Formulations of adenosine receptor antagonist

Abstract

Provided here are pharmaceutical formulations containing A2B adenosine receptor antagonists and one or more excipients. The method of treating diseases or disorders associated with or would benefit from modulation of A2B adenosine receptor activity, and the combination treatment thereof are also provided.

Description

FORMULATIONS OF ADENOSINE RECEPTOR ANTAGONIST CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 680,291 filed on August 7, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Adenosine, an endogenous nucleoside, ubiquitously exists inside and outside of living cells. It plays multiple physiological roles to maintain the homeostasis of cells, tissues, and organs. Adenosine can exert its biological effects by interacting with a family of adenosine receptors known as A1, A2A, A2B, and A3 adenosine receptors. A1 adenosine receptors mediate mechanisms of tissue protection, especially for cardioprotection. A2A adenosine receptors modulate coronary vasodilation and cancer immunity. A2B adenosine receptors play a role in signaling pathways.

[0003] Some A2Badenosine receptor antagonists are relatively insoluble in aqueous media and / or difficult to formulate using conventional pharmaceutical excipients, and thus can be difficult to formulate in a manner that provides reproducible plasma levels of the compound in mammals, in particular humans A need exists for improving the bioavailability A2Badenosine receptor antagonists. SUMMARY

[0004] The present disclosure is directed to pharmaceutical composition for Compound 1, wherein Compound I has the structure:The compositions described herein provide a desirable dissolution profile by having an optimized particle size of the composition while also minimizing water content thereby minimizing degradation of Compound 1.

[0005] The present disclosure provides a composition comprising about 1 to about 100 %w / w Compound 1:pharmaceutically acceptable salt, co-crystal, or solvate thereof; wherein the particle size (D50), measured using a laser diffraction method, of Compound 1 is less than about 5000 nm.

[0006] In certain embodiments, the composition further comprising less than about 10% w / w of Compound 2:or a pharmaceutically acceptable salt, or solvate thereof.

[0007] In certain embodiments, the composition comprising about 0.1 to less than about 10% w / w of Compound 2. In certain embodiments, the composition comprising about 0.1 to less than about 5% w / w of Compound 2.

[0008] In certain embodiments, the D50 is about 500 to about 5000 nm.

[0009] In certain embodiments, the D50is about 100 to about 500 nm when measured in a suspension. In certain embodiments, the D50, measured in a suspension, is less than 500 nm after storage for one month at temperatures from 0-8 ℃.

[0010] In certain embodiments, the D50 is from about 100 to about 250 nm.

[0011] In certain embodiments, the composition further comprises less than about 5.0% w / w (or less than about 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, 1% w / w, or 0.5% w / w) water content.

[0012] In certain embodiments, the composition provided herein further comprises less than about 5.0% w / w (e.g. less than 4% w / w, less than about 3.5% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1.0% w / w, less than about 0.9% w / w, less than about 0.8% w / w, less than about 0.7% w / w, less than about 0.6% w / w, less than about 0.5% w / w, less than about 0.4% w / w, less than about 0.3% w / w, less than about 0.1% w / w, less than about 0.1% w / w) water content. In certain preferred embodiments, the water content is less than 5.0% w / w, less than 2.5% w / w, less than 1.5% w / w, or less than 0.5% w / w.

[0013] In certain embodiments, the composition further comprises a stabilizer. In certain embodiments, the stabilizer is present in an amount of about 0.1-40 %w / w (or about 0.1-30 %w / w, 0.1-20 %w / w, 0.1-10 %w / w, 0.1-5 %w / w, 0.1-4 %w / w, 0.1-3 %w / w, 0.1-2 %w / w, 0.1-1 %w / w, 0.1-0.9 %w / w, 0.1-0.8 %w / w, 0.1-0.7 %w / w, 0.1-0.6 %w / w, 0.1-0.5 %w / w, 0.1-0.4 %w / w, 0.1-0.3 %w / w, 1-35 %w / w, 1-30%w / w, 1- 25 %w / w, 1-20 %w / w, 1-15 %w / w, or 1-10 %w / w. In some embodiments, the stabilizer is present in an amount less than about 0.5%w / w, 1%w / w, 2%w / w, 3 %w / w, 4%w / w, 5%w / w, 6%w / w, 7%w / w, 8%w / w, 9%w / w, 10%w / w, 15%w / w, 20%w / w, 25%w / w, 30%w / w, 35%w / w, or 40%w / w).

[0014] In certain embodiments, the stabilizer comprises a surfactant, a polymer, and combinations thereof.

[0015] In certain embodiments, the stabilizer is a polymer.

[0016] In certain embodiments, the polymer comprises PVP (Povidone), PVA (Polyvinyl alcohol), PEG (Polyethylene glycol), HPMC (Hypromellose), HPMC-AS (Hydroxypropyl methylcellulose acetate succinate), Eudragit®, HPC (Hydroxypropyl cellulose, approx.50,000–1,250,000 g / mol), HEC (Hydroxyethyl cellulose), methylcellulose (MC, approx.10,000–200,000 g / mol), Plantacare® 2000 (decyl glucoside) and Na alginate chitosan, NaCMC (Carboxymethylcellulose sodium), or any combination thereof.

[0017] In certain embodiments, the polymer is present in an amount of about 0.1-about 20 %w / w (or 0.2- 20 %w / w, 0.3-20 %w / w, 0.4-20 %w / w, 0.5-20 %w / w, 0.6-20 %w / w, 0.7-20 %w / w, 0.8-20 %w / w, 0.9-20 %w / w, 1-20 %w / w, 2-20 %w / w, 3-20 %w / w, 4-20 %w / w, 5-20 %w / w, 6-20 %w / w, 7-20 %w / w, 8-20 %w / w, 9-20 %w / w, 10-20 %w / w, 15-20 %w / w, 0.2-10 %w / w, 0.3-10 %w / w, 0.4-10 %w / w, 0.5-10 %w / w, 0.6-10 %w / w, 0.7-10 %w / w, 0.8-10 %w / w, 0.9-10 %w / w, 1-10 %w / w, 2-10 %w / w, 3-10 %w / w, 4-10 %w / w, 5-10 %w / w, 6-10 %w / w, 7-10 %w / w, 8-10 %w / w, 9-10 %w / w, 1-8%w / w, 1-6%w / w, 1- 4%w / w, 2-8%w / w, 2-6%w / w, or 2-5%w / w.).

[0018] In certain embodiments, the polymer is present in an amount of more than about 0.1 %w / w (or more than about 0.2 %w / w, about 0.3 %w / w, 0.4 %w / w, about 0.5 %w / w, about 0.6 %w / w, about 0.7 %w / w, about 0.8 %w / w, about 0.9 %w / w, about 1 %w / w, about 2 %w / w, about 3 %w / w, about 4 %w / w, about 5 %w / w, about 6 %w / w, about 7 %w / w, about 8 %w / w, about 9 %w / w, about 10 %w / w, about 1 1%w / w, about 12 %w / w, about 13 %w / w, about 14 %w / w, about 15 %w / w, about 16 %w / w, about 17 %w / w, about 18 %w / w, about 19 %w / w, or 20 %w / w).

[0019] In certain embodiments, the polymer is present in an amount of less than about 20 %w / w (or less than about 19 %w / w, about 18 %w / w, 17 %w / w, about 16 %w / w, about 15 %w / w, about 14 %w / w, about 13 %w / w, about 12 %w / w, about 11 %w / w, about 10 %w / w, about 9 %w / w, about 8 %w / w, about 7 %w / w, about 6 %w / w, about 5 %w / w, about 4 %w / w, about 3 %w / w, about 2 %w / w, about 1 %w / w,about 0.9 %w / w, about 0.8 %w / w, about 0.7 %w / w, about 0.6 %w / w, about 0.5 %w / w, about 0.4 %w / w, about 0.3 %w / w, about 0.2 %w / w, or 0.1 %w / w).

