Pharmaceutical composition for treating depressive disorders

Abstract

Pharmaceutical compositions comprising (a) about 0.1 mg to about 5 mg 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine2,2- dioxide ("COMPOUND A"); (b) a diluent; (c) a disintegrant; (d) a binder; and (e) a lubricant and methods of preparing the same are disclosed.

Description

PHARMACEUTICAL COMPOSITION FOR TREATING DEPRESSIVE DISORDERSTECHNICAL FIELD

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 637,337, filed April 22, 2024; U.S. Provisional Application No. 63 / 640,771 , filed April 30, 2024; U.S. Provisional Application No. 63 / 641 ,890, filed May 2, 2024; U.S. Provisional Application No. 63 / 641 ,908, filed May 2, 2024; U.S. Provisional Application No. 63 / 691 ,572, filed September 6, 2024; U.S. Provisional Application No. 63 / 707,311 , filed October 15, 2024; U.S. Provisional Application No. 63 / 709,014, filed October 18, 2024; U.S. Provisional Application No. 63 / 767,686, filed March 6, 2025; and U.S. Provisional Application No. 63 / 767,812, filed March 6, 2025. The contents of each of these applications are herein incorporated by reference in their entirety.

[0002] Disclosed herein are pharmaceutical compositions comprising about 0.1 mg to about 5 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”). Also disclosed herein are methods of preparing a pharmaceutical composition comprising about 0.1 mg to about 5 mg of COMPOUND A.BACKGROUND

[0003] 9-[4-(Cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A” or “CMPD A”) is a potent and selective positive allosteric modulator (PAM) of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptors. COMPOUND A is useful in the treatment of depressive disorders.

[0004] Synthesis and characterization of COMPOUND A may proceed according to the procedures disclosed in U.S. Patent No. 8,575,154, the entirety of which is hereby incorporated by reference.COMPOUND A

[0005] COMPOUND A is also known as 9-[4-(cyclohexyloxy)phenyl]-7-methyl- 3,4-dihydro-2H-2A6-pyrazino[2, 1 -c][1 , 2, 4]thiadiazine-2, 2-dione (International Nonproprietary Name, World Health Organization).BRIEF SUMMARY

[0006] The present invention generally provides pharmaceutical compositions comprising COMPOUND A. The pharmaceutical compositions provide efficient release of COMPOUND A and while maintaining storage stability.

[0007] Disclosed herein are pharmaceutical compositions comprising about 0.1 mg to about 5 mg of COMPOUND A.

[0008] In one embodiment, the pharmaceutical composition comprises:(a) about 0.1 mg to about 5 mg COMPOUND A;(b) a diluent;(c) a disintegrant;(d) a binder; and(e) a lubricant.

[0009] Also disclosed herein are methods of preparing a pharmaceutical composition comprising about 0.1 mg to about 5 mg of COMPOUND A.

[0010] In one embodiment, the method comprises:(a) combining purified water and a binder to prepare a binder solution;(b) mixing about 0.1 mg to about 5 mg of COMPOUND A and a first portion of a diluent with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with a second portion of a diluent, a disintegrant, and a lubricant to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition.BRIEF DESCRIPTION OF THE FIGURES

[0011] FIG. 1 shows a process flow diagram for the production of pharmaceutical compositions according to the present disclosure.

[0012] FIG. 2 shows the dissolution profile of an exemplary immediate-release tablet according to the present disclosure.DETAILED DESCRIPTIONDefinitions:

[0013] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0014] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs.

[0015] As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. “A,” “one or more,” and “at least one” are used interchangeably herein.

[0016] As used herein, the term “about,” when used to modify a numeric value or numeric range, indicate that deviations of up to 10% above and down to 10% below the value or range remain within the intended meaning of the recited value orrange. In some embodiments, “about” refers to ± 10%. In some embodiments, “about” refers to ± 9%. In some embodiments, “about” refers to ± 8%. In some embodiments, “about” refers to ± 7%. In some embodiments, “about” refers to ± 6%. In some embodiments, “about” refers to ± 5%. In some embodiments, “about” refers to ± 4%. In some embodiments, “about” refers to ± 3%. In some embodiments, “about” refers to ± 2%. In some embodiments, “about” refers to ± 1 %. It is understood that wherever aspects are described herein with the language “about” a numeric value or range, otherwise analogous aspects referring to the specific numeric value or range (without “about”) are also provided. It is also understood that wherever aspects are described herein referring to a numeric value or range without the language “about,” otherwise analogous aspects referring to “about” the specific numeric value or range are also provided.

[0017] As used herein, the terms “treatment” and “administration” of an agent to a subject may be used interchangeably and include any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable oral or non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and administration by another.

[0018] As used herein, the term “pharmaceutically acceptable” means a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” means any nontoxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure.

[0019] As used herein, “isotopic variant” means a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen(1H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (140), oxygen-15 (150), oxygen-16 (160), oxygen-17 (170), oxygen-18 (180), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35CI), chlorine-36 (36CI), chlorine-37 (37CI), bromine-79 (79Br), bromine- 81 (81Br), iodine-123 (123l), iodine-125 (125l), iodine-127 (127l), iodine-129 (129l), and iodine-131 (131l). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), and oxygen-18 (18O). In certain embodiments, an “isotopic variant” of a compound is in an unstable form, that is, radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), and oxygen-15 (15O). It will be understood that, in a compound as provided herein, any hydrogen can be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, and any oxygen can be18O, as example, where feasible according to the judgment of one of skill in the art. In certain embodiments, an “isotopic variant” of a compound contains an unnatural proportion of deuterium. With regard to the compounds provided herein, it is understood that in some embodiments where a compound contains an unnatural proportion of deuterium, the abundance of deuterium at a given position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

[0020] As used herein, the term “solid form” includes any solid form of a compound, such as COMPOUND A, including a substantially crystalline form, a crystalline form, an amorphous form, a solid dispersion, a solvate, a co-crystal, or a salt of the compound that is in solid form.

[0021] As used herein, the terms “crystalline form,” “crystal form,” and “Form” interchangeably refer to a solid having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid state nuclear magnetic resonance (SS-NMR), differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Accordingly, as used herein, a reference to a Form of a compound, such as a Form of COMPOUND A, including, but not limited to, Form I of COMPOUND A, Mono-Chloroform Solvate Form of COMPOUND A, and camphor sulfonic acid Solid Form of COMPOUND A, refers to a unique crystalline form that can be identified and distinguished from other forms using one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SS NMR, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of this disclosure are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 26).

[0022] As used herein, the term “solvate” refers to a crystal form comprising one or more molecules of a compound of the present disclosure and one or more molecules of a solvent or solvents incorporated into the crystal lattice instoichiometric or nonstoichiometric amounts. When the solvent incorporated into the crystal lattice is water, the solvate is referred to as a “hydrate.”

[0023] As used herein, the term “co-crystal” refers to a crystalline material composed of two or more different molecules, such as COMPOUND A and at least one co-crystal former (or coformer), in the same crystal lattice. In some embodiments, co- crystal components are in a neutral state and interact nonionically.

[0024] As used herein, the term “coformer” refers to a component that interacts nonionically with the API in the crystal lattice, is not a solvent (including water), and is typically nonvolatile.

[0025] As used herein, the term “solid form dose” includes, but is not limited to, a tablet (including an immediate-release tablet), capsule, granule, or an agglomerated powder. Capsules or tablets can be formulated and can be manufactured to be easy to swallow or chew. For the avoidance of doubt, it is to be understood that a “solid form dose” may, but need not, comprise a “solid form” as described and defined elsewhere in this disclosure.Non-Limiting Embodiments:

