspects, the present disclosure provides pharmaceutical composition No. 4. In some aspects, the present disclosure provides a pharmaceutical composition No. 3 or a bioequivalent formulation thereof. In some aspects, the present disclosure provides a pharmaceutical composition No. 2 or a bioequivalent formulation thereof. In some aspects, the present disclosure provides pharmaceutical composition No. 1 or a bioequivalent formulation thereof.
In embodiments of the compositions provided herein, including pharmaceutical compositions and oral formulations (e.g., tablets, capsules, granules, powders, and beads), the compositions do not comprise other active pharmaceutical ingredients other than one or more A2A receptor antagonists. In some aspects of the compositions provided herein, including pharmaceutical compositions, oral formulations (e.g., tablets, capsules, granules, powders, and beads), the compositions comprise only a single type of A2A receptor antagonist. In some aspects of the compositions provided herein, including pharmaceutical compositions, oral formulations (e.g., tablets, capsules, granules, powders, and beads), the compositions include only a single type of A2A receptor antagonist, and no other active pharmaceutical ingredient. In some aspects of the compositions provided herein, including pharmaceutical compositions, oral formulations (e.g., tablets, capsules, granules, powders, and beads), the compositions include only a single type of A2A receptor antagonist, without a pharmaceutical excipient or other active pharmaceutical ingredient.
Oral formulations
In some aspects, the pharmaceutical compositions described herein are oral formulations. Oral formulations include tablets, pills, powders, sachets, stick packs, dragees, capsules, wafers, films, liquids, lozenges, gels, syrups, slurries, suspensions and the like, suitable for ingestion by a patient. Solid oral formulations include powders, tablets, granules, beads, capsules, films, wafers, chewable formulations and dispersible granules. Liquid oral formulations include solutions, suspensions, and emulsions. Other oral dosage formulations include oromucosal formulations, such as sublingual or buccal formulations (e.g., tablets, films or wafers).
In some aspects, the oral formulation is a tablet as described herein. In some aspects, the tablet is a compressed tablet. In some aspects, the tablet is encapsulated within an outer layer. In some aspects, the tablet is encapsulated within an outer enteric layer. In some aspects, the tablet is a rapidly disintegrating tablet. In some aspects, the tablet is a sublingual tablet. In some aspects, the tablet is a buccal tablet. In some aspects, the tablet is a rapidly disintegrating sublingual tablet. In some aspects, the tablet is a rapidly disintegrating buccal tablet. In some aspects, the tablet is formed by compressing a pharmaceutical composition described herein. In some aspects, the tablets are formed by compressing the granules described herein. In some aspects, the tablet is formed by compressing a granule described herein, wherein the granule has an outer coating layer, and wherein the tablet optionally further comprises an outer coating layer. In some aspects, the tablet is formed by compressing a pharmaceutical composition described herein. In some aspects, the tablet is formed by compressing a powder described herein. In some aspects, the tablet is formed by compressing a bead as described herein. In some aspects, the tablet is formed by compressing the beads described herein, wherein the beads have an outer coating layer, and wherein the tablet optionally further comprises an outer coating layer. In some aspects, the outer coating layer comprises an enteric coating.
In some aspects, the oral formulation is a capsule. In some aspects, the capsule comprises a pharmaceutical composition described herein encapsulated within a capsule shell, wherein the capsule shell is optionally further encapsulated within an outer coating layer. In some aspects, the capsule comprises a granule described herein encapsulated within a capsule shell, wherein the capsule shell is optionally further encapsulated within an outer coating layer. In some aspects, the capsule comprises a granule described herein encapsulated within a capsule shell, wherein the granule comprises an outer coating layer, and wherein the capsule shell is optionally further encapsulated within the outer coating layer. In some aspects, the capsule comprises a bead described herein encapsulated within a capsule shell, wherein the bead comprises an outer coating layer, and wherein the capsule shell is optionally further encapsulated within the outer coating layer. In some aspects, the capsule comprises a powder described herein encapsulated within a capsule shell, wherein the capsule shell is optionally further encapsulated within an outer coating layer. In some aspects, the oral formulation is a solid capsule. In some aspects, the capsule is a rapidly disintegrating capsule. In some aspects, the outer coating layer comprises an enteric coating. In some aspects, the capsule shell comprises an enteric polymer.