[0020] In certain embodiments, the polymer is present in an amount of about 0.1 %w / w (or about 0.2 %w / w, about 0.3 %w / w, 0.4 %w / w, about 0.5 %w / w, about 0.6 %w / w, about 0.7 %w / w, about 0.8 %w / w, about 0.9 %w / w, about 1 %w / w, about 2 %w / w, about 3 %w / w, about 4 %w / w, about 5 %w / w, about 6 %w / w, about 7 %w / w, about 8 %w / w, about 9 %w / w, about 10 %w / w, about 11%w / w, about 12 %w / w, about 13 %w / w, about 14 %w / w, about 15 %w / w, about 16 %w / w, about 17 %w / w, about 18 %w / w, about 19 %w / w, or 20 %w / w).

[0021] In certain embodiments, the stabilizer is a surfactant.

[0022] In certain embodiments, the surfactant comprises SD (Docusate sodium), SLS (Sodium lauryl sulfate), PEI (Polyethylene imine), Tweens (e.g. Tween 80 or Tween 20), poloxamers (poloxamer 188, poloxamer 338, or poloxamer 407), polysorbates, sorbitan esters, TPGS (D-α-tocopheryl polyethylene glycol succinate), Vitamin E TPGS (VE TPGS), PEO (Polyethylene oxide) and PPO (Polypropylene oxide), Soluplus®, Sporanox®, gelatin, hydrophobin, cyclodextrins, and any combination thereof.

[0023] In certain embodiments, the surfactant is present in an amount of about 0.1% w / w -30% w / w (or about 0.1% w / w -25% w / w, 0.1% w / w -20% w / w, 0.1% w / w -15% w / w, 0.1% w / w -10% w / w, 0.1% w / w -9% w / w, 0.1% w / w -8% w / w, 0.1% w / w -7% w / w, 0.1% w / w -6% w / w, 0.1% w / w -5% w / w, 0.1% w / w -4% w / w, 0.1% w / w -3% w / w, 0.1% w / w -2% w / w, 0.1% w / w -1% w / w, 1% w / w -30% w / w, 5% w / w - 30% w / w, 10% w / w -30% w / w, 15% w / w -30% w / w, 20% w / w -30% w / w, 25% w / w -30% w / w, 1% w / w -25% w / w, 1% w / w -20% w / w, 1% w / w -15% w / w, 5% w / w -15% w / w, 10% w / w -15% w / w, 1% w / w - 10% w / w, 1% w / w -9% w / w, 1% w / w -8% w / w, 1% w / w -7% w / w, 1% w / w -6% w / w, 1% w / w -5% w / w, 2% w / w -9% w / w, 2% w / w -8% w / w, 2% w / w -7% w / w, 2% w / w -6% w / w, 2.5% w / w -8.5% w / w, 2.5% w / w -8% w / w, 2.5% w / w -7.5% w / w, 2.5% w / w -7% w / w, 2.5% w / w -6.5% w / w, 2.5% w / w -6 % w / w, 2.5% w / w -5.5% w / w, 2.5% w / w -5% w / w, 2.5% w / w -4.5% w / w, 2.5% w / w -4% w / w, 3% w / w -10% w / w, 3.5% w / w -9% w / w, or 4% w / w -7% w / w).

[0024] In certain embodiments, the surfactant is present in an amount of less than about 10% w / w (or less than about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0025] In certain embodiments, the surfactant is present in an amount of about 10% w / w (or less than about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0026] In certain embodiments, the stabilizer comprises poloxamer, sodium lauryl sulfate, and combinations thereof. In certain embodiments, the surfactant is sodium lauryl sulfate and poloxamer. Incertain embodiments, the stabilizer comprises about 2-6% w / w of poloxamer 188 and about 0.1-1 % w / w of SLS.

[0027] In certain embodiments, the particle size (D50), measured using a laser diffraction method, of sodium lauryl sulfate and poloxamer is less than about 5000 nm when measured in a suspension.

[0028] In certain embodiments, the particle size (D50), measured using a laser diffraction method, of sodium lauryl sulfate and poloxamer is 500 to about 5000 nm when measured in a suspension.

[0029] In certain embodiments, the particle size (D50), measured using a laser diffraction method, of sodium lauryl sulfate and poloxamer is 100 to 500 nm when measured in a suspension.

[0030] In certain embodiments, the composition further comprises a bulking agent.

[0031] In certain embodiments, the bulking agent are selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, talc, and combinations thereof.

[0032] In certain embodiments, the bulking agent is present in an amount of about 10-85% w / w (or about 10-80% w / w, 10-75% w / w, 10-70% w / w, 10-65% w / w, 10-60% w / w, 10-55% w / w, 10-50% w / w, 10- 45% w / w, 10-40% w / w, 10-35% w / w, 10-30% w / w, 10-25% w / w, 10-20% w / w, 20-80% w / w, 20-75% w / w, 20-70% w / w, 20-65% w / w, 20-60% w / w, 20-55% w / w, 20-50% w / w, 20-45% w / w, 20-40% w / w, 20-35% w / w, 20-30% w / w, 20-25% w / w, 30-80% w / w, 30-75% w / w, 30-70% w / w, 30-65% w / w, 30- 60% w / w, 30-55% w / w, 30-50% w / w, 30-45% w / w, 30-40% w / w, 30-35% w / w, 40-80% w / w, 40-75% w / w, 40-70% w / w, 40-65% w / w, 40-60% w / w, 40-55% w / w, 40-50% w / w, 40-45% w / w, 50-80% w / w, 50-75% w / w, 50-70% w / w, 50-65% w / w, 50-60% w / w, or 50-55% w / w).

[0033] In certain embodiments, the bulking agent is present in an amount of less than about 85% w / w (or less than about 80% w / w, less than about 75% w / w, less than about 70% w / w, less than about 65% w / w, less than about 60% w / w, less than about 55% w / w, less than about 50% w / w, less than about 45% w / w, less than about 40% w / w, less than about 35% w / w, less than about 30% w / w, less than about 25% w / w, less than about 20% w / w, or less than about 15% w / w).

[0034] In certain embodiments, the bulking agent is present in an amount of about 85% w / w (or about 80% w / w, about 75% w / w, about 70% w / w, about 65% w / w, about 60% w / w, about 55% w / w, about 50% w / w, about 45% w / w, about 40% w / w, about 35% w / w, about 30% w / w, about 25% w / w, about 20% w / w, or about 15% w / w).

[0035] In certain embodiments, the bulking agent is mannitol.

[0036] In certain embodiments, the bulking agent is mannitol and the stabilizer is poloxamer.

[0037] In certain embodiments, the bulking agent is mannitol and the stabilizer is poloxamer and sodium lauryl sulfate.

[0038] In certain embodiments, the mannitol is present in an amount of about 10-85 % w / w, the poloxamer is present in an amount of about 1-30 % w / w, and the sodium lauryl sulfate is present in an amount of about 0.1-20 % w / w.

[0039] In certain embodiments, the mannitol is present in an amount of about 50-80 % w / w, the poloxamer is present in an amount of about 2-6 % w / w, and the sodium lauryl sulfate is present in an amount of about 0.1-1 % w / w.

[0040] In certain embodiments, the bulking agent is mannitol and the stabilizer is sodium lauryl sulfate. In certain embodiments, the mannitol is present in an amount of about 20-50 % w / w, and the sodium lauryl sulfate is present in an amount of about 15-30% w / w.

[0041] In certain embodiments, the composition further comprises one or more selected from the group consisting of a disintegrant, a lubricant, and combinations thereof.