[0026] Without limitation, some embodiments of the disclosure include:1 . A pharmaceutical composition comprising(a) about 0.1 mg to about 5 mg 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1 -c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”);(b) a diluent;(c) a disintegrant;(d) a binder; and(e) a lubricant.2. The pharmaceutical composition according to Embodiment 1 , comprising about 1 mg to about 3 mg of the COMPOUND A.3. The pharmaceutical composition according to Embodiment 1 or Embodiment 2, comprising about 1 mg of the COMPOUND A.4. The pharmaceutical composition according to Embodiment 1 or Embodiment2, comprising about 3 mg of the COMPOUND A.5. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 10% to about 90%, by weight of the composition, of the diluent.6. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 40% to about 90%, by weight of the composition, of the diluent.7. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 80% to about 90%, by weight of the composition, of the diluent.8. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the diluent comprises mannitol, microcrystalline cellulose, starch, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, lactose, or any combination thereof.9. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the diluent comprises microcrystalline cellulose, mannitol, lactose, or any combination thereof.10. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the diluent comprises a combination of microcrystalline cellulose and mannitol.11 . The pharmaceutical composition according to Embodiment 10, wherein the composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 40% to about 90%, by weight of the composition, of mannitol.12. The pharmaceutical composition according to Embodiment 11 , wherein the composition comprises about 10% to about 20%, by weight of the composition, ofmicrocrystalline cellulose, and about 65% to about 75%, by weight of the composition, of mannitol.13. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 1 % to about 20%, by weight of the composition, of the disintegrant.14. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 2% to about 10%, by weight of the composition, of the disintegrant.15. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 3% to about 8%, by weight of the composition, of the disintegrant.16. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the disintegrant comprises carboxymethylcellulose, croscarmellose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium starch glycolate, com starch, hydroxypropyl starch, partially pregelatinized starch, or any combination thereof.17. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the disintegrant comprises sodium starch glycolate.18. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 0.5% to about 20%, by weight of the composition, of the binder.19. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 1 % to about 10%, by weight of the composition, of the binder.20. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 2% to about 6%, by weight of the composition, of the binder.21 . The pharmaceutical composition according to any one of the preceding Embodiments, wherein the binder comprises microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, or any combination thereof.22. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the binder comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof.23. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the binder comprises hydroxypropyl cellulose.24. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 0.1 % to about 5%, by weight of the composition, of the lubricant.25. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 0.2% to about 3%, by weight of the composition, of the lubricant.26. The pharmaceutical composition according to any one of the preceding Embodiments, comprising about 0.5% to about 1 .5%, by weight of the composition, of the lubricant.27. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the lubricant comprises magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, or any combination thereof.28. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the lubricant comprises magnesium stearate, calcium stearate, sodium stearyl fumarate, or any combination thereof.29. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the lubricant comprises magnesium stearate.30. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition further comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof.31 . The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition is in the form of a solid form dose.32. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition is in the form of a tablet.33. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition is in the form of an immediate release tablet.34. The pharmaceutical composition according to Embodiment 32 or Embodiment 33, wherein the tablet or the immediate-release tablet is wet-granulated.35. The pharmaceutical composition according to Embodiment 34, wherein the tablet or the immediate release tablet comprises an intragranular component and an extragranular component.36. The pharmaceutical composition according to Embodiment 35, wherein the intragranular component comprises COMPOUND A, a first portion of the diluent, and the binder, and the extragranular component comprises a second portion of the diluent and comprises the disintegrant and the lubricant.37. The pharmaceutical composition according to any one of Embodiments 32-36, wherein the tablet or the immediate-release tablet comprises a film coating.38. The pharmaceutical composition according to Embodiments 37, wherein the film coating comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof.39. The pharmaceutical composition according to any one of the preceding Embodiments, comprising:(a) about 0.1 mg to about 5 mg COMPOUND A;(b) about 40% to about 90%, by weight of the composition, of the diluent;(c) about 2% to about 10%, by weight of the composition, of the disintegrant;(d) about 1 % to about 10%, by weight of the composition, of the binder; and(e) about 0.1 % to about 5%, by weight of the composition, of the lubricant. The pharmaceutical composition according to any one of the precedingEmbodiments, comprising(a) about 0.1 mg to about 5 mg COMPOUND A;(b1 ) about 5% to about 25%, by weight of the composition, of microcrystalline cellulose;(b2) about 40% to about 90%, by weight of the composition, of mannitol;(c) about 2% to about 10%, by weight of the composition, of sodium starch glycolate;(d) about 1 % to about 10%, by weight of the composition, of hydroxypropyl cellulose; and(e) about 0.1 % to about 5%, by weight of the composition, of magnesium stearate. The pharmaceutical composition according to any one of the preceding Embodiments, comprising(a) about 1 mg to about 3 mg COMPOUND A;(b1 ) about 10% to about 20%, by weight of the composition, of microcrystalline cellulose;(b2) about 65% to about 80%, by weight of the composition, of mannitol;(c) about 3% to about 8%, by weight of the composition, of sodium starch glycolate;(d) about 2% to about 6%, by weight of the composition, of hydroxypropyl cellulose;(e) about 0.5% to about 1 .5%, by weight of the composition, of magnesium stearate; and(f) a film coating. The pharmaceutical composition according to Embodiment 40 or Embodiment41 , wherein the composition is in the form of a tablet including an intragranular component comprising COMPOUND A, a first portion of themicrocrystalline cellulose, and comprising the mannitol and the hydroxypropyl cellulose, and an extragranular component comprising a second portion of the microcrystalline cellulose and comprising the sodium starch glycolate and the magnesium stearate. The pharmaceutical composition according to any one of the preceding Embodiments comprising, in the form of an immediate-release tablet, (a) 1.0 mg COMPOUND A;(b1 ) 22.5 mg microcrystalline cellulose(b2) 113.0 mg mannitol;(c) 7.5 mg sodium starch glycolate;(d) 4.5 mg hydroxypropyl cellulose; and(e) 1.5 mg magnesium stearate. The pharmaceutical composition according to any one of the preceding Embodiments comprising, in the form of an immediate-release tablet, (a) 3.0 mg COMPOUND A;(b1 ) 22.5 mg microcrystalline cellulose(b2) 111.0 mg mannitol;(c) 7.5 mg sodium starch glycolate;(d) 4.5 mg hydroxypropyl cellulose; and(e) 1.5 mg magnesium stearate. The pharmaceutical composition according to Embodiment 43 or Embodiment 44, wherein the immediate release tablet includes an intragranular component comprising the COMPOUND A, 15.0 mg of the microcrystalline cellulose, the mannitol, and the hydroxypropyl cellulose, and an extragranular component comprising 7.5 mg of the microcrystalline cellulose, the sodium starch glycolate, and the magnesium stearate. The pharmaceutical composition according to Embodiment 45, wherein the immediate release tablet further comprises 6.1 mg of film coating.The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition has a particle size dio of about 0.1 pm to about 3 pm. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition has a particle size dio of about 1 pm to about 2 pm. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition has a particle size dso of about 3 pm to about 10 pm. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition has a particle size dso of about 4 pm to about 8 pm. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition has a particle size doo of about 10 pm to about 40 pm. The pharmaceutical composition according to any one of the preceding Embodiments, wherein the composition has a particle size doo of about 13 pm to about 30 pm. The pharmaceutical composition according to any one of the preceding Embodiments, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 70% of COMPOUND A after 30 minutes in Japanese pharmacopoeia 2ndfluid for dissolution test (JP2) with 0.1 % hexadecyltrimethylammonium bromide (CTAB) using a paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at 37°C. The pharmaceutical composition according to Embodiment 53, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 75% of COMPOUND A.The pharmaceutical composition according to Embodiment 53 or Embodiment 54, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 85% of COMPOUND A. The pharmaceutical composition according to any one of Embodiments 53-55, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 90% of COMPOUND A. The pharmaceutical composition according to any one of Embodiments 53-56, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 95% of COMPOUND A. The pharmaceutical composition according to any one of Embodiments 53-57, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 97% of COMPOUND A. A method of preparing a pharmaceutical composition comprising:(a) combining purified water and a binder to prepare a binder solution;(b) mixing about 0.1 mg to about 5 mg 9-[4-(cyclohexyloxy)phenyl]-7-methyl- 3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) and a first portion of a diluent with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with a second portion of a diluent, a disintegrant, and a lubricant to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition.60. The method according to Embodiment 59, wherein in (b) about 1 mg to about 3 mg of the COMPOUND A is used to prepare the granulated composition.61 . The method according to Embodiment 59 or Embodiment 60, wherein in (b) about 1 mg of the COMPOUND A is used to prepare the granulated composition.62. The method according to Embodiment 59 or Embodiment 60, wherein in (b) about 3 mg of the COMPOUND A is used to prepare the granulated composition.63. The method according to any one of Embodiments 59-62, wherein (b) is performed in a fluid bed granulator.64. The method according to any one of Embodiments 59-63, wherein the milling in (c) is performed in a screening mill.65. The method according to Embodiment 64, wherein the screening mill has a rotating impeller.66. The method according to any one of Embodiments 59-65, wherein (d) is performed in a diffusion mixer.67. The method according to Embodiment 66, wherein the diffusion mixer is a horizonal blender or a drum blender.68. The method according to any one of Embodiments 59-68, wherein in (e) the pharmaceutical composition is compressed into a tablet.69. The method according to Embodiment 68, wherein (e) is performed using a tablet press.70. The method according to Embodiment 68 or Embodiment 69, further comprising (f) coating the tablet with a film coating agent.71 . The method according to Embodiment 70, wherein the coating in (f) is pan coating.72. The method according to Embodiment 71 , wherein the pan coating is performed using a perforated coating system.73. The method according to any one of Embodiments 70-72, wherein the film coating comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof.74. The method according to any one of Embodiments 59-73, wherein the binder comprises microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, or any combination thereof.75. The method according to any one of Embodiments 59-74, wherein the binder comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof.76. The method according to any one of Embodiments 59-75, wherein the binder comprises hydroxypropyl cellulose.77. The method according to any one of Embodiments 59-76, wherein the diluent comprises mannitol, microcrystalline cellulose, starch, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, lactose, or any combination thereof.78. The method according to any one of Embodiments 59-77, wherein the diluent comprises microcrystalline cellulose, mannitol, lactose, or any combination thereof.79. The method according to any one of Embodiments 59-78, wherein the diluent comprises a combination of microcrystalline cellulose and mannitol.80. The method according to any one of Embodiments 59-79, wherein the first portion of the diluent comprises microcrystalline cellulose and mannitol.81 . The method according to any one of Embodiments 59-80, wherein the second portion of the diluent comprises microcrystalline cellulose.82. The method according to any one of Embodiments 59-81 , wherein the disintegrant comprises carboxymethylcellulose, croscarmellose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium starch glycolate, com starch, hydroxypropyl starch, partially pregelatinized starch, or any combination thereof.83. The method according to any one of Embodiments 59-82, wherein the disintegrant comprises sodium starch glycolate.84. The method according to any one of Embodiments 59-83, wherein the lubricant comprises magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, or any combination thereof.85. The method according to any one of Embodiments 59-84, wherein the lubricant comprises magnesium stearate, calcium stearate, sodium stearyl fumarate, or any combination thereof.86. The method according to any one of Embodiments 59-85, wherein the lubricant comprises magnesium stearate.87. The method according to any one of Embodiments 59-86 comprising,(a) combining purified water and hydroxypropyl cellulose to prepare a binder solution;(b) mixing about 0.1 mg to about 5 mg COMPOUND A, microcrystalline cellulose, and mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with microcrystalline cellulose, sodium starch glycolate, and magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet.The method according to any one of Embodiments 59-87 comprising,(a) combining purified water and 4.5 mg hydroxypropyl cellulose to prepare a binder solution;(b) mixing 1 mg COMPOUND A, 15.0 mg microcrystalline cellulose, and 113.0 mg mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with 7.5 mg microcrystalline cellulose, 7.5 mg sodium starch glycolate, and 1.5 mg magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet. The method according to any one of Embodiments 59-88 comprising,(a) combining purified water and 4.5 mg hydroxypropyl cellulose to prepare a binder solution;(b) mixing 3 mg COMPOUND A, 15.0 mg microcrystalline cellulose, and 111.0 mg mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with 7.5 mg microcrystalline cellulose, 7.5 mg sodium starch glycolate, and 1.5 mg magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet. The method according to any one of Embodiments 87-89, further comprising(f) coating the tablet with 6.1 mg of film coating. The method according to any one of Embodiments 59-90, wherein the pharmaceutical composition has a particle size dio of about 0.1 pm to about 3 pm.92. The method according to any one of Embodiments 59-91 , wherein the pharmaceutical composition has a particle size dio of about 1 pm to about 2 pm.93. The method according to any one of Embodiments 59-92, wherein the pharmaceutical composition has a particle size dso of about 3 pm to about 10 pm.94. The method according to any one of Embodiments 59-93, wherein the pharmaceutical composition has a particle size dso of about 4 pm to about 8 pm.95. The method according to any one of Embodiments 59-94, wherein the pharmaceutical composition has a particle size doo of about 10 pm to about 40 pm.96. The method according to any one of Embodiments 59-95, wherein the pharmaceutical composition has a particle size doo of about 13 pm to about 30 pm.