In some aspects, the oral formulation is a granule, wherein the granule comprises the pharmaceutical composition. In some aspects, the granule comprises a coating layer. In some aspects, the plurality of granules includes a coating layer, and the plurality of granules does not include a coating layer. In some aspects, the granules are dusted on or in a food or liquid, or are used directly for oral administration.
In some aspects, the oral formulation is a powder, wherein the powder comprises a pharmaceutical composition described herein. In some aspects, the oral formulation is a reconstitutable powder. A reconstitutable powder may be added to a liquid for ingestion, wherein the powder dissolves in the liquid or the powder forms a suspension in the liquid. In some aspects, the powder is dusted on or in food for oral administration.
In some aspects, the present disclosure provides sachets containing the pharmaceutical compositions described herein. In some aspects, the present disclosure provides a sachet comprising a granule as described herein. In some aspects, the present disclosure provides sachets comprising the powders described herein. In some aspects, the present disclosure provides a sachet comprising the beads described herein. Sachets are a useful packaging material in which the contents are intended to be sprinkled in food or added to a liquid.
In some aspects, the present disclosure provides a stick pack containing a pharmaceutical composition described herein. In some aspects, the present disclosure provides a stick pack containing the granules described herein. In some aspects, the present disclosure provides a stick pack containing the powder described herein. In some aspects, the present disclosure provides a stick pack containing the beads described herein. Stick packs are a useful packaging material in which the contents are intended to be sprinkled on food or added to a liquid.
In embodiments, oral formulations (including tablets, capsules, granules, and beads) described herein include a coating. In some aspects, the coating surrounds the formulation, i.e., the coating forms a layer, wherein the formulation is surrounded within (surrounded by) the layer. In some aspects, the coating partially surrounds the formulation. In some aspects, the oral formulation is a tablet comprising a coating. In some aspects, the oral formulation is a compressed tablet comprising a coating. In some aspects, the oral formulation is a capsule comprising a coating. In some aspects, the oral formulation comprises a granule surrounded by a coating. In some aspects, the oral formulation comprises a bead surrounded by a coating. In some aspects, the coating is an enteric coating.
In some aspects, the oral formulations described herein (including tablets, capsules, granules, powders, and beads) comprise an adenosine A2A receptor antagonist dose of about 1mg to about 1,000 mg. In some aspects, the dosage of the adenosine A2A receptor antagonist is from about 1mg to about 900 mg. In some aspects, the dosage of the adenosine A2A receptor antagonist is from about 1mg to about 800 mg. In some aspects, the dosage of the adenosine A2A receptor antagonist is from about 1mg to about 700 mg. In some aspects, the dosage of the adenosine A2A receptor antagonist is from about 1mg to about 600 mg. In some aspects, the dosage of the adenosine A2A receptor antagonist is from about 1mg to about 500 mg. In some aspects, the dosage of the adenosine A2A receptor antagonist is from about 1mg to about 400 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 1mg to about 50 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 5mg to about 40 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 5mg to about 30 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 5mg to about 20 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 5mg to about 10 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 5 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 10 mg. In some aspects, the oral formulations, such as tablets and capsules, comprise an adenosine A2A receptor antagonist dose of about 20 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 25 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 20mg to about 100 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 25mg to about 75 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 30mg to about 70 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 40mg to about 60 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 45mg to about 55 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 50 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 50mg to about 150 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 75mg to about 125 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 80mg to about 120 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 85mg to about 115 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 90mg to about 110 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 95mg to 105 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 100 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 100mg to about 200 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 110mg to about 190 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 120mg to about 180 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 130mg to about 170 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 140mg to about 160 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 150 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 150mg to about 250 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 170mg to about 230 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 180mg to about 220 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 185mg to about 215 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 190mg to about 210 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 195mg to 205 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 200 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 200mg to about 300 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 210mg to about 290 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 220mg to about 280 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 230mg to about 270 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 240mg to about 260 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 250 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 250mg to about 350 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 270mg to about 330 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 280mg to about 320 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 285mg to about 315 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 290mg to about 310 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 295mg to 305 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 300 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 300mg to about 400 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 310mg to about 390 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 320mg to about 380 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 330mg to about 370 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 340mg to about 360 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 350 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 350mg to about 450 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 370mg to about 430 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 380mg to about 420 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 385mg to about 415 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 390mg to about 410 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 395mg to 405 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 400 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 400mg to about 500 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 410mg to about 490 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 420mg to about 480 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 430mg to about 470 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 440mg to about 460 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 450 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 450mg to about 550 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 470mg to about 530 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 480mg to about 520 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 485mg to about 515 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 490mg to about 510 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 495mg to 505 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 500 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 500mg to about 600 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 510mg to about 590 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 520mg to about 580 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 530mg to about 570 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 540mg to about 560 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 550 mg.