[0042] In certain embodiments, the disintegrant comprises starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross- linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, gum, or combinations thereof.

[0043] In certain embodiments, the disintegrant is croscarmellose sodium.

[0044] In certain embodiments, the disintegrant is present in an amount of about 1-10 % w / w, optionally about 3 % w / w.

[0045] In certain embodiments, the bulking agent is mannitol and the stabilizer is sodium lauryl sulfate.

[0046] In certain embodiments, the mannitol is present in an amount of about 20-50 % w / w, and the sodium lauryl sulfate is present in an amount of about 10-20% w / w.

[0047] In certain embodiments, the mannitol is present in an amount of about 30 % w / w, and the sodium lauryl sulfate is present in an amount of about 20% w / w.

[0048] In certain embodiments, the composition provided herein further comprises about 0.1-2.0 %w / w lubricant. In certain embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, or any combination thereof.

[0049] In certain embodiments, the composition provided herein further comprises about 1-10 %w / w granulation binder. In certain embodiments, the granulation binder comprises carboxymethyl cellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethyl cellulose (e.g. Hypromellose USP Pharmacoat- 603, hydroxypropylmethyl cellulose acetate stearate (Aqoat HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel® ), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids,bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®, lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum® polyethylene glycol, waxes, sodium alginate, or combinations thereof.

[0050] In certain embodiments, the composition provided herein is granule.

[0051] In certain embodiments, the granule is in a dosage form of tablet, capsule, or sachet.

[0052] In one aspect, the present disclosure provides a composition comprising about 1 to about 100 %w / w Compound 1:or pharmaceutically acceptable salt, co-crystal, or solvate thereof; wherein the water content is less than about 5.0% w / w (e.g. less than about 4% w / w, less than about 3.5% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1.0% w / w, less than about 0.9% w / w, less than about 0.8% w / w, less than about 0.7% w / w, less than about 0.6% w / w, less than about 0.5% w / w, less than about 0.4% w / w, less than about 0.3% w / w, less than about 0.2% w / w, less than about 0.1% w / w).

[0053] In certain embodiments, the composition further comprises less than about 10% w / w of Compound 2:or a pharmaceutically acceptable salt or solvate thereof.

[0054] In certain embodiments, the water content is less than about 2.5% w / w, less than about 1.0 % w / w, or less than about 0.5% w / w.

[0055] In one aspect of the present disclosure, the composition comprises a capsule, a tablet, a sachet, or granule.

[0056] In one aspect, the present disclosure provides a capsule comprisingabout 1 to about 100 %w / w Compound 1:or a pharmaceutically acceptable salt or solvate thereof; wherein the particle size (D50), measured using a laser diffraction method, of the composition is less than about 5000 nm.

[0057] In certain embodiments, the capsule further comprises less than about 10% w / w of Compound 2:or a pharmaceutically acceptable salt or solvate thereof.

[0058] In certain embodiments, the capsule, in a total powder from about 500 mg-700 mg (e.g. from about 550 mg-678 mg), comprises about 120 to about 300 mg (e.g. about 120-280 mg, about 120-250 mg, about 120-230 mg, about 120-200 mg, about 120-180 mg, about 150-300 mg, about 180-300 mg, about 200-300 mg, about 220-300 mg, about 250-300 mg or 280-300 mg) of Compound 1.

[0059] In certain embodiments, the capsule comprises about 120 mg of Compound 1.

[0060] In certain embodiments, the capsule provided herein further comprises about 0.1 to less than about 10% w / w of Compound 2. In certain embodiments, the capsule provided herein further comprises about 0.1 to less than about 5% w / w of Compound 2.

[0061] In certain embodiments, the D50is about 500 to about 5000 nm. In certain embodiments, the D50is about 100 to 500 nm when measured in an aqueous suspension. In certain embodiments, the D50, measured in an aqueous suspension, is less than about 500 nm after storage for one month at temperatures from 0-8 ℃. In certain embodiments, the D50 is from about 100 to about 250 nm.

[0062] In certain embodiments, the capsule provided herein further comprises about 0.1-40% w / w of a stabilizer.

[0063] In certain embodiments, the stabilizer comprises PVP (Povidone), PVA (Polyvinyl alcohol), PEG (Polyethylene glycol), HPMC (Hypromellose), HPMC-AS (Hydroxypropyl methylcellulose acetate succinate), Eudragit®, HPC (Hydroxypropyl cellulose, approx.50,000–1,250,000 g / mol), HEC (Hydroxyethyl cellulose), methylcellulose (MC, approx.10,000–200,000 g / mol), Plantacare® 2000(decyl glucoside) and Na alginate chitosan, NaCMC (Carboxymethylcellulose sodium), SD (Docusate sodium), SLS (Sodium lauryl sulfate), PEI (polyethylene imine), Tweens (e.g. Tween 80 or Tween 20), poloxamers (poloxamer 188, poloxamer 338, or poloxamer 407), polysorbates, sorbitan esters, TPGS (D- α-tocopheryl polyethylene glycol succinate), Vitamin E TPGS (VE TPGS), PEO (Polyethylene oxide) and PPO (Polypropylene oxide), Soluplus®, Sporanox®, gelatin, hydrophobin, cyclodextrins, or any combinations thereof.

[0064] In certain embodiments, the capsule provided herein further comprises a bulking agent. In certain embodiments, the bulking agent is lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, talc, and combinations thereof. In certain embodiments, the bulking agent is mannitol.

[0065] In certain embodiments, the capsule provided herein further comprises a disintegrant. In certain embodiments, the disintegrant is natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, gum, or combinations thereof.

[0066] In certain embodiments, the capsule further comprises a lubricant. In certain embodiments, the lubricant is stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, or combinations thereof.

[0067] In certain embodiments, the capsule comprises about 10-60 %w / w Compound 1; about 0.01-5.0% w / w of Compound 2; about 50-85% w / w of bulking agent; about 1-10 %w / w disintegrant; about 0.1-2.0 %w / w lubricant; and about 1-10 %w / w stabilizer.

[0068] In certain embodiments, the capsule further comprises less than about 5.0% w / w (e.g. less than about 4% w / w, less than about 3.5% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1.0% w / w, less than about 0.9% w / w, less than about 0.8% w / w, less than about 0.7% w / w, less than about 0.6% w / w, less than about 0.5% w / w, less than about 0.4% w / w, less than about 0.3% w / w, less than about 0.2% w / w, less than about 0.1% w / w) water content.

[0069] In one aspect, the present disclosure provides a tablet comprisingabout 5% w / w - about 50% w / w of Compound 1or pharmaceutically acceptable salt, co-crystal, or solvate thereof; about 0.01-5.0% w / w of Compound 2or a pharmaceutically acceptable salt or solvate thereof; about 20-85% w / w of bulking agent; about 1-10 %w / w disintegrant; about 5-30 %w / w stabilizer; about 0.1-2.0 %w / w lubricant; and about 1-10 %w / w granulation binder.

[0070] In certain embodiments, the bulking agent comprises lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, talc, or combinations thereof.

[0071] In certain embodiments, the bulking agent is present in an amount of about 10-85% w / w (or about 10-80% w / w, 10-75% w / w, 10-70% w / w, 10-65% w / w, 10-60% w / w, 10-55% w / w, 10-50% w / w, 10- 45% w / w, 10-40% w / w, 10-35% w / w, 10-30% w / w, 10-25% w / w, 10-20% w / w, 20-80% w / w, 20-75% w / w, 20-70% w / w, 20-65% w / w, 20-60% w / w, 20-55% w / w, 20-50% w / w, 20-45% w / w, 20-40% w / w, 20-35% w / w, 20-30% w / w, 20-25% w / w, 30-80% w / w, 30-75% w / w, 30-70% w / w, 30-65% w / w, 30- 60% w / w, 30-55% w / w, 30-50% w / w, 30-45% w / w, 30-40% w / w, 30-35% w / w, 40-80% w / w, 40-75% w / w, 40-70% w / w, 40-65% w / w, 40-60% w / w, 40-55% w / w, 40-50% w / w, 40-45% w / w, 50-80% w / w, 50-75% w / w, 50-70% w / w, 50-65% w / w, 50-60% w / w, or 50-55% w / w).