[0027] Disclosed herein are pharmaceutical compositions comprising about 0.1 mg to about 5 mg of COMPOUND A.

[0028] In some embodiments, the pharmaceutical composition further comprises at least one additive. Non-limiting examples of such additives include diluents, binders, disintegrants, lubricants, glidants, colorants, pH adjusters, surfactants, stabilizers, acidulants, sweeteners, flavors, coating agents, coating additives, and combinations of any of the foregoing.

[0029] In some embodiments, the at least one additive is chosen from diluents, binders, disintegrants, lubricants, and combinations of any of the foregoing.

[0030] In one embodiment, the pharmaceutical composition comprises:(a) about 0.1 mg to about 5 mg COMPOUND A;(b) a diluent;(c) a disintegrant;(d) a binder; and(e) a lubricant.

[0031] In some embodiments, the pharmaceutical composition comprises COMPOUND A. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of COMPOUND A. In some embodiments, the pharmaceutical composition comprises an isotopic variant of COMPOUND A. In some embodiments, the pharmaceutical composition comprises a solid form of COMPOUND.

[0032] Salts of COMPOUND A (including pharmaceutically acceptable salts) may include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like. In some embodiments, the salts with inorganic bases include alkali metal salts, such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, and ammonium salt. In some embodiments, the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N’-dibenzylethylenediamine, and the like. In some embodiments, the salts with inorganic acids include salts with hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. In some embodiments, the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. In some embodiments, the salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. In some embodiments, the salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like. In some embodiments, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.) and the like, ammonium salts, and the like are used. In some embodiments, when the compoundhas a basic functional group, salts with inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like are used.

[0033] In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 4.75 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 4.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 4.25 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 4 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 3.75 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 3.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 3.25 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.75 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.25 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .5 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .75 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.25 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.5 mg to about 3 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 2.75 mg COMPOUND A. In some embodiments, the pharmaceuticalcomposition comprises about 1 mg to about 2.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 2.25 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 2 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 1.75 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 1.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 1.25 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg to about 2.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg to about 2 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg to about 1.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg to about 1 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg to about 0.75 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg to about 0.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 2.5 mg COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.75 mg to about 2 mg COMPOUND A.

[0034] In some embodiments, the pharmaceutical composition comprises about 0.1 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.15 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.2 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.25 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.3 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.35 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.4 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.45 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of COMPOUND A. In some embodiments, the pharmaceuticalcomposition comprises about 0.55 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.6 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.65 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.7 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.75 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.8 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.85 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.9 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 0.95 mg of COMPOUND A.

[0035] In some embodiments, the pharmaceutical composition comprises about 1 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.05 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.1 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.15 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.2 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .25 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .3 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.35 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.4 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .45 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .5 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.55 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.6 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .65 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.7 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.75 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprisesabout 1.8 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .85 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1 .9 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 1.95 mg of COMPOUND A.

[0036] In some embodiments, the pharmaceutical composition comprises about 2 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.05 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.1 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.15 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.2 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.25 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.3 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.35 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.4 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.45 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.5 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.55 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.6 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.65 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.7 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.75 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.8 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.85 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.9 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 2.95 mg of COMPOUND A.

[0037] In some embodiments, the pharmaceutical composition comprises about 3 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.05 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.1 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.15 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.2 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.25 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.3 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.35 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.4 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.45 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.5 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.55 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.6 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.65 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.7 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.75 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.8 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.85 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.9 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 3.95 mg of COMPOUND A.

[0038] In some embodiments, the pharmaceutical composition comprises about 4 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.05 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.1 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.15 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprisesabout 4.2 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.25 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.3 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.35 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.4 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.45 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.5 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.55 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.6 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.65 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.7 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.75 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.8 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.85 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.9 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 4.95 mg of COMPOUND A. In some embodiments, the pharmaceutical composition comprises about 5 mg of COMPOUND A.

[0039] In some embodiments, whether in the form of COMPOUND A, an isotopic variant thereof, or a pharmaceutically acceptable salt of COMPOUND A, the dosages of COMPOUND A disclosed herein refers to the total amount in milligrams of COMPOUND A calculated based on the free base of COMPOUND A. For example, when COMPOUND A is in the form of a pharmaceutically acceptable salt, an equivalent amount of one or more pharmaceutically acceptable salts of COMPOUND A based on the weight of the free base therein may further be present.

[0040] In some embodiments, the pharmaceutical composition comprises (b) a diluent. Non-limiting examples of diluents include one or more pharmaceutically acceptable excipient(s) that reduce the concentration of the active ingredient(COMPOUND A). The diluent can also increase bulk volume and / or improve content uniformity of the pharmaceutical composition.

[0041] In some embodiments, the pharmaceutical composition comprises about 10% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 10% to about 85%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 10% to about 80%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 10% to about 75%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 10% to about 70%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 10% to about 66%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 10% to about 65%, by weight of the composition, of the diluent.

[0042] In some embodiments, the pharmaceutical composition comprises about 20% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 20% to about 85%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 20% to about 80%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 20% to about 75%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 20% to about 70%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 20% to about 66%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 20% to about 65%, by weight of the composition, of the diluent.

[0043] In some embodiments, the pharmaceutical composition comprises about 30% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 30% to about 85%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 30% to about 80%, by weight of thecomposition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 30% to about 75%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 30% to about 70%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 30% to about 66%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 30% to about 65%, by weight of the composition, of the diluent.

[0044] In some embodiments, the pharmaceutical composition comprises about 40% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 40% to about 85%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 40% to about 80%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 40% to about 75%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 40% to about 70%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 40% to about 66%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 40% to about 65%, by weight of the composition, of the diluent.

[0045] In some embodiments, the pharmaceutical composition comprises about 45% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 45% to about 85%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 45% to about 80%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 45% to about 75%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 45% to about 70%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 45% to about 66%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 45% to about 65%, by weight of the composition, of the diluent.