In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 550mg to about 650 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 570mg to about 630 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 580mg to about 620 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 585mg to about 615 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 590mg to about 610 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 595mg to 605 mg. In some aspects, the oral formulations (e.g., tablets and capsules) comprise an adenosine A2A receptor antagonist dose of about 600 mg.
Properties of
The pharmaceutical compositions described herein (e.g., oral formulations, tablets, capsules, beads, granules, powders) have excellent chemical (e.g., stability, dissolution, disintegration) and biological (e.g., pharmacokinetic) properties.
In embodiments, the pharmaceutical composition (e.g., oral formulation, tablet, bead, capsule, granule) is fast-dissolving as measured by a type II (paddle) dissolution apparatus of chapter < 711 in United States Pharmacopeia (USP). In some aspects, the dissolution rate is at least 55% within 60 minutes. In some aspects, the dissolution rate is at least 60% in 60 minutes. In some aspects, the dissolution rate is at least 65% within 60 minutes. In some aspects, the dissolution rate is at least 70% in 60 minutes. In some aspects, the dissolution rate is at least 75% within 60 minutes. In some aspects, the dissolution rate is at least 80% within 60 minutes. In some aspects, the dissolution rate is at least 81% in 60 minutes. In some aspects, the dissolution rate is at least 82% in 60 minutes. In some aspects, the dissolution rate is at least 83% within 60 minutes. In some aspects, the dissolution rate is at least 84% within 60 minutes. In some aspects, the dissolution rate is at least 85% in 60 minutes. In some aspects, the dissolution rate is at least 86% in 60 minutes. In some aspects, the dissolution rate is at least 87% in 60 minutes. In some aspects, the dissolution rate is at least 88% in 60 minutes. In some aspects, the dissolution rate is at least 90% within 60 minutes. In some aspects, the dissolution rate is at least 95% in 60 minutes. "dissolution" or "dissolution rate" as used herein is measured by a dissolution apparatus of the United States Pharmacopoeia (USP) < 711 > Chapter II (paddle).
In embodiments, the dissolution is at least 55% in 30 minutes as measured by a type II (paddle) dissolution apparatus, chapter < 711, United States Pharmacopoeia (USP). In some aspects, the dissolution rate is at least 60% within 30 minutes. In some aspects, the dissolution rate is at least 65% within 30 minutes. In some aspects, the dissolution rate is at least 70% within 30 minutes. In some aspects, the dissolution rate is at least 75% within 30 minutes. In some aspects, the dissolution rate is at least 80% within 30 minutes. In some aspects, the dissolution rate is at least 85% within 30 minutes. In some aspects, the dissolution rate is at least 90% within 30 minutes. In some aspects, the dissolution rate is at least 95% within 30 minutes. "dissolution" or "dissolution rate" as used herein is measured by a dissolution apparatus of the United States Pharmacopoeia (USP) < 711 > Chapter II (paddle).
In embodiments, the dissolution is at least 50% in 10 minutes as measured by a type II (paddle) dissolution apparatus, chapter < 711, United States Pharmacopoeia (USP). In some aspects, the dissolution rate is at least 55% within 10 minutes. In some aspects, the dissolution rate is at least 60% within 10 minutes. In some aspects, the dissolution rate is at least 65% within 10 minutes. In some aspects, the dissolution rate is at least 70% within 10 minutes. In some aspects, the dissolution rate is at least 75% within 10 minutes. In some aspects, the dissolution rate is at least 80% within 10 minutes. In some aspects, the dissolution rate is at least 85% in 10 minutes. In some aspects, the dissolution rate is at least 90% within 10 minutes. "dissolution" or "dissolution rate" as used herein is measured by a dissolution apparatus of the United States Pharmacopoeia (USP) < 711 > Chapter II (paddle).