[0072] In certain embodiments, the bulking agent is present in an amount of less than about 85% w / w (or less than about 80% w / w, less than about 75% w / w, less than about 70% w / w, less than about 65% w / w, less than about 60% w / w, less than about 55% w / w, less than about 50% w / w, less than about 45% w / w,less than about 40% w / w, less than about 35% w / w, less than about 30% w / w, less than about 25% w / w, less than about 20% w / w, or less than about 15% w / w).

[0073] In certain embodiments, the bulking agent is present in an amount of about 85% w / w (or about 80% w / w, about 75% w / w, about 70% w / w, about 65% w / w, about 60% w / w, about 55% w / w, about 50% w / w, about 45% w / w, about 40% w / w, about 35% w / w, about 30% w / w, about 25% w / w, about 20% w / w, or about 15% w / w).

[0074] In certain embodiments, the bulking agent is present in an amount of about 30 % w / w, or about 70.11 % w / w.

[0075] In certain embodiments, the stabilizer comprises poloxamers (e.g. Pluronics®, i.e., poloxamer 407 (Pluronic® F127) and poloxamer 188 (Pluronic® F68)), celluloses (e.g. hydroxypropyl methylcellulose (HPMC), HPMC-AS (Hydroxypropyl methylcellulose acetate succinate), Eudragit®, hydroxypropylcellulose (HPC, approx.50,000–1,250,000 g / mol), hydroxyethylcellulose (HEC), and methylcellulose (MC, approx.10,000–200,000 g / mol)), polysorbates, sorbitan esters, vitamin E TPGS, sodium lauryl sulfate (SLS), Soluplus®, Sporanox®, gelatin, hydrophobin, cyclodextrins, or any combination thereof.

[0076] In certain embodiments, the stabilizer is present in an amount of about 0.1-40 %w / w (or about 0.1-30 %w / w, 0.1-20 %w / w, 0.1-10 %w / w, 0.1-5 %w / w, 0.1-4 %w / w, 0.1-3 %w / w, 0.1-2 %w / w, 0.1-1 %w / w, 0.1-0.9 %w / w, 0.1-0.8 %w / w, 0.1-0.7 %w / w, 0.1-0.6 %w / w, 0.1-0.5 %w / w, 0.1-0.4 %w / w, 0.1- 0.3some embodiments, the stabilizer is present in an amount less than about 0.5%w / w, 1%w / w, 2%w / w, 3 %w / w, 4%w / w, 5%w / w, 6%w / w, 7%w / w, 8%w / w, 9%w / w, 10%w / w, 15%w / w, 20%w / w, 25%w / w, 30%w / w, 35%w / w, or 40%w / w).

[0077] In certain embodiments, the disintegrant comprises natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, gum, or combinations thereof.

[0078] In certain embodiments, the lubricant is stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, or any combinations thereof.

[0079] In certain embodiments, the granulation binder comprises carboxymethyl cellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethyl cellulose (e.g. Hypromellose USP Pharmacoat- 603, hydroxypropylmethyl cellulose acetate stearate (Aqoat HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel® ), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose(e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®, lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum® polyethylene glycol, waxes, sodium alginate, or any combinations thereof.

[0080] In certain embodiments, the granulation binder is present in an amount of about 1-10% w / w (or about 2% w / w -9% w / w, 2.5% w / w -8.5% w / w, 2.5% w / w -8% w / w, 2.5% w / w -7.5% w / w, 2.5% w / w - 7% w / w, 2.5% w / w -6.5% w / w, 2.5% w / w -6 % w / w, 2.5% w / w -5.5% w / w, 2.5% w / w -5% w / w, 2.5% w / w -4.5% w / w, 2.5% w / w -4% w / w, 3% w / w -10% w / w, 3.5% w / w -9% w / w, or 4% w / w -7% w / w).

[0081] In certain embodiments, the granulation binder is present in an amount of less than about 10% w / w (or less than about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0082] In certain embodiments, the granulation binder is present in an amount of about 10% w / w (or less than about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0083] In certain embodiments, the Compound 1 is present in an amount of about 5% w / w - about 15% w / w, optionally about 10% w / w.

[0084] In certain embodiments, the bulking agent is lactose monohydrate and microcrystalline cellulose. In certain embodiments, the lactose monohydrate is present in an amount of about 30-85 %w / w, 40-75 %w / w, or 50-70 %w / w, optionally 53.0% w / w, and the microcrystalline cellulose is present in an amount of about 10-25 %w / w, or 15-20 %w / w, optionally about 17.5 %w / w.

[0085] In certain embodiments, the Compound 1 is present in an amount of about 35% w / w - about 45% w / w, optionally about 40% w / w.

[0086] In certain embodiments, the Compound 2 is present in an amount of about 0.01-1 % w / w after storage for 24 months at temperatures from 0-25 ℃.

[0087] In certain embodiments, the bulking agent is mannitol. In certain embodiments, the mannitol is present in an amount of about 20-50 %w / w, optionally 30% w / w.

[0088] In certain embodiments, the disintegrant is croscarmellose sodium. In certain embodiments, the croscarmellose sodium is present in an amount of about 2-8 %w / w, 4-8%w / w, optionally about 6 %w / w.

[0089] In certain embodiments, the stabilizer comprises sodium lauryl sulfate. In certain embodiments, the sodium lauryl sulfate is present in an amount of about 5% w / w-25% w / w, optionally about 10 % w / w or about 20 % w / w.

[0090] In certain embodiments, the lubricant is magnesium stearate. In certain embodiments, the magnesium stearate is present in an amount of about 0.1% w / w-1.0 % w / w, optionally about 0.5 % w / w or about 1.0 % w / w.

[0091] In certain embodiments, the granulation binder is hydroxypropyl cellulose. In certain embodiments, hydroxypropyl cellulose is present in an amount of about 2-5 %w / w, optionally about 3 %w / w.

[0092] In certain embodiments, the tablet further comprises less than about 5.0% w / w (e.g. less than about 4% w / w, less than about 3.5% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1.0% w / w, less than about 0.9% w / w, less than about 0.8% w / w, less than about 0.7% w / w, less than about 0.6% w / w, less than about 0.5% w / w, less than about 0.4% w / w, less than about 0.3% w / w, less than about 0.1% w / w, less than about 0.1% w / w) water content.

[0093] In certain embodiments, the tablet, in a total powder from about 100 mg-200 mg, comprises about 120 mg or less (e.g. less than about 120 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, or about 10 mg) of Compound 1.

[0094] In one aspect, the present disclosure provides a method of treating a disease or disorder, comprising administering the composition provided herein to a subject in need thereof.

[0095] In one aspect, the present disclosure provides use of the composition provided herein in the manufacture of medicament for treating a disease or disorder, comprising administering the medicament to a subject in need thereof.

[0096] In one aspect, the present disclosure provides the composition provided herein for use in the treatment of a disease or disorder.

[0097] In one aspect, the present disclosure provides a method of treating a disease or disorder selected from of cardiovascular diseases, fibrosis, neurological disorders, type I hypersensitivity disorders, chronic and acute liver diseases, lung diseases, renal diseases, diabetes, obesity, and cancer, comprising administering to a patient in need thereof the composition provided herein.