[0046] In some embodiments, the pharmaceutical composition comprises about 50% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 50% to about 85%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 50% to about 80%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 50% to about 75%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 50% to about 70%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 50% to about 66%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 50% to about 65%, by weight of the composition, of the diluent.

[0047] In some embodiments, the pharmaceutical composition comprises about 55% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 60% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 65% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 70% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 75% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 80% to about 90%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 85% to about 90%, by weight of the composition, of the diluent.

[0048] In some embodiments, the pharmaceutical composition comprises about 10%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 11 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 12%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 13%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about14%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 15%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 16%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 17%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 18%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 19%, by weight of the composition, of the diluent.

[0049] In some embodiments, the pharmaceutical composition comprises about 20%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 21 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 22%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 23%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 24%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 25%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 26%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 27%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 28%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 29%, by weight of the composition, of the diluent.

[0050] In some embodiments, the pharmaceutical composition comprises about 30%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 31 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 32%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 33%, by weight of the composition, ofthe diluent. In some embodiments, the pharmaceutical composition comprises about 34%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 35%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 36%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 37%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 38%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 39%, by weight of the composition, of the diluent.

[0051] In some embodiments, the pharmaceutical composition comprises about 40%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 41 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 42%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 43%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 44%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 45%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 46%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 47%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 48%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 49%, by weight of the composition, of the diluent.

[0052] In some embodiments, the pharmaceutical composition comprises about 50%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 51 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 52%, by weight of the composition, of the diluent. In some embodiments, thepharmaceutical composition comprises about 53%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 54%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 55%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 56%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 57%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 58%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 59%, by weight of the composition, of the diluent.

[0053] In some embodiments, the pharmaceutical composition comprises about 60%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 61 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 62%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 63%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 64%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 65%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 66%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 67%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 68%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 69%, by weight of the composition, of the diluent.

[0054] In some embodiments, the pharmaceutical composition comprises about 70%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 71 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about72%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 73%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 74%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 75%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 76%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 77%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 78%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 79%, by weight of the composition, of the diluent.

[0055] In some embodiments, the pharmaceutical composition comprises about 80%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 81 %, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 82%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 83%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 84%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 85%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 86%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 87%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 88%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 89%, by weight of the composition, of the diluent. In some embodiments, the pharmaceutical composition comprises about 90%, by weight of the composition, of the diluent.

[0056] In some embodiments, the diluent comprises mannitol, microcrystalline cellulose, starch, anhydrous calcium phosphate, precipitated calcium carbonate,calcium silicate, lactose, or any combination thereof. In some embodiments, the diluent comprises microcrystalline cellulose, mannitol, lactose, or any combination thereof.

[0057] In some embodiments, the diluent comprises a combination of microcrystalline cellulose and mannitol. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the diluent comprises mannitol.

[0058] Non-limiting examples of mannitol diluent include D-mannitol (for example, PEARLITOL® 50C from Roquette Co.).

[0059] Non-limiting examples of microcrystalline cellulose diluent include CEOLUS™ PH-101 from Asahi Kasei Co., Ltd.

[0060] Non-limiting examples of starch diluent include com starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch.

[0061] Non-limiting examples of lactose diluent include anhydrous lactose and lactose hydrate.

[0062] In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 40% to about 90%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 20%, by weight of the composition, of microcrystalline cellulose, and about 40% to about 90%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 10% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 40% to about 90%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 10% to about 20%, by weight of the composition, of microcrystalline cellulose, and about 40% to about 90%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 45% to about 90%, by weight of the composition, of mannitol. In some embodiments, thepharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 50% to about 90%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 55% to about 90%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 65% to about 90%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 45% to about 85%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 45% to about 80%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 45% to about 75%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 55% to about 85%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 60% to about 80%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 10% to about 20%, by weight of the composition, of microcrystalline cellulose, and about 65% to about 75%, by weight of the composition, of mannitol.

[0063] In some embodiments, the pharmaceutical composition comprises about 14.5%, by weight of the composition, of microcrystalline cellulose, and about 70%, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 14.5%, by weight of the composition, of microcrystalline cellulose, and about 71 %, by weight of the composition, of mannitol. In some embodiments, the pharmaceutical composition comprises about 14.5%, by weight of the composition, of microcrystalline cellulose, and about 72%, by weight of the composition, of mannitol. In some embodiments, the pharmaceuticalcomposition comprises about 14.5%, by weight of the composition, of microcrystalline cellulose, and about 73%, by weight of the composition, of mannitol.

[0064] In some embodiments, the pharmaceutical composition comprises (c) a disintegrant. Non-limiting examples of disintegrants include one or more pharmaceutically acceptable excipient(s) that cause disintegration of the pharmaceutical composition to support the release of the active ingredient (COMPOUND A) therefrom.

[0065] In some embodiments, the pharmaceutical composition comprises about 1 % to about 20%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 % to about 15%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 % to about 10%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2% to about 10%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 % to about 9.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2% to about 9.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 % to about 9%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2% to about 9%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 % to about 8.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2% to about 8.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 % to about 8%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 .5% to about 8%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2% to about 8%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% to about 8%,by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 3% to about 8%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 3% to about 7.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 3% to about 7%, by weight of the composition, of the disintegrant.

[0066] In some embodiments, the pharmaceutical composition comprises about 1 %, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 1 .5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 3%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 4%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 4.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 5.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 6%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 6.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 7%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 7.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 8%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 8.5%, by weight of the composition, of the disintegrant. In some embodiments, thepharmaceutical composition comprises about 9%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 9.5%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 10%, by weight of the composition, of the disintegrant.

[0067] In some embodiments, the pharmaceutical composition comprises about 11 %, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 12%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 13%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 14%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 15%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 16%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 17%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 18%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 19%, by weight of the composition, of the disintegrant. In some embodiments, the pharmaceutical composition comprises about 20%, by weight of the composition, of the disintegrant.

[0068] In some embodiments, the disintegrant comprises carboxymethylcellulose, croscarmellose, low-substituted hydroxypropyl cellulose (L- HPC), carboxymethylcellulose calcium, croscarmellose sodium, sodium starch glycolate, com starch, hydroxypropyl starch, partially pregelatinized starch, or any combination thereof.

[0069] In some embodiments, the disintegrant comprises sodium starch glycolate. In some embodiments, the sodium starch glycolate is Type A.

[0070] Non-limiting examples of sodium starch glycolate Type A disintegrant include Primojel® from DFE Pharma.

[0071] Non-limiting examples of croscarmellose sodium disintegrant include Ac-Di-Sol® from IFF Pharma Solutions.

[0072] In some embodiments, the pharmaceutical composition comprises (d) a binder. Non-limiting examples of binders include one or more pharmaceutically acceptable excipient(s) that impart enhanced cohesion by binding the active ingredient (COMPOUND A) and other excipients (e.g., the diluent, the disintegrant, and / or the lubricant) together in a mixture. Non-limiting examples of binders also include one or more pharmaceutically acceptable excipient(s) that impart binding properties between the particles of the pharmaceutical composition during dry or wet granulation and / or during direct compression.

[0073] In some embodiments, the pharmaceutical composition comprises about 0.5% to about 20%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 20%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 15%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 15%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 10%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 9.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 9%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 8.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 8%, by weight of the composition, of the binder.

[0074] In some embodiments, the pharmaceutical composition comprises about 1 % to about 10%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 9.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 9%, by weight of thecomposition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 8.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 8%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 7.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 7%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 6.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 6%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 5.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 % to about 5%, by weight of the composition, of the binder.

[0075] In some embodiments, the pharmaceutical composition comprises about 2% to about 10%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 9.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 9%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 8.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 8%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 7.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 7%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 6.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2% to about 6%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2.5% to about 6%, by weight of the composition, of the binder. Insome embodiments, the pharmaceutical composition comprises about 3% to about 6%, by weight of the composition, of the binder.

[0076] In some embodiments, the pharmaceutical composition comprises about 0.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 %, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 1 .5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 2.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 3%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 3.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 4%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 4.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 5.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 6%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 6.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 7%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 7.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 8%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 8.5%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 9%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 9.5%, by weight of the composition, of the binder. In some embodiments, thepharmaceutical composition comprises about 10%, by weight of the composition, of the binder.

[0077] In some embodiments, the pharmaceutical composition comprises about 11 %, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 12%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 13%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 14%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 15%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 16%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 17%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 18%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 19%, by weight of the composition, of the binder. In some embodiments, the pharmaceutical composition comprises about 20%, by weight of the composition, of the binder.

[0078] In some embodiments, the binder comprises microcrystalline cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), povidone, copovidone, or a combination thereof. In some embodiments, the binder comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof.

[0079] In some embodiments, the binder comprises hydroxypropyl cellulose (HPC).

[0080] Non-limiting examples of microcrystalline cellulose binder include microcrystalline cellulose (such as CEOLUS™ KG-802 and CEOLUS™ PH-302 from Asahi Kasei Co., Ltd.), microcrystalline cellulose granulates, and microcrystalline cellulose fine particles.