In embodiments, the pharmaceutical composition (e.g., oral formulation, tablet, bead, capsule, granule) is rapidly disintegrating as measured by the disintegration test of chapter < 701 > of the United States Pharmacopeia (USP). In some aspects, the pharmaceutical composition has a disintegration time of about 30 minutes or less. In some aspects, the pharmaceutical composition has a disintegration time of about 25 minutes or less. In some aspects, the pharmaceutical composition has a disintegration time of about 20 minutes or less. In some aspects, the pharmaceutical composition has a disintegration time of about 19 minutes or less. In some aspects, the disintegration time is about 18 minutes or less. In some aspects, the disintegration time is about 17 minutes or less. In some aspects, the disintegration time is about 16 minutes or less. In some aspects, the disintegration time is about 15 minutes or less. In some aspects, the disintegration time is about 14 minutes or less. In some aspects, the disintegration time is about 13 minutes or less. In some aspects, the disintegration time is about 12 minutes or less. In some aspects, the disintegration time is about 11 minutes or less. In some aspects, the disintegration time is about 10 minutes or less. In some aspects, the disintegration time is about 9 minutes or less. In some aspects, the disintegration time is about 8 minutes or less. In some aspects, the disintegration time is about 7 minutes or less. In some aspects, the disintegration time is about 6 minutes or less. In some aspects, the disintegration time is about 5 minutes or less. In some aspects, the disintegration time is about 4 minutes or less. In some aspects, the disintegration time is about 3 minutes or less. In some aspects, the disintegration time is about 2 minutes or less. In some aspects, the disintegration time is about 1 minute or less. "disintegration" or "disintegration time" or "disintegration rate" is measured by the disintegration test in United States Pharmacopoeia (USP) < 701 > chapter.
In embodiments, the pharmaceutical compositions described herein (e.g., oral formulations, tablets, beads, capsules, granules) have a total impurity level of less than 3% under the following conditions: stored closed for 4 weeks at 40 ℃, 75% relative humidity, as measured by high performance liquid chromatography followed by ultraviolet spectrophotometry (HPLC-UV). In some aspects, the impurity level is less than 2.5%. In some aspects, the impurity level is less than 2%. In some aspects, the impurity level is less than 1.9%. In some aspects, the impurity level is less than 1.8%. In some aspects, the impurity level is less than 1.7%. In some aspects, the impurity level is less than 1.6%. In some aspects, the impurity level is less than 1.5%. In some aspects, the impurity level is less than 1.4%. In some aspects, the impurity level is less than 1.3%. In some aspects, the impurity level is less than 1.2%. In some aspects, the impurity level is less than 1.1%. In some aspects, the impurity level is less than 1%. In some aspects, the impurity level is less than 0.9%. In some aspects, the impurity level is less than 0.8%. In some aspects, the impurity level is less than 0.7%. In some aspects, the impurity level is less than 0.6%. In some aspects, the impurity level is less than 0.5%. In some aspects, the impurity level is less than 0.4%. In some aspects, the total impurity level is from about 0.5% to less than 2.0%. In some aspects, the total impurity level is from about 0.5% to less than 1.5%. In some aspects, the total impurity level is from about 0.5% to less than 1.4%. In some aspects, the total impurity level is from about 0.5% to less than 1.3%. In some aspects, the total impurity level is from about 0.5% to less than 1.2%. In some aspects, the total impurity level is from about 0.5% to less than 1.1%. In some aspects, the total impurity level is from about 0.5% to less than 1.0%. In some aspects, the total impurity level is from about 0.5% to less than 0.9%.