[0098] In certain embodiments, the disease or disorder is selected from the group consisting of cardiovascular diseases, fibrosis, neurological disorders, type I hypersensitivity disorders, chronic and acute liver diseases, lung diseases, renal diseases, diabetes, obesity, and cancer.

[0099] In certain embodiments, the disease or disorder is cancer. In certain embodiments, the cancer is a hormone-related cancer. In certain embodiments, the hormone-related cancer is breast cancer,endometrial cancer, ovarian cancer, prostate cancer, testicular cancer, thyroid cancer or osteosarcoma. In certain embodiments, the hormone-related cancer is metastatic castration resistant prostate cancer. In certain embodiments, the hormone-related cancer is breast cancer.

[0100] In certain embodiments, the treatment further comprises a second therapeutic agent.

[0101] In certain embodiments, the second therapeutic agent comprises at least one antiandrogen or at least one immune checkpoint inhibitor.

[0102] In certain embodiments, the antiandrogen is selected from the group consisting of flutamide, hydroxyflutamide, bicalutamide, enzalutamide, nilutamide, apalutamide, darolutamide, seviteronel, zanoterone, proxalutamide, cimetidine, ketoconazole, and topilutamide.

[0103] In certain embodiments, the antiandrogen is selected from the group consisting of abiraterone, canrenone, chlormadinone, cyproterone, delmadinone, dienogest, drospirenone, medrogestone, megestrol, nomegestrol, osaterone, oxendolone, potassium canrenoate, and spironolactone.

[0104] In certain embodiments, the antiandrogen is selected from the group consisting of aminoglutethimide, ketoconazole, or abiraterone acetate, finasteride, and dutasteride.

[0105] In certain embodiments, the antiandrogen is selected from the group consisting of leuprorelin, goserelin, triptorelin, histrelin, degarelix, relugolix and cetrorelix.

[0106] In certain embodiments, the immune checkpoint inhibitor is an anti-PD-1 agent or an anti-PD-L1 agent.

[0107] In certain embodiments, the anti-PD-1 agent or anti-PD-L1 agent is nivolumab, pembrolizumab, cemiplimab, labrolizumab, avelumab, durvalumab or atezolizumab. BRIEF DESCRIPTION OF THE DRAWINGS

[0108] FIG.1A-1B shows the particle size distribution data of milled granules of T1-T7.

[0109] FIG.2 shows in-vitro dissolution profile of T1-T7 tablets.

[0110] FIG.3A shows accelerated stability dissolution summary for T140 mg tablets stored at 40±2 °C / 75±5% RH for up to 8 weeks.

[0111] FIG.3B shows accelerated stability dissolution summary for T240 mg tablets stored at 40±2 °C / 75±5% RH for up to 8 weeks.

[0112] FIG.3C shows accelerated stability dissolution summary for T440 mg tablets stored at 40±2 °C / 75±5% RH for up to 8 weeks.

[0113] FIG.3D shows accelerated stability dissolution summary for T640 mg tablets (2 g silica gel) stored at 40±2 °C / 75±5% RH for up to 8 weeks.

[0114] FIG.3E shows accelerated stability dissolution summary for T640 mg tablets (3 g molecular sieve) stored at 40±2 °C / 75±5% RH for up to 8 weeks.

[0115] FIG.4A-4E shows PK results of engineering batch, T1, T2, T4 and T6 tablets.

[0116] FIG.5 shows the results of X-ray powder diffraction (XRPD) of F2 and F5216 hr after the jet milling in the nano-suspension. DETAILED DESCRIPTION Definitions

[0117] Before describing the disclosure in detail, it is to be understood that this disclosure is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0118] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In case of doubt, or should there be no art recognized common understanding regarding the error range for a certain value or parameter, “about” means ± 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of this value or parameter.

[0119] It is understood that aspects and embodiments of the disclosure described herein include “comprising,” “consisting,” and “consisting essentially of aspects and embodiments.

[0120] The term “prodrug” refers to any compound (e.g., Compound 1) that becomes an active form of a drug (e.g., Compound 2) when administered to a subject, e.g., upon metabolic processing of the prodrug.

[0121] Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0122] The term “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[0123] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation and / or amelioration of the signs, symptoms, or causes of a disease, slowing of disease progression, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0124] The term “treating” or “treatment” encompasses administration of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and / or (iii) prophylactic treatment for preventing the onset of additional symptoms of the disease, such as cancer.

[0125] As used herein, the term “subject” or “patient” refers to a living organism that is treated with compounds as described herein, including, but not limited to, any mammal, such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.

[0126] The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.

[0127] In the present context, the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and / or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated. For example, an effective amount is an amount sufficient to effectuate a beneficial or desired clinical result. The effective amounts can be provided all at once in a single administration or in fractional amounts that provide the effective amount in several administrations. The precise determination of what would be considered an effective amountmay be based on factors individual to each subject, including their size, age, injury, and / or disease or injury being treated, and amount of time since the injury occurred or the disease began. One skilled in the art will be able to determine the effective amount for a given subject based on these considerations which are routine in the art.

[0128] The term “derivative” can be used interchangeably with the term “analog.” Compound 1 can be a derivative or analog if 1, 2, 3, 4, or 5 atoms of compound 1 is replaced by another atom or a functional group (e.g., amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkyl) to form the compounds of the disclosure.

[0129] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0130] The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. Adenosine receptor antagonists

[0131] Disclosed herein are compounds, compositions, formulations, and methods related to A2Badenosine receptor antagonist. For example, the compounds, compositions, and / or formulations disclosed herein can be used in a method of treating a condition in a subject in need thereof. The condition can be cardiovascular diseases, chronic and acute liver disease, lung disease, renal disease, diabetes, obesity, and / or cancer.

[0132] The compound ethyl 3-ethyl-2,6-dioxo-1-propyl-8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4- yl)-1,2,3,6-tetrahydro-7H-purine-7-carboxylate, designated herein as Compound 1, has the following formula:

[0133] Compound 1 is an antagonist of adenosine A2B receptors and is described as Compound O in PCT International Application Publication No. WO 2019 / 173380. The synthesis and method of use thereof is described in PCT International Application Publication No. WO 2019 / 173380 which is herein incorporated by reference in its entirety.

[0134] In one aspect, the present disclosure provides a composition comprising about 1 to about 100 %w / w Compound 1:or pharmaceutically acceptable salt, co-crystal, or solvate thereof.

[0135] Compound 1 is a prodrug which rapidly and near completely hydrolyses in plasma to release Compound 2:

[0136] Compound 2 is the active form of Compound 1, a novel high affinity selective adenosine 2B receptor (A2BR) antagonist which blocks A2BRs on cancer cells and immune cells.

[0137] The term “co-crystal” refers to a molecular complex of a compound disclosed herein and one or more non-ionized co-crystal formers connected via non-covalent interactions. In some embodiments, the co-crystals disclosed herein may include a non-ionized form of Compound I (e.g., Compound I free form) and one or more non-ionized co-crystal formers, where non-ionized Compound I and the co-crystal former(s) are connected through non-covalent interactions. In some embodiments, co-crystals disclosed herein may include an ionized form of Compound I (e.g., a salt of Compound I) and one or more non- ionized co-crystals formers, where ionized Compound I and the co-crystal former(s) are connected through non-covalent interactions. Co-crystals may additionally be present in anhydrous, solvated or hydrated forms. In certain instances, co-crystals may have improved properties as compared to the parent form (i.e., the free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, increased stability, a crystalline form of a normally amorphous compound, acrystalline form of a difficult to salt or unsaltable compound, decreased form diversity, more desired morphology, and the like. Methods for making and characterizing co-crystals are known to those of skill in the art.

[0138] The term “co-crystal former” or “co-former” refers to one or more pharmaceutically acceptable bases or pharmaceutically acceptable acids disclosed herein in association with Compound I, or any other compound disclosed herein.