[0081] Non-limiting examples of hydroxypropyl methylcellulose (HPMC) binder include PHARMACOAT® (Hypromellose 2910), TC-5 (grades: E, M, R) from Shin- Etsu Chemical Co., Ltd.

[0082] Non-limiting examples of hydroxypropyl cellulose (HPC) binder include NISSO HPC / CELNY™ grades L, SL, or SSL from Nippon Soda Co., Ltd.

[0083] In some embodiments, the pharmaceutical composition comprises (e) a lubricant. Non-limiting examples of lubricants include one or more pharmaceutically acceptable excipient(s) that reduce friction, heat, and wear among the active ingredient (COMPOUND A) and other excipients (e.g., the diluent, the disintegrant, and / or the lubricant) in the pharmaceutical composition.

[0084] In some embodiments, the pharmaceutical composition comprises about 0.1 % to about 5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.2% to about 5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.2% to about 4.5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.2% to about 4%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.2% to about 3.5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.2% to about 3%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% to about 3%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% to about 2.5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% to about 2%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% to about 1 .5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.4% to about 1.5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 1 .5%, by weight of the composition, of the lubricant.

[0085] In some embodiments, the pharmaceutical composition comprises about 0.1 %, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.2%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3%, by weight of the composition, of the lubricant, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.4%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 1 %, by weight of the composition, of the lubricant, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 1 .25%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 1 .5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 1.75%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 2%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 2.25%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 2.5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 2.75%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 3%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 3.25%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 3.5%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 3.75%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 4%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 4.25%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 4.5%, by weight ofthe composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 4.75%, by weight of the composition, of the lubricant. In some embodiments, the pharmaceutical composition comprises about 5%, by weight of the composition, of the lubricant.

[0086] In some embodiments, the lubricant comprises magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, or any combination thereof. In some embodiments, the lubricant comprises magnesium stearate, calcium stearate, sodium stearyl fumarate, or any combination thereof.

[0087] In some embodiments, the lubricant comprises magnesium stearate.

[0088] In some embodiments, the pharmaceutical composition further comprises a coating agent. Exemplary coating agents include sugar-coating agents and film coating agents, such as water-soluble film coating agents, enteric film coating agents, and sustained release film coating agents.

[0089] In some embodiments, the pharmaceutical composition further comprises a film coating agent, such as a water-soluble film coating agent. Nonlimiting examples of film coating agents include one or more pharmaceutically acceptable excipient(s) that form a barrier, protecting the pharmaceutical composition from moisture, light, air, or other environmental conditions which could cause degradation or loss of effectiveness. Non-limiting examples of film coating agents also include one or more pharmaceutically acceptable excipient(s) that smooth the surface of the pharmaceutical composition, such as to improve aesthetics and / or to facilitate tablet swallowing. Exemplary film coating agents include polymers, such as water-soluble polymers. In some embodiments, the film coating agent (such as a water-soluble film coating agent) is a cellulose-based polymer (such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, and methyl hydroxylethyl ceullose), a synthetic polymer (such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, and polyvinylpyrrolidone), or a polysaccharide (such as pullulan). In some embodiments, the film coating agent is hydroxypropyl methylcellulose (HPMC). In some embodiments, the film coating agent (such as a water-soluble film coatingagent) enables formation of a film coating (such as a water-based film coating) that does not affect the dissolution profile of the pharmaceutical composition.

[0090] Non-limiting examples of hydroxypropyl methylcellulose (HPMC) film coating agent include PHARMACOAT® (Hypromellose) 2910, TC-5 (grades: E, M, R) from Shin-Etsu Chemical Co., Ltd.

[0091] Non-limiting examples of hydroxypropyl cellulose (HPC) film coating agent include NISSO HPC / CELNY™ grades L, SL, or SSL from Nippon Soda Co., Ltd.

[0092] Non-limiting examples of aminoalkyl methacrylate copolymer E film coating agent include EUDRAGIT® E from Evonik.

[0093] In some embodiments, the pharmaceutical composition further comprises a plasticizer. Exemplary plasticizers include polyethylene glycol (PEG), such as PEG 8000 or Macrogol 6000, triethyl citrate, castor oil, and polysorbates.

[0094] In some embodiments, the pharmaceutical composition further comprises a pigment. The pigment provides black or white tint to the pharmaceutical composition. Exemplary pigments include titanium dioxide.

[0095] In some embodiments, the pharmaceutical composition further comprises a colorant. The colorant imparts color (or hue) to the pharmaceutical composition. Exemplary colorants include food colorants, such as red ferric oxide, yellow ferric oxide, food yellow 5, food red 2, food blue 2, and edible lake pigments.

[0096] In some embodiments, the pharmaceutical composition further comprises a glidant. Exemplary glidants include talc, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate.

[0097] In some embodiments, the pharmaceutical composition further comprises a pH adjuster. Exemplary pH adjusters include citrates, phosphates, carbonates, tartrates, fumarates, acetates, and amino acid salts.

[0098] In some embodiments, the pharmaceutical composition further comprises a sweetener. Exemplary sweeteners include aspartame, acesulfame K, thaumatin, saccharin sodium, and dipotassium glycyrrhizinate.

[0099] In some embodiments, the pharmaceutical composition further comprises a flavor. Exemplary flavors include menthol, peppermint oil, lemon oil, and vanillin.

[0100] In some embodiments, the pharmaceutical composition further comprises a coating additive. Non-limiting examples of coating additives include light-shielding agents such as titanium oxide, glidants such as talc, colorants such as red ferric oxide and yellow ferric oxide, plasticizers such as polyethylene glycol, triethyl citrate, castor oil, and polysorbates, and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid.

[0101] In some embodiments, the pharmaceutical composition further comprises a solvent. Any pharmaceutically acceptable solvent may be employed, such as purified water. In some embodiments, the solvent is substantially removed during processing and is not present in the final pharmaceutical composition.

[0102] In some embodiments, the pharmaceutical composition is in the form of a solid form dose. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of an immediate-release tablet.

[0103] In some embodiments, the tablet or the immediate-release tablet is prepared by wet granulation, dry granulation, or dry compression. In some embodiments, the tablet or immediate-release tablet is wet-granulated.

[0104] In some embodiments, the tablet or the immediate-release tablet comprises an intragranular component and an extragranular component.

[0105] In some embodiments, the intragranular component comprises COMPOUND A and a first portion of the diluent. In some embodiments, the intragranular component further comprises the binder.

[0106] In some embodiments, the extragranular component comprises a second portion of the diluent. In some embodiments, the extragranular component further comprises the disintegrant and the lubricant.

[0107] In some embodiments, the tablet or the immediate-release tablet comprises a film coating. In some embodiments, the film coating comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof. In some embodiments, the film coating comprises a film coating agent, a plasticizer, a pigment, a colorant, and, optionally, a solvent. In some embodiments, the film coating agent comprises OPADRY® Red (03F45081 ) from Colorcon Japan. In some embodiments, the film coating agent comprises OPADRY® Yellow (03F42240) from Colorcon Japan. In some embodiments, the film coating agent comprises OPADRY® Red (03F45081 ) and OPADRY® Yellow (03F42240) from Colorcon Japan. In some embodiments, the film coating agent includes purified water. In some embodiments, the purified water is removed during processing.

[0108] In some embodiments, the tablet or the immediate release tablet comprises about 6 mg of film coating, such as 6.1 mg of film coating.

[0109] In some embodiments, the pharmaceutical composition comprises:(a) about 0.1 mg to about 5 mg COMPOUND A;(b) about 45% to about 95%, by weight of the composition, of the diluent;(c) about 0.5% to about 10%, by weight of the composition, of the disintegrant;(d) about 0.5% to about 10%, by weight of the composition, of the binder; and(e) about 0.1 % to about 5%, by weight of the composition, of the lubricant

[0110] In some embodiments, the pharmaceutical composition comprises:(a) about 0.1 mg to about 5 mg COMPOUND A;(b1 ) about 5% to about 25%, by weight of the composition, ofmicrocrystalline cellulose;(b2) about 40% to about 90%, by weight of the composition, of mannitol;(c) about 0.5% to about 10%, by weight of the composition, of sodium starch glycolate;(d) about 0.5% to about 10%, by weight of the composition, of hydroxypropyl cellulose; and(e) about 0.1 % to about 5%, by weight of the composition, of magnesium stearate.

[0111] In some embodiments, the pharmaceutical composition comprises:(a) about 1 mg to about 3 mg COMPOUND A;(b1 ) about 10% to about 20%, by weight of the composition, of microcrystalline cellulose;(b2) about 65% to about 80%, by weight of the composition, of mannitol;(c) about 3% to about 7%, by weight of the composition, of sodium starch glycolate;(d) about 1 % to about 5%, by weight of the composition, of hydroxypropyl cellulose;(e) about 0.3% to about 2%, by weight of the composition, of magnesium stearate; and(f) a film coating.

[0112] In some embodiments, the pharmaceutical composition comprises, in the form of an immediate-release tablet:(a) 1.0 mg COMPOUND A;(b1 ) 22.5 mg microcrystalline cellulose(b2) 113.0 mg mannitol;(c) 7.5 mg sodium starch glycolate;(d) 4.5 mg hydroxypropyl cellulose; and(e) 1.5 mg magnesium stearate.