In embodiments, a pharmaceutical composition described herein (e.g., oral formulation, tablet, bead, capsule, granule) has a total impurity level of less than 3% under any of the following conditions: (i) storage under closed conditions at 40 ℃, 75% relative humidity, with or without desiccant, for 6 months, as measured by high performance liquid chromatography followed by ultraviolet spectrophotometry (HPLC-UV); (ii) storage under closed conditions at 25 ℃, 60% relative humidity, with or without desiccant, for 6 months, as measured by HPLC-UV; (iii) storage under closed conditions at 40 ℃, 75% relative humidity, with or without desiccant for 3 months, as measured by HPLC-UV; or (iv) storage under closed conditions at 25 ℃, 60% relative humidity with or without desiccant for 3 months as measured by HPLC-UV. In some aspects, the impurity level is less than 2.5%. In some aspects, the impurity level is less than 2%. In some aspects, the impurity level is less than 1.9%. In some aspects, the impurity level is less than 1.8%. In some aspects, the impurity level is less than 1.7%. In some aspects, the impurity level is less than 1.6%. In some aspects, the impurity level is less than 1.5%. In some aspects, the impurity level is less than 1.4%. In some aspects, the impurity level is less than 1.3%. In some aspects, the impurity level is less than 1.2%. In some aspects, the impurity level is less than 1.1%. In some aspects, the impurity level is less than 1%. In some aspects, the impurity level is less than 0.9%. In some aspects, the impurity level is less than 0.8%. In some aspects, the impurity level is less than 0.7%. In some aspects, the impurity level is less than 0.6%. In some aspects, the impurity level is less than 0.5%. In some aspects, the impurity level is less than 0.4%. In some aspects, the total impurity level is from about 0.5% to less than 2.0%. In some aspects, the total impurity level is from about 0.5% to less than 1.5%. In some aspects, the total impurity level is from about 0.5% to less than 1.4%. In some aspects, the total impurity level is from about 0.5% to less than 1.3%. In some aspects, the total impurity level is from about 0.5% to less than 1.2%. In some aspects, the total impurity level is from about 0.5% to less than 1.1%. In some aspects, the total impurity level is from about 0.5% to less than 1.0%. In some aspects, the total impurity level is from about 0.5% to less than 0.9%.
In embodiments, a pharmaceutical composition described herein (e.g., oral formulation, tablet, bead, capsule, granule) has an assay-indicated amount% (LC) of about 90% to about 110%. In some aspects, the LC% is about 91% to about 109%. In some aspects, the LC% is about 92% to about 108%. In some aspects, the LC% is about 93% to about 107%. In some aspects, the LC% is from about 94% to about 106%. In some aspects, the LC% is about 95% to about 105%. In some aspects, the LC% is from about 96% to about 104%. In some aspects, the LC% is about 97% to about 103%. In some aspects, the LC% is about 97% to about 103%. In some aspects, the LC% is about 98% to about 102%. In some aspects, the LC% is about 99% to about 101%.
Method of treatment
In embodiments, the present disclosure provides methods of treating cancer in a patient by administering to the patient a therapeutically effective amount of a pharmaceutical composition, oral formulation, granule, bead, tablet, capsule, powder, or oral formulation described herein. The methods are effective in treating any cancer, particularly cancers modulated by the adenosine A2A receptor. In some aspects, the pharmaceutical composition, granule, bead, or oral formulation is for treating metastatic cancer. In some aspects, the method is for treating lung cancer, melanoma, renal cell carcinoma, breast cancer, colorectal cancer, bladder cancer, prostate cancer, or head and neck cancer. In some aspects, the methods are used to treat non-small cell lung cancer, malignant melanoma, renal cell carcinoma, triple negative breast cancer, colorectal cancer, or bladder cancer. In some aspects, the method is for treating lung cancer. In some aspects, the method is for treating non-small cell lung cancer. In some aspects, the methods are used to treat melanoma. In some aspects, the methods are used to treat malignant melanoma. In some aspects, the methods are used to treat renal cell carcinoma. In some aspects, the method is for treating breast cancer. In some aspects, the method is for treating triple negative breast cancer. In some aspects, the method is for treating colorectal cancer. In some aspects, the methods are used to treat microsatellite unstable colorectal cancer. In some aspects, the methods are used to treat bladder cancer. In some aspects, the methods are used to treat head and neck cancer. In some aspects, the methods are used to treat prostate cancer. In some aspects, the methods are used to treat castration-resistant prostate cancer. In some aspects, the methods are used to treat metastatic castration-resistant prostate cancer. The methods of treating cancer include methods of treating metastatic cancer, methods of treating cancer tumors, and methods of treating metastatic cancer tumors.