[0139] The term “solvate” can include, but is not limited to, a solvate that retains one or more of the activities and / or properties of the compound and that is not undesirable. Examples of solvates include, but are not limited to, a compound in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.

[0140] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0141] The term “salt” can include, but are not limited to, salts that retain one or more of the activities and properties of the free acids and bases and that are not undesirable. Illustrative examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0142] In some embodiments, the Compound 1 described herein is present in an amount of about 1-100 %w / w.

[0143] In some embodiments, the Compound 1 described herein are present in an amount of about 1-50 %w / w, about 1-25 %w / w, about 10-50 %w / w, about 10-25 %w / w, optionally about 10%w / w, about 21.82%w / w, about 22%w / w, or about 40 %w / w.

[0144] In certain embodiments, the composition provided herein further comprises less than about 10 (or less than about 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5) % w / w of Compound 2, or a pharmaceutically acceptable salt or solvate thereof.

[0145] In certain embodiments, the composition provided herein comprises Compound 2, which is present at about 0.01 to less than about 10% w / w (e.g. about 0.01 to less than about 9% w / w, about 0.01 to less than about 8% w / w, about 0.01 to less than about 7% w / w, about 0.01 to less than about 6% w / w, about 0.01 to less than about 5% w / w, about 0.1 to less than about 4% w / w, about 0.01 to less than about 3% w / w, about 0.01 to less than about 2% w / w, about 0.01 to less than about 1% w / w, or about 0.01 to less than about 0.5% w / w, about 0.01 to less than about 5% w / w, about 0.01 to less than about 4.5% w / w, about 0.01 to less than about 4% w / w, about 0.01 to less than about 3.5% w / w, about 0.01 to less than about 3% w / w, about 0.1 to less than about 2.5% w / w, about 0.01 to less than about 2% w / w, about 0.01 to less than about 1.5% w / w, about 0.01 to less than about 1% w / w, about 0.1 to less than about 9% w / w, about 0.1 to less than about 8% w / w, about 0.1 to less than about 7% w / w, about 0.1 to less than about 6% w / w, about 0.1 to less than about 5% w / w, about 0.1 to less than about 4% w / w, about 0.1 to less than about 3% w / w, about 0.1 to less than about 2% w / w, about 0.1 to less than about 1% w / w, about 0.1 to less than about 0.5% w / w, about 0.01 to less than about 0.9% w / w, about 0.01 to less than about 0.8% w / w, about 0.01 to less than about 0.7% w / w, about 0.01 to less than about 0.6% w / w, about 0.01 to less than about 0.5% w / w, about 0.01 to less than about 0.4% w / w, or about 0.01 to less than about 0.3% w / w, about 0.01 to less than about 0.2% w / w, or about 0.01 to less than about 0.1% w / w).

[0146] In certain embodiments, the composition provided herein comprises Compound 2, which is present at about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.2% w / w, about 1.5% w / w, about 1.7% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, or about 5% w / w. Pharmaceutical formulations

[0147] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or morepharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0148] In one aspect, the present disclosure provides a composition, which includes the compounds provided herein (such as Compound 1 and / or Compound 2) and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, bulking agent, suspending agent, flavoring agent, sweetening agent, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.

[0149] The pharmaceutical formulation facilitates administration of the compositions to a mammal. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of the compositions provided herein are administered to a mammal having a disease, disorder, or condition to be treated.

[0150] Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0151] In certain embodiments, the particle size (D50) of the compositions, the compound 1 or the stabilizer provided herein, as measured by a static laser diffraction method in suspension, is less than about 5000 nm.

[0152] The term “particle size” refers to the dimensions / diameter of solid, liquid, or gas particles. It is usually measured in microns or nanometers. Particle size is an important property in various industries and can impact the manufacture of many products. Measurement of particle size includes particle size distribution (PSD) based on number, surface area or volume.

[0153] The particle size distribution (PSD) is typically expressed by D10, D50and D90. D50(or DV(0.9)) is the median particle size distribution. If the D50 of a sample is 5 μm by volume distribution, it means that the volume of particles less than 5 μm accounts for 50% of the total sample volume, and likewise, the volume of particles greater than 5 μm is also 50%. Similarly, the definition of D10 and D90 can also be given, which are important parameters as well.

[0154] PSD of an active pharmaceutical ingredient (API) can influence important properties of the final product, such as the content uniformity of tablets and the dissolution rate of the drug to the patient.

[0155] Measurement methods of PSD are various depending on the different principle of measurement or definition of size, including sieving, sedimentation, electrical sensing zone (ESZ), laser diffraction (LD), single particle optical sizing (SPOS), traditional microscopy techniques, automated image analysis methods.

[0156] In certain embodiments, the PSD of the compositions provided herein are measured by the laser diffraction (LD) method. The laser diffraction (LD) method, also known as static light scattering, is based upon Mie scattering by particles in a dilute suspension. It is a common method use to measure particle size distributions. It provides an equivalent diameter of a sphere based on the measured diffraction pattern. It works on the principle that particles of a given size diffract light at an angle that increases with decreasing particle size. It assumes the particle shape to be spherical. Because of the increased number of particles per unit volume, this leads to an overestimation of the volume concentration of particles if the particles are in reality platy; however, size calculations are not much affected, since the diffraction pattern is not much influenced by the third dimension of a particle. Particle size results are biased by the random orientation of particles in 3D space (since theflow is more likely to be turbulent during the measurement process), and the assumed optical properties (refractive index and absorption coefficient) of the material. This method is applicable for particles of size between 0.1 and 2000 µm.

[0157] An appropriately selected particle size provides a desirable dissolution profile of the composition.

[0158] In certain embodiments, the composition, the compound 1 or the stabilizer provided herein has a D50 of about 500 to about 5000 nm, about 500 to about 4500 nm, about 500 to about 4000 nm, about 500 to about 3500 nm, about 500 to about 3000 nm, about 500 to about 2500 nm, about 500 to about 2000 nm, about 500 to about 1500 nm, about 500 to about 1000 nm, about 500 to about 900 nm, about 500 to about 800 nm, or about 500 to about 700 nm.

[0159] In certain embodiments, the composition, the compound 1 or the stabilizer provided herein has a D50less than about 5000 nm, less than about 4500 nm, less than about 4000 nm, less than about 3500 nm, less than about 3000 nm, less than about 2500 nm, less than about 2000 nm, less than about 1500 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, or less than about 600 nm.

[0160] In certain embodiments, the composition, the compound 1 or the stabilizer provided herein has a D50 of about 100 to about 500 nm, about 100 to about 450 nm, about 100 to about 400 nm, about 100 to about 350 nm, about 100 to about 300 nm, about 100 to about 250 nm, about 100 to about 200 nm, or about 100 to about 150 nm.

[0161] In certain embodiments, the composition, the compound 1 or the stabilizer provided herein has a D50less than about 500 nm, about 450 nm, about 400 nm, about 350 nm, about 300 nm, about 250 nm, about 200 nm, or about 150 nm.

[0162] In certain embodiments, the particle size is measured in an aqueous suspension.

[0163] In certain embodiments, the PSD of the composition, the compound 1 or the stabilizer provided herein is measured after storage for a period, such as 3 days, 5 days, one week, two weeks, three weeks, one month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, or 24 months.

[0164] In certain embodiments, the storage temperature is from about 0-8 ℃, 2-8 °C, 2-6 ℃, 4-6 ℃, or 3-5 ℃. In certain embodiments, the storage temperature is about 0℃, about 1 ℃, about 2 ℃, about 3 ℃, about 4 ℃, about 5 ℃, about 6 ℃, about 7 ℃, or about 8 ℃.