[0113] In some embodiments, the pharmaceutical composition comprises, in the form of an immediate-release tablet:(a) 3.0 mg COMPOUND A;(b1 ) 22.5 mg microcrystalline cellulose(b2) 111.0 mg mannitol;(c) 7.5 mg sodium starch glycolate;(d) 4.5 mg hydroxypropyl cellulose; and(e) 1.5 mg magnesium stearate.

[0114] In some embodiments, the pharmaceutical composition is in the form of a tablet or an immediate-release tablet including an intragranular component and an extragranular component.

[0115] In some embodiments, the intragranular component comprises a first portion of the microcrystalline cellulose, COMPOUND A, mannitol, and hydroxypropyl cellulose. In some embodiments, the intragranular component comprises COMPOUND A, 15.0 mg of microcrystalline cellulose, mannitol, and hydroxypropyl cellulose.

[0116] In some embodiments, the extragranular component comprises a second portion of microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. In some embodiments, the extragranular component comprises 7.5 mg of microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[0117] In some embodiments, the pharmaceutical composition has a particle size distribution as determined by laser diffraction particle size distribution measurement. A useful apparatus for measuring particle size distribution includes a HELOS / BR laser diffraction sensor that is combined with a RODOS dry dispersion unit (Sympatec).

[0118] In some embodiments, the pharmaceutical composition has a particle size dw of about 0.1 pm to about 3 pm. In some embodiments, the pharmaceutical composition has a particle size dio of about 1 pm to about 2 pm.

[0119] In some embodiments, the pharmaceutical composition has a particle size dso of about 3 pm to about 10 pm. In some embodiments, the pharmaceutical composition has a particle size dso of about 4 pm to about 8 pm.

[0120] In some embodiments, the pharmaceutical composition has a particle size doo of about 10 pm to about 40 pm. In some embodiments, the pharmaceutical composition has a particle size doo of about 13 pm to about 30 pm.

[0121] In some embodiments, the pharmaceutical composition has a particle size as follows: dio = 2 pm, dso = 8 pm, doo = 30 pm. In some embodiments, the pharmaceutical composition has a particle size as follows: dio = 1 pm, dso = 4 pm, doo = 13 pm.

[0122] In some embodiments, the pharmaceutical composition has a dissolution profile as determined by testing in Japanese pharmacopoeia 2ndfluid for dissolution test (JP2) with 0.1 % hexadecyltrimethylammonium bromide (CTAB) using a paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at 37°C. JP2 is a 25 mM phosphate buffer with a pH of 6.8.

[0123] In some embodiments, the pharmaceutical composition comprises the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of COMPOUND A after 30 minutes as determined testing in Japanese pharmacopoeia 2ndfluid for dissolution test (JP2) with 0.1 % hexadecyltrimethylammonium bromide (CTAB) using a paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at 37°C.

[0124] Also disclosed herein are methods of preparing a pharmaceutical composition comprising about 0.1 mg to about 5 mg of COMPOUND A.

[0125] In one embodiment, the method comprises:(a) combining purified water and a binder to prepare a binder solution;(b) mixing about 0.1 mg to about 5 mg of COMPOUND A and a firstportion of a diluent with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with a second portion of a diluent, a disintegrant, and a lubricant to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition.

[0126] In some embodiments, in (b) about 1 mg to about 3 mg of the COMPOUND A is used to prepare the granulated composition. In some embodiments, in (b) about 1 mg of the COMPOUND A is used to prepare the granulated composition. In some embodiments, in (b) about 3 mg of the COMPOUND A is used to prepare the granulated composition.

[0127] In some embodiments, (b) is performed in a fluid bed granulator.

[0128] In some embodiments, the milling in (c) is performed in a screening mill. In some embodiments, the screening mill has a rotating impeller.

[0129] In some embodiments, (d) is performed in a diffusion mixer. In some embodiments, the diffusion mixer is a horizonal blender or a drum blender.

[0130] In some embodiments, the pharmaceutical composition is compressed into a tablet or an immediate release tablet in (e). In some embodiments, (e) is performed using a tablet press.

[0131] In some embodiments, the method comprises:(a) combining purified water and hydroxypropyl cellulose to prepare a binder solution;(b) mixing about 0.1 mg to about 5 mg COMPOUND A, microcrystalline cellulose, and mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milledcomposition;(d) blending the milled composition with microcrystalline cellulose, sodium starch glycolate, and magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet

[0132] In some embodiments, the method comprises:(a) combining purified water and 4.5 mg hydroxypropyl cellulose to prepare a binder solution;(b) mixing 1 mg COMPOUND A, 15.0 mg microcrystalline cellulose, and 113.0 mg mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with 7.5 mg microcrystalline cellulose, 7.5 mg sodium starch glycolate, and 1.5 mg magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet.

[0133] In some embodiments, the method comprises:(a) combining purified water and 4.5 mg hydroxypropyl cellulose to prepare a binder solution;(b) mixing 3 mg COMPOUND A, 15.0 mg microcrystalline cellulose, and 111.0 mg mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with 7.5 mg microcrystalline cellulose, 7.5 mg sodium starch glycolate, and 1.5 mg magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet.

[0134] In some embodiments, the method further comprises (f) coating the pharmaceutical composition with a film coating agent. In some embodiments, (f) includes coating the pharmaceutical composition with about 6 mg of film coating. In some embodiments, the pharmaceutical composition is a tablet or an immediate release tablet and the method further comprises (f) coating the tablet or the immediate release tablet with a film coating agent.

[0135] In some embodiments, the coating in (f) is pan coating. In some embodiments, the pan coating is performed using a perforated coating system.

[0136] In some embodiments, the film coating comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof.

[0137] In some embodiments, the method results in a pharmaceutical composition having a particle size dio of about 0.1 pm to about 3 pm. In some embodiments, method results in a pharmaceutical composition having a particle size dw of about 1 pm to about 2 pm.

[0138] In some embodiments, method results in a pharmaceutical composition having a particle size dso of about 3 pm to about 10 pm. In some embodiments, method results in a pharmaceutical composition having a particle size dso of about 4 pm to about 8 pm.

[0139] In some embodiments, method results in a pharmaceutical composition having a particle size doo of about 10 pm to about 40 pm. In some embodiments, method results in a pharmaceutical composition having a particle size doo of about 13 pm to about 30 pm.

[0140] In some embodiments, method results in a pharmaceutical composition having a particle size as follows: dio = 2 pm, dso = 8 pm, doo = 30 pm. In some embodiments, method results in a pharmaceutical composition having a particle size as follows: dio = 1 pm, dso = 4 pm, doo = 13 pm.Examples:Example 1 : Formulation of COMPOUND A in an immediate-release tablet.

[0141] COMPOUND A was formulated in an immediate-release tablet for oral administration as follows: purified water and hydroxypropyl cellulose were combined to prepare a binder solution. COMPOUND A, mannitol, and microcrystalline cellulose were then mixed with the prepared binder solution in a fluid bed granulator to prepare a granulated composition. The granulated composition was then dried and milled to prepare a milled composition. The milled composition was then blended with microcrystalline cellulose, sodium starch glycolate (Type A), and magnesium stearate to prepare a blended composition and the blended composition was then compressed into tablets. After a metal check and dedusting step, a film coating comprising OPADRY® Red (03F45081 ), OPADRY® Yellow (03F42240), and purified water was then applied to the compressed tablets to film coat the tablets and result in an immediate-release tablet comprising COMPOUND A. These process steps, along with associated in process controls and tests, are illustrated in the process flow diagram of FIG. 1.

[0142] The compositions of immediate-release tablets prepared according to the procedure of the preceding paragraph with 0.1 mg, 1 mg, 3 mg, or 5 mg of COMPOUND A are described in Table 1.Table 1. Immediate-release tablet composition.1COMPOUND A was a free base, no salt correction factor was applied.2Essentially removed during processing.3Quantum sufficit.

[0143] As will be understood by one of ordinary skill in the art, additional dosages of immediate-release tablets according to the present example (with COMPOUND A present in an amount of about 0.1 mg to about 5 mg) can be prepared by adjusting the amount of mannitol to account for the change in the amount of COMPOUND A. For example, a 2 mg tablet can be prepared by using 2 mg COMPOUND A, 112.0 mg mannitol, and the above-identified amounts of the remaining components. Similarly, a 4 mg tablet can be prepared by using 4 mg COMPOUND A, 110.0 mg mannitol, and the above-identified amounts of the remaining components.

[0144] The dissolution profile of each immediate-release tablet in Table 1 was determined by testing in a dissolution medium containing Japanese pharmacopoeia 2ndfluid for dissolution test (JP2) and 0.1 % hexadecyltrimethylammonium bromide (CTAB) using a paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at 37°C. The dissolution profile for an exemplary immediate-release tablet is displayed in FIG. 2. As can be seen from the profile, the immediate-release tablet exhibited at least 95% dissolution after 30 minutes.