The pharmaceutical compositions, oral formulations, granules, beads, tablets, capsules, powders, and oral formulations described herein contain a therapeutically effective amount (i.e., an amount effective to treat cancer) of an adenosine A2A receptor antagonist. When administered to a method of treating cancer, such compositions will contain an amount of the active ingredient effective to achieve a desired result comprising one or more of: (i) slowing the progression of the cancer; (ii) enhancing anti-tumor immune memory; (iii) exceeding one or more of CD8+ cell infiltration, T cell activation, interferon-gamma pathway gene expression, and T cell clonal expansion beyond baseline; (iv) preventing the size or volume of the tumor from increasing over time; (v) decreasing the size or volume of a cancerous tumor over time; and (vi) preventing metastasis of cancerous tumors. Determination of a therapeutically effective amount of an adenosine A2A receptor antagonist is within the ability of those skilled in the art, particularly in light of the detailed disclosure herein.
In embodiments of methods of treating cancer with the pharmaceutical compositions and oral formulations (e.g., granules, beads, tablets, capsules, powders) described herein, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 1mg to about 1,000 mg. In some aspects, the therapeutically effective amount is from about 1mg to about 900 mg. In some aspects, the therapeutically effective amount is from about 1mg to about 800 mg. In some aspects, the therapeutically effective amount is from about 1mg to about 700 mg. In some aspects, the therapeutically effective amount is from about 1mg to about 600 mg. In some aspects, the therapeutically effective amount is from about 1mg to about 500 mg. In some aspects, the therapeutically effective amount is from about 1mg to about 400 mg.
In embodiments of methods of treating cancer with the pharmaceutical compositions and oral formulations (e.g., granules, beads, tablets, capsules, powders) described herein, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 100mg to about 1,000 mg. In some aspects, the therapeutically effective amount is from about 100mg to about 900 mg. In some aspects, the therapeutically effective amount is about 100mg to about 850 mg. In some aspects, the therapeutically effective amount is about 100mg to about 800 mg. In some aspects, the therapeutically effective amount is about 100mg to about 700 mg. In some aspects, the therapeutically effective amount is from about 100mg to about 600 mg. In some aspects, the therapeutically effective amount is about 100mg to about 500 mg. In some aspects, the therapeutically effective amount is about 100mg to about 450 mg. In some aspects, the therapeutically effective amount is about 100mg to about 400 mg. In some aspects, the therapeutically effective amount is about 100mg to about 300 mg. In some aspects, the therapeutically effective amount is about 150mg to about 250 mg. In some aspects, the therapeutically effective amount is about 200mg to about 400 mg. In some aspects, the therapeutically effective amount is about 250mg to about 350 mg. In some aspects, the therapeutically effective amount is about 300mg to about 500 mg. In some aspects, the therapeutically effective amount is about 350mg to about 450 mg. In some aspects, this therapeutically effective amount of administration is QD. In some aspects, this therapeutically effective amount of administration is BID.
In embodiments of methods of treating cancer with the pharmaceutical compositions and oral formulations (e.g., granules, beads, tablets, capsules, powders) described herein, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 100 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 125 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 150 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 175 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 200 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 225 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 250 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 275 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 300 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 325 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 350 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 375 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 400 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 425 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 450 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 475 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 500 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 525 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 550 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 575 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 600 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 625 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 650 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 675 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 700 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 725 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 750 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 775 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 800 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 825 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 850 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 875 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 900 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 950 mg. In some aspects, the therapeutically effective amount of the adenosine A2A receptor antagonist is about 1,000 mg. In some aspects, this therapeutically effective amount of administration is QD. In some aspects, this therapeutically effective amount of administration is BID.