[0165] In certain embodiments, the storage temperature is about 5±3 °C, about 25±2 °C / 60±5% relative humidity (RH), or about 40±2 °C / 75±5% RH.

[0166] In certain embodiments, the composition, the compound 1 or the stabilizer provided herein has a D50 less than about 500 nm, about 450 nm, about 400 nm, about 350 nm, about 300 nm, about 250 nm, about 200 nm, or about 150 nm after storage for one month at temperatures from 0-8 ℃.

[0167] In some embodiments, the composition provided herein includes bulking agent. A “bulking agent” refers to a liquid, solid or semi-solid ingredient used either alone or in combination with another material (e.g., a polymer) to partially or fully seal or fill a void (e.g., a diverticulum) or lumen within a host. Bulking agent also refers to compound and mixtures that undergo a chemical reaction, precipitation, or crystallization in situ, which can partially or fully seal or fill a void or lumen within a host. Bulking agents can be used to increase the volume, extend, or dilute other solids. A bulking agent may have a fixed volume or may increase in volume as it comes into contact with body fluids in the host and begins to swell.

[0168] In certain embodiments of the present disclosure, the bulking agent is a solid ingredient. Representative examples of bulking agents include materials such as lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, talc, and combinations thereof.

[0169] In certain embodiments, the bulking agent is present in an amount of about 10-85 %w / w, about 20-80%w / w, about 25-75%w / w, about 30-75%w / w, or about 30-72%w / w.

[0170] In certain embodiments, the bulking agent includes lactose. In certain embodiments, the lactose includes lactose monohydrate. In certain embodiments, the lactose is present in an amount of about 30-85 %w / w, about 40-75 %w / w, or about 50-70 %w / w. In certain embodiments, the lactose is present in an amount of about 53.0 %w / w.

[0171] In certain embodiments, the bulking agent includes microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is present in an amount of about 10-25 %w / w, or about 15-20 %w / w, optionally about 17.5 %w / w.

[0172] In certain embodiments, the bulking agent includes lactose monohydrate and microcrystalline cellulose. In certain embodiments, the lactose monohydrate is present in an amount of about 30-85 %w / w, about 40-75 %w / w, or about 50-70 %w / w, optionally about 53 %w / w, and the microcrystalline cellulose is present in an amount of about 10-25 %w / w, or about 15-20 %w / w, optionally about 17.5 %w / w. In certain embodiments, the lactose monohydrate is present in an amount of about 53 %w / w, and microcrystalline cellulose is present in an amount of about 17.5 %w / w. In certain embodiments, the lactose monohydrate and microcrystalline cellulose are present in an amount of about 70.5%w / w.

[0173] In certain embodiments, the bulking agent includes mannitol. In certain embodiments, the mannitol is present in an amount of about 10-85 %w / w, 10-50 %w / w, 10-40 %w / w, 20-50 %w / w, 20-40 %w / w, 65-85 %w / w, 65-80 %w / w, 50-80 %w / w, or 65-75 %w / w, optionally about 30 %w / w or about 70.11 %w / w.

[0174] In certain embodiments, the composition of the present disclosure needs to maintain a low level of water content to prevent degradation of Compound 1. This can be achieved by adding the bulking agent, such as mannitol.

[0175] In certain embodiments, the composition has a water content of less than about 5 %w / w (e.g. less about w / w).

[0176] In certain embodiments, the composition has mannitol present in an amount of about 10-85 %w / w, 10-50 %w / w, 10-40 %w / w, 20-50 %w / w, 20-40 %w / w, 65-85 %w / w, 65-80 %w / w, 50-80 %w / w, or 50-75 %w / w, optionally about 30 %w / w or about 70.11 %w / w, and low water content of less than about 5 %w / w, less than about 2.5 %w / w, less than about 1.0 %w / w, or less than about 0.5 %w / w.

[0177] In some embodiments, the composition provided herein includes disintegrant. “Disintegrant” is an important excipient that is used to enhance the dissolution and bioavailability of active pharmaceutical ingredients (APIs). These excipients facilitate the disintegration and rapid breakup of granules or tablets or capsules, which ultimately increases their rate of absorption in the body. Examples of disintegrant includes natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, crosscarmellose®, Ac-Di-Sol®, Nymce ZSX®, Primellose®Solutab®, Vivasol®L-HPC, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, crospovidone M®, cross-linked polyvinylpyrrolidone, Kollidon®, polyplasdone®, sodium starch, glycolate, explotab®, sodium alginate, Primogel®, Alginicacid NF, Statialgine®, soy polysaccharides, Emcosoy®, calcium silicate, a clay, gum, and any combinations thereof.

[0178] In certain embodiments, the disintegrant is present in an amount of about 1-10% w / w (or about 2% w / w -9% w / w, 2% w / w -8% w / w, 2% w / w -5% w / w, 2.5% w / w -8.5% w / w, 2.5% w / w -8% w / w, 2.5% w / w -7.5% w / w, 2.5% w / w -7% w / w, 2.5% w / w -6.5% w / w, 2.5% w / w -6 % w / w, 2.5% w / w -5.5% w / w, 2.5% w / w -5% w / w, 2.5% w / w -4.5% w / w, 2.5% w / w -4% w / w, 3% w / w -10% w / w, 3.5% w / w -9% w / w, 4% w / w -7% w / w, or 4% w / w -8% w / w).

[0179] In certain embodiments, the disintegrant is present in an amount of less than about 10% w / w (or less than about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0180] In certain embodiments, the disintegrant is present in an amount of about 10% w / w (or about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0181] In certain embodiments, the disintegrant is present in an amount of about 2-8 %w / w, about 2-5 %w / w, or about 4-8 %w / w, optionally about 3 %w / w or about 6 %w / w.

[0182] In certain embodiments, the disintegrant includes croscarmellose sodium. In certain embodiments, the croscarmellose sodium is present in an amount of about 1-10 %w / w. In certain embodiments, the croscarmellose sodium is present in an amount of about 2-8 %w / w, about 2-5 %w / w, or about 4-8 %w / w, optionally about 3 %w / w or about 6 %w / w.

[0183] In some embodiments, the composition provided herein includes lubricant. Lubricants are added to the powder mixture prior to the tableting or encapsulation step to reduce the friction between the tablet / capsule and the die metal surface and ensure that the tablet / capsule is ejected properly from the press.

[0184] The lubricant used can include, without limitation, stearic acid; a metal salt of stearic acid such as calcium stearate or magnesium stearate, talc; colloid silica; a wax variety such as beads wax or spermaceti; boric acid; adipic acid, a sulphate such as sodium sulphate; glycol, fumaric acid, stearyl sodium fumarate; sucrose aliphatic acid ester, sodium benzoate, D,L-leucine; a lauryl sulphate such as sodium lauryl sulphate or magnesium lauryl sulphate; a kind of silicic acid such as silicic anhydride or silicic acid hydrate; or a starch derivative such as corn starch, potato starch, α-starch or dextrin, etc. Preferred lubricant is a metal salt of stearic acid, such as magnesium stearate, or stearyl sodium fumarate.

[0185] In some embodiments, the lubricant is present in an amount of about 0.1-2.0 %w / w.

[0186] In certain embodiments, the lubricant is present in an amount of about 0.1-2.0 %w / w (or about 0.2-2.0 %w / w, 0.3-2.0 %w / w, 0.4-2.0 %w / w, 0.5-2.0 %w / w, 0.6-2.0 %w / w, 0.7-2.0 %w / w, 0.8-2.0%w / w, 0.9-2.0 %w / w, 1.0-2.0 %w / w, 1.5-2.0 %w / w, 0.1-1.5 %w / w, 0.2-1.5 %w / w, 0.3-1.5 %w / w, 0.4- 1.5 %w / w, 0.5-1.5 %w / w, 0.6-1.5 %w / w, 0.7-1.5 %w / w, 0.8-1.5 %w / w, 0.9-1.5 %w / w, 1.0-1.5 %w / w).