[0145] Example 2: Batch formulation of COMPOUND A for 1 mg and 3 mg immediate-release tablets.

[0146] 1 mg and 3 mg immediate-release tablets were batch produced according to the following procedure. Hydroxypropyl cellulose was dissolved in purified water by stirring to prepare a binder solution (6 w / w%). Mannitol was milled through a screening mill at an impeller speed of about 3,000 rpm with a fixed screen size of 1.5 mm. The milled mannitol, COMPOUND A, and microcrystalline cellulose were mixed and granulated by spraying 12,940 g of the binder solution in a 96 L fluid bed granulator using a spray rate of 180 g / min to achieve a final intra-granular composition of 3.37 w / w % hydroxypropyl cellulose. The intra-granular composition was dried in the fluid bed granulator (23,030 g / batch scale) until a product temperature of 45°C was reached. The dried intra-granular composition was milled through a screening mill at an impeller speed of about 3,000 rpm with a fixed screen size of 1 .5 mm. The milled intra-granular composition was blended with microcrystalline cellulose, sodium starch glycolate, and magnesium stearate in adiffusion blender to prepare a blended composition. The blended composition was compressed into uncoated tablets (150 mg / tablet) with a target thickness of 3.85 mm and hardness of not less than 30 N, using a gravity fed, fully tooled tablet press with 24 stations and operated at a press speed of 30 rpm. A solution (10 w / w%) consisting of OPADRY® Red 03F45081 , OPADRY® Yellow 03F42240, and purified water was prepared by stirring. The uncoated tablets were coated with the filmcoating suspension targeting a weight gain of 4.07 % (6.1 mg / tablet) using a 75 L pan coater. The film coated tablets (156.1 mg / tablet) were visually inspected. The bulk drug products were packaged into bulk packaging for shipping.

[0147] The quantities of components utilized to create the 1 mg and 3 mg immediate-release tablets are shown in Table 2 below. The process parameters for the granulation (Table 3), milling (Table 4), blending (Table 5), compression (Table 6), and film coating (Table 7) stages are also shown below.Table 2. Immediate-release tablet composition and batch formula.1Essentially removed during processing.2Binder solution was prepared in excess; the reported quantities per batch values show the 161 % extra prepared to spray fixed amounts of binder.3Film coating suspension was prepared in excess; the reported quantities per batch values show the 196% extra prepared to coat all the tablets in a single coating run.4The reported quantities per batch is a sum of the tablet core components plus the coating materials required to achieve the target weight gain of 4.07%.Table 3. Process parameters for granulation.Table 4. Process parameters for milling.Table 5. Process parameters for blending.Table 6. Process parameters for compression.Table 7. Process parameters for film coating.

[0148] Tablets produced as described above exhibited the following particle size distributions: 1 mg - dio = 1 pm, dso = 4 pm, doo = 13 pm and 3 mg - dio = 2 pm, dso = 8 pm, doo = 30 pm.

[0149] Although the disclosure has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments.

[0150] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

What is claimed is:1 . A pharmaceutical composition comprising(a) about 0.1 mg to about 5 mg 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”);(b) a diluent;(c) a disintegrant;(d) a binder; and(e) a lubricant.

2. The pharmaceutical composition according to claim 1 , comprising about 1 mg to about 3 mg of the COMPOUND A.

3. The pharmaceutical composition according to claim 1 or claim 2, comprising about 1 mg of the COMPOUND A.

4. The pharmaceutical composition according to claim 1 or claim 2, comprising about 3 mg of the COMPOUND A.

5. The pharmaceutical composition according to any one of the preceding claims, comprising about 10% to about 90%, by weight of the composition, of the diluent.

6. The pharmaceutical composition according to any one of the preceding claims, comprising about 40% to about 90%, by weight of the composition, of the diluent.

7. The pharmaceutical composition according to any one of the preceding claims, comprising about 80% to about 90%, by weight of the composition, of the diluent.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the diluent comprises mannitol, microcrystalline cellulose, starch, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, lactose, or any combination thereof.

9. The pharmaceutical composition according to any one of the preceding claims, wherein the diluent comprises microcrystalline cellulose, mannitol, lactose, or any combination thereof.

10. The pharmaceutical composition according to any one of the preceding claims, wherein the diluent comprises a combination of microcrystalline cellulose and mannitol.11 . The pharmaceutical composition according to claim 10, wherein the composition comprises about 5% to about 25%, by weight of the composition, of microcrystalline cellulose, and about 40% to about 90%, by weight of the composition, of mannitol.

12. The pharmaceutical composition according to claim 11 , wherein the composition comprises about 10% to about 20%, by weight of the composition, of microcrystalline cellulose, and about 65% to about 75%, by weight of the composition, of mannitol.

13. The pharmaceutical composition according to any one of the preceding claims, comprising about 1 % to about 20%, by weight of the composition, of the disintegrant.

14. The pharmaceutical composition according to any one of the preceding claims, comprising about 2% to about 10%, by weight of the composition, of the disintegrant.

15. The pharmaceutical composition according to any one of the preceding claims, comprising about 3% to about 8%, by weight of the composition, of the disintegrant.

16. The pharmaceutical composition according to any one of the preceding claims, wherein the disintegrant comprises carboxymethylcellulose, croscarmellose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium starch glycolate, corn starch, hydroxypropyl starch, partially pregelatinized starch, or any combination thereof.

17. The pharmaceutical composition according to any one of the preceding claims, wherein the disintegrant comprises sodium starch glycolate.

18. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.5% to about 20%, by weight of the composition, of the binder.

19. The pharmaceutical composition according to any one of the preceding claims, comprising about 1 % to about 10%, by weight of the composition, of the binder.

20. The pharmaceutical composition according to any one of the preceding claims, comprising about 2% to about 6%, by weight of the composition, of the binder.21 . The pharmaceutical composition according to any one of the preceding claims, wherein the binder comprises microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, or any combination thereof.

22. The pharmaceutical composition according to any one of the preceding claims, wherein the binder comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof.

23. The pharmaceutical composition according to any one of the preceding claims, wherein the binder comprises hydroxypropyl cellulose.

24. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.1 % to about 5%, by weight of the composition, of the lubricant.

25. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.2% to about 3%, by weight of the composition, of the lubricant.

26. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.5% to about 1 .5%, by weight of the composition, of the lubricant.

27. The pharmaceutical composition according to any one of the preceding claims, wherein the lubricant comprises magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, or any combination thereof.

28. The pharmaceutical composition according to any one of the preceding claims, wherein the lubricant comprises magnesium stearate, calcium stearate, sodium stearyl fumarate, or any combination thereof.

29. The pharmaceutical composition according to any one of the preceding claims, wherein the lubricant comprises magnesium stearate.

30. The pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof.31 . The pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of a solid form dose.

32. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of a tablet.

33. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of an immediate release tablet.

34. The pharmaceutical composition according to claim 32 or claim 33, wherein the tablet or the immediate-release tablet is wet-granulated.

35. The pharmaceutical composition according to claim 34, wherein the tablet or the immediate release tablet comprises an intragranular component and an extragranular component.

36. The pharmaceutical composition according to claim 35, wherein the intragranular component comprises COMPOUND A, a first portion of the diluent, and the binder, and the extragranular component comprises a second portion of the diluent and comprises the disintegrant and the lubricant.

37. The pharmaceutical composition according to any one of claims 32-36, wherein the tablet or the immediate-release tablet comprises a film coating.

38. The pharmaceutical composition according to claim 37, wherein the film coating comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof.

39. The pharmaceutical composition according to any one of the preceding claims, comprising:(a) about 0.1 mg to about 5 mg COMPOUND A;(b) about 40% to about 90%, by weight of the composition, of the diluent;(c) about 2% to about 10%, by weight of the composition, of the disintegrant;(d) about 1 % to about 10%, by weight of the composition, of the binder; and(e) about 0.1 % to about 5%, by weight of the composition, of the lubricant.

40. The pharmaceutical composition according to any one of the preceding claims, comprising(a) about 0.1 mg to about 5 mg COMPOUND A;(b1 ) about 5% to about 25%, by weight of the composition, of microcrystalline cellulose;(b2) about 40% to about 90%, by weight of the composition, of mannitol;(c) about 2% to about 10%, by weight of the composition, of sodium starch glycolate;(d) about 1 % to about 10%, by weight of the composition, of hydroxypropyl cellulose; and(e) about 0.1 % to about 5%, by weight of the composition, of magnesium stearate.41 . The pharmaceutical composition according to any one of the preceding claims, comprising(a) about 1 mg to about 3 mg COMPOUND A;(b1 ) about 10% to about 20%, by weight of the composition, of microcrystalline cellulose;(b2) about 65% to about 80%, by weight of the composition, of mannitol;(c) about 3% to about 8%, by weight of the composition, of sodium starch glycolate;(d) about 2% to about 6%, by weight of the composition, of hydroxypropyl cellulose;(e) about 0.5% to about 1 .5%, by weight of the composition, of magnesium stearate; and(f) a film coating.