The frequency of administration (e.g., once daily, twice daily, three times daily) and duration (e.g., one week, two weeks, one month, two months, six months, 1 year, 5 to 10 years, or until disease progression) of the pharmaceutical compositions described herein can vary depending on a variety of factors, e.g., whether the patient has another disease, as well as the route of administration; size, age, sex, health, weight; the nature and extent of the disease symptoms being treated; whether concurrent treatment (e.g., with chemotherapeutic agents, radiation therapy, or immunomodulatory compounds), complications of the cancer being treated, or other health-related issues exist. Adjustment and manipulation of the frequency and duration of treatment is within the ability of those skilled in the art. In some aspects, the pharmaceutical compositions described herein are administered to a patient once daily (QD). In some aspects, the pharmaceutical composition is administered twice daily (BID). In some aspects, the pharmaceutical composition is administered three times per day. In some aspects, the pharmaceutical composition is administered once daily for about 7 days. In some aspects, the pharmaceutical composition is administered once daily for about 14 days. In some aspects, the pharmaceutical composition is administered once daily for about 21 days. In some aspects, the pharmaceutical composition is administered once daily for about one month. In some aspects, the pharmaceutical composition is administered once daily until disease progression. In some aspects, the pharmaceutical composition is administered twice daily for about 7 days. In some aspects, the pharmaceutical composition is administered twice daily for about 14 days. In some aspects, the pharmaceutical composition is administered twice daily for about 21 days. In some aspects, the pharmaceutical composition is administered twice daily for one month. In some aspects, the pharmaceutical composition is administered twice daily until disease progression. Another administration cycle may begin immediately after 14 days of administration, or the treatment may be stopped for 14 days or a month, followed by another administration cycle. Another administration cycle may begin immediately after one month of administration, or the treatment may be stopped for 14 days or one month, followed by another administration cycle. Thus, after one cycle of administration (e.g., once/twice/three times daily for 7 days, 14 days, 21 days, 1 month), another cycle of administration may be started immediately, or treatment may be stopped for a period of time (e.g., 7 days, 14 days, 21 days, 1 month) followed by another cycle of administration. The cycles of administration and/or discontinuation can be the same time period (e.g., 14 days) or different time periods (e.g., 14 days for one cycle and 21 days for another cycle).
Manufacturing process
In embodiments, the adenosine A2A receptor antagonist (e.g., the compound of formula (III)) is micronized. The adenosine A2A receptor antagonist may be micronized by any method known in the art. In some aspects, the adenosine A2A receptor antagonist may be micronized by dry milling, alone or with one or more pharmaceutically acceptable excipients. An exemplary dry milling device is a jet mill. In some aspects, the adenosine A2A receptor antagonist is micronized by wet milling, either alone or with one or more pharmaceutically acceptable excipients. Exemplary wet milling apparatuses include planetary ball mills, stirred bead mills (agitator mills), and spray dryers.
After the adenosine A2A receptor antagonist is micronized, it is sieved and blended with pharmaceutically acceptable excipients as described herein. The screening step may be performed with any grinding or screening device known in the art, such as a rotary screen, roller screen, vibratory screen, roller vibratory screen, or comil. Any suitable mesh size may be used in this step of the process. In some aspects, the mesh size is #16 mesh U.S. standard sieve; or #18 mesh U.S. standard sieve; or #20 mesh U.S. standard sieve. In some aspects, the mesh size is #20 mesh U.S. standard sieve; or #30 mesh U.S. standard sieve; or #35 mesh U.S. standard sieve.
After sieving and blending the adenosine A2A receptor antagonist and the pharmaceutically acceptable excipient, the blended formulation is granulated to form agglomerates of the adenosine A2A receptor antagonist and the pharmaceutically acceptable excipient. Granulation techniques include wet granulation (e.g., low shear, high shear, fluidized bed); dry granulation (e.g., roller compaction), and the like. The granules are then dried (e.g., oven tray drying, fluid bed drying) to remove any moisture if the granules were not produced by a drying process.
After or in series with granulation, using techniques known in the artAny grinding device known to grind formulations, such as rotary sifters, roller sifters, vibratory sifters, or roller vibratory sifters. In some aspects, use may be made ofA pulverizer (Fitzpatrick Company (The Fitzpatrick Company)). For some dry granulation processes, a grinding step may be coupled to and immediately follow the granulation process. This formulation may then be further blended with pharmaceutically acceptable excipients, compressed into tablets, and optionally coated with (a)
These methods of forming the compositions described herein are described in more detail in the examples.
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