42. The pharmaceutical composition according to claim 40 or claim 41 , wherein the composition is in the form of a tablet including an intragranular component comprising COMPOUND A, a first portion of the microcrystalline cellulose, and comprising the mannitol and the hydroxypropyl cellulose, and an extragranular component comprising a second portion of the microcrystalline cellulose and comprising the sodium starch glycolate and the magnesium stearate.

43. The pharmaceutical composition according to any one of the preceding claims comprising, in the form of an immediate-release tablet,(a) 1.0 mg COMPOUND A;(b1 ) 22.5 mg microcrystalline cellulose(b2) 113.0 mg mannitol;(c) 7.5 mg sodium starch glycolate;(d) 4.5 mg hydroxypropyl cellulose; and(e) 1.5 mg magnesium stearate.

44. The pharmaceutical composition according to any one of the preceding claims comprising, in the form of an immediate-release tablet,(a) 3.0 mg COMPOUND A;(b1 ) 22.5 mg microcrystalline cellulose (b2) 111.0 mg mannitol;(c) 7.5 mg sodium starch glycolate;(d) 4.5 mg hydroxypropyl cellulose; and(e) 1.5 mg magnesium stearate.

45. The pharmaceutical composition according to claim 43 or claim 44, wherein the immediate release tablet includes an intragranular component comprising the COMPOUND A, 15.0 mg of the microcrystalline cellulose, the mannitol, and the hydroxypropyl cellulose, and an extragranular component comprising 7.5 mg of the microcrystalline cellulose, the sodium starch glycolate, and the magnesium stearate.

46. The pharmaceutical composition according to claim 45, wherein the immediate release tablet further comprises 6.1 mg of film coating.

47. The pharmaceutical composition according to any one of the preceding claims, wherein the composition has a particle size dio of about 0.1 pm to about 3 pm.

48. The pharmaceutical composition according to any one of the preceding claims, wherein the composition has a particle size dio of about 1 pm to about 2 pm.

49. The pharmaceutical composition according to any one of the preceding claims, wherein the composition has a particle size dso of about 3 pm to about 10 pm.

50. The pharmaceutical composition according to any one of the preceding claims, wherein the composition has a particle size dso of about 4 pm to about 8 pm.51 . The pharmaceutical composition according to any one of the preceding claims, wherein the composition has a particle size doo of about 10 pm to about 40 pm.

52. The pharmaceutical composition according to any one of the preceding claims, wherein the composition has a particle size doo of about 13 pm to about 30 pm.

53. The pharmaceutical composition according to any one of the preceding claims, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 70% of COMPOUND A after 30 minutes in Japanese pharmacopoeia 2ndfluid for dissolution test (JP2) with 0.1 % hexadecyltrimethylammonium bromide (CTAB) using a paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at 37°C.

54. The pharmaceutical composition according to claim 53, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 75% of COMPOUND A.

55. The pharmaceutical composition according to claim 53 or claim 54, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 85% of COMPOUND A.

56. The pharmaceutical composition according to any one of claims 53-55, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 90% of COMPOUND A.

57. The pharmaceutical composition according to any one of claims 53-56, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 95% of COMPOUND A.

58. The pharmaceutical composition according to any one of claims 53-57, comprising the diluent, the disintegrant, the binder, and the lubricant in amounts sufficient for the composition to exhibit a dissolution of at least 97% of COMPOUND A.

59. A method of preparing a pharmaceutical composition comprising:(a) combining purified water and a binder to prepare a binder solution;(b) mixing about 0.1 mg to about 5 mg 9-[4-(cyclohexyloxy)phenyl]-7-methyl- 3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) and a first portion of a diluent with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with a second portion of a diluent, a disintegrant, and a lubricant to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition.

60. The method according to claim 59, wherein in (b) about 1 mg to about 3 mg of the COMPOUND A is used to prepare the granulated composition.61 . The method according to claim 59 or claim 60, wherein in (b) about 1 mg of the COMPOUND A is used to prepare the granulated composition.

62. The method according to claim 59 or claim 60, wherein in (b) about 3 mg of the COMPOUND A is used to prepare the granulated composition.

63. The method according to any one of claims 59-62, wherein (b) is performed in a fluid bed granulator.

64. The method according to any one of claims 59-63, wherein the milling in (c) is performed in a screening mill.

65. The method according to claim 64, wherein the screening mill has a rotating impeller.

66. The method according to any one of claims 59-65, wherein (d) is performed in a diffusion mixer.

67. The method according to claim 66, wherein the diffusion mixer is a horizonal blender or a drum blender.

68. The method according to any one of claims 59-68, wherein in (e) the pharmaceutical composition is compressed into a tablet.

69. The method according to claim 68, wherein (e) is performed using a tablet press.

70. The method according to claim 68 or claim 69, further comprising (f) coating the tablet with a film coating agent.71 . The method according to claim 70, wherein the coating in (f) is pan coating.

72. The method according to claim 71 , wherein the pan coating is performed using a perforated coating system.

73. The method according to any one of claims 70-72, wherein the film coating comprises a film coating agent, a plasticizer, a pigment, a colorant, a solvent, or any combination thereof.

74. The method according to any one of claims 59-73, wherein the binder comprises microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, or any combination thereof.

75. The method according to any one of claims 59-74, wherein the binder comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof.

76. The method according to any one of claims 59-75, wherein the binder comprises hydroxypropyl cellulose.

77. The method according to any one of claims 59-76, wherein the diluent comprises mannitol, microcrystalline cellulose, starch, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, lactose, or any combination thereof.

78. The method according to any one of claims 59-77, wherein the diluent comprises microcrystalline cellulose, mannitol, lactose, or any combination thereof.

79. The method according to any one of claims 59-78, wherein the diluent comprises a combination of microcrystalline cellulose and mannitol.

80. The method according to any one of claims 59-79, wherein the first portion of the diluent comprises microcrystalline cellulose and mannitol.81 . The method according to any one of claims 59-80, wherein the second portion of the diluent comprises microcrystalline cellulose.

82. The method according to any one of claims 59-81 , wherein the disintegrant comprises carboxymethylcellulose, croscarmellose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium starch glycolate, com starch, hydroxypropyl starch, partially pregelatinized starch, or any combination thereof.

83. The method according to any one of claims 59-82, wherein the disintegrant comprises sodium starch glycolate.

84. The method according to any one of claims 59-83, wherein the lubricant comprises magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, or any combination thereof.

85. The method according to any one of claims 59-84, wherein the lubricant comprises magnesium stearate, calcium stearate, sodium stearyl fumarate, or any combination thereof.

86. The method according to any one of claims 59-85, wherein the lubricant comprises magnesium stearate.

87. The method according to any one of claims 59-86 comprising,(a) combining purified water and hydroxypropyl cellulose to prepare a binder solution;(b) mixing about 0.1 mg to about 5 mg COMPOUND A, microcrystalline cellulose, and mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milledcomposition;(d) blending the milled composition with microcrystalline cellulose, sodium starch glycolate, and magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet.

88. The method according to any one of claims 59-87 comprising,(a) combining purified water and 4.5 mg hydroxypropyl cellulose to prepare a binder solution;(b) mixing 1 mg COMPOUND A, 15.0 mg microcrystalline cellulose, and 113.0 mg mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with 7.5 mg microcrystalline cellulose, 7.5 mg sodium starch glycolate, and 1.5 mg magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet.

89. The method according to any one of claims 59-88 comprising,(a) combining purified water and 4.5 mg hydroxypropyl cellulose to prepare a binder solution;(b) mixing 3 mg COMPOUND A, 15.0 mg microcrystalline cellulose, and 111.0 mg mannitol with the binder solution to prepare a granulated composition;(c) drying and milling the granulated composition to prepare a milled composition;(d) blending the milled composition with 7.5 mg microcrystalline cellulose, 7.5 mg sodium starch glycolate, and 1.5 mg magnesium stearate to prepare a blended composition; and(e) compressing the blended composition to form a pharmaceutical composition in the form of a tablet.

90. The method according to any one of claims 87-89, further comprising (f) coating the tablet with 6.1 mg of film coating.91 . The method according to any one of claims 59-90, wherein the pharmaceutical composition has a particle size dio of about 0.1 pm to about 3 pm.

92. The method according to any one of claims 59-91 , wherein the pharmaceutical composition has a particle size dio of about 1 pm to about 2 pm.

93. The method according to any one of claims 59-92, wherein the pharmaceutical composition has a particle size dso of about 3 pm to about 10 pm.

94. The method according to any one of claims 59-93, wherein the pharmaceutical composition has a particle size dso of about 4 pm to about 8 pm.

95. The method according to any one of claims 59-94, wherein the pharmaceutical composition has a particle size doo of about 10 pm to about 40 pm.

96. The method according to any one of claims 59-95, wherein the pharmaceutical composition has a particle size doo of about 13 pm to about 30 pm.

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