[0187] In embodiments, the lubricant is present in an amount of about 0.5 %w / w or about 1.0 %w / w.

[0188] In some embodiments, the lubricant includes magnesium stearate. In some embodiments, the magnesium stearate is present in an amount of about 0.1-2 %w / w, optionally about 0.5 %w / w or about 1.0 %w / w.

[0189] In some embodiments, the composition provided herein includes granulation binder. Binders or granulation binders impart cohesiveness to solid oral dosage form formulations. For powder filled capsule formulation, the binders aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethyl cellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethyl cellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethyl cellulose acetate stearate (Aqoat HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®, lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone®CL, Kollidon®CL, Polyplasdone®XL-10, and Povidone®K-12), larch arabogalactan, Veegum®polyethylene glycol, waxes, sodium alginate, and combinations thereof.

[0190] Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Those skilled in art can determine the binder level for the formulations.

[0191] In certain embodiments, the granulation binder is present in an amount of about 1-10% w / w (or about 2% w / w -9% w / w, 2.5% w / w -8.5% w / w, 2.5% w / w -8% w / w, 2.5% w / w -7.5% w / w, 2.5% w / w - 7% w / w, 2.5% w / w -6.5% w / w, 2.5% w / w -6 % w / w, 2.5% w / w -5.5% w / w, 2.5% w / w -5% w / w, 2.5% w / w -4.5% w / w, 2.5% w / w -4% w / w, 3% w / w -10% w / w, 3.5% w / w -9% w / w, or 4% w / w -7% w / w).

[0192] In certain embodiments, the granulation binder is present in an amount of less than about 10% w / w (or less than about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0193] In certain embodiments, the granulation binder is present in an amount of about 10% w / w (or less than about 9.5% w / w, 9% w / w, 8.5% w / w, 8% w / w, 7.5% w / w, 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or 1% w / w).

[0194] In some embodiments, the granulation binder includes hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose is present in an amount of about 2-5 %w / w, optionally about 3 %w / w.

[0195] In some embodiments, the composition provided herein includes stabilizer. Stabilizers are incorporated into formulations to prevent aggregation, agglomeration or flocculation. Commonly used stabilizers include polymers and surfactants. They achieve stabilization though electrostatic repulsion and / or steric hindrance. Polymeric stabilizers include PVP (Povidone), PVA (Polyvinyl alcohol), PEG (Polyethylene glycol), HPMC (Hypromellose), HPMC-AS (Hydroxypropyl methylcellulose acetate succinate), Eudragit®, HPC (Hydroxypropyl cellulose, approx.50,000–1,250,000 g / mol), HEC (Hydroxyethyl cellulose), methylcellulose (MC, approx.10,000–200,000 g / mol), Plantacare® 2000 (decyl glucoside) and Na alginate chitosan, NaCMC (Carboxymethylcellulose sodium). Surfactant stabilizers include SD (Docusate sodium), SLS (Sodium lauryl sulfate), PEI (Polyethylene imine), Tweens (e.g. Tween 80 or Tween 20), poloxamers (poloxamer 188, poloxamer 338, or poloxamer 407), polysorbates, sorbitan esters, TPGS (D-α-tocopheryl polyethylene glycol succinate), Vitamin E TPGS (VE TPGS), PEO (Polyethylene oxide) and PPO (Polypropylene oxide), Soluplus®, Sporanox®, gelatin, hydrophobin, cyclodextrins. Further stabilizers include food proteins, amino acids and other co- polymers. One or more stabilizers can be combined in any suitable form.

[0196] In some embodiments, the stabilizer is present in an amount of about 0.1-40 %w / w, about 0.1-30 %w / w, about 0.1-20 %w / w, about 0.1-10 %w / w, about 0.1-5 %w / w, about 0.1-4 %w / w, about 0.1-3 0.1-0.7about 1-35 %w / w, about 1-30%w / w, about 1-25 %w / w, about 1-20 %w / w, about 1-15 %w / w, or about 1-10 %w / w. In some embodiments, the stabilizer is present in an amount less than about 0.5%w / w, 1%w / w, 2%w / w, 330%w / w, 35%w / w, or 40%w / w.

[0197] In some embodiments, the stabilizer includes sodium lauryl sulfate (SLS).

[0198] In some embodiments, the SLS is present in an amount of 5-30 %w / w, 5-15 %w / w, or 15-30 %w / w, optionally about 10 %w / w or about 20 %w / w. In some embodiments, the SLS is present in an amount of 0.1-3.0 %w / w, or 0.1-1.0 %w / w, optionally about 2.29%w / w or about 0.42 %w / w.

[0199] In some embodiments, the stabilizer includes poloxamer, such as poloxamer-188, poloxamer-338, or poloxamer-407. The poloxamer is usually categorized as a surfactant. However, it is sometimes also categorized as a polymer.

[0200] In some embodiments, the poloxamer is present in an amount of 2-6 %w / w, optionally about 2 %w / w or about 4.16 %w / w. In some embodiments, the poloxamer is present in an amount of 20-25 %w / w, optionally about 22.86 %w / w. In some embodiments, the poloxamer-188 is present in an amount of 1-6 %w / w, optionally about 2 %w / w or about 4.16 %w / w. In some embodiments, the poloxamer-188 is present in an amount of 20-25 %w / w, optionally about 22.86 %w / w.

[0201] In some embodiments, the stabilizer includes SLS and poloxamer (such as poloxamer-188).

[0202] In some embodiments, the SLS is present in an amount of about 0.1-3.0 %w / w, or about 0.1-1.0 %w / w, optionally about 2.29%w / w and the poloxamer (such as poloxamer-188) is present in an amount of 20-25 %w / w, optionally about 22.86 %w / w.

[0203] In some embodiments, the SLS is present in an amount of about 0.1-3.0 %w / w, or about 0.1-1.0 %w / w, optionally about 0.42 %w / w or about 0.2 %w / w, and the poloxamer (such as poloxamer-188) is present in an amount of about 1-6 %w / w, optionally about 4.16 %w / w or about 2 %w / w.

[0204] In some embodiments, the SLS is present in an amount of about 0.42 %w / w and poloxamer (such as poloxamer-188) is present in an amount of about 4.16 %w / w.

[0205] In some embodiments, the SLS is present in an amount of about 0.2 %w / w and poloxamer (such as poloxamer-188) is present in an amount of about 2 %w / w.

[0206] The total sum of the combination of components of the formulations of the present invention is 100%.

[0207] Pharmaceutical compositions incorporating a compound described herein may take any physical form that is pharmaceutically acceptable. Pharmaceutical compositions for oral administration are particularly preferred. For example, such pharmaceutical compositions include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, sachets, or syrups or elixirs.

[0208] Known methods of formulating used in pharmaceutical science may be followed to prepare pharmaceutical compositions. All of the usual types of compositions are contemplated, including, but not limited to, tablets, chewable tablets, capsules, granules, and solutions.

[0209] Known methods of formulating used in pharmaceutical science may be followed to prepare pharmaceutical compositions. All of the usual types of compositions are contemplated, including, but not limited to, tablets, chewable tablets, capsules, suspensions and solutions. Capsules may be prepared by mixing the A2B antagonist compound described herein, or the combination of the A2B antagonist compound and the hormone deprivation compound described herein, with a suitable diluent and filling theproper amount of the mixture in capsules. Tablets may be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators, as well as the A2B antagonist compound described herein, or the combination of the A2Bantagonist compound and the hormone deprivation compound described herein, as an active therapeutic agent or active therapeutic agents. A lubricant in a tablet formulation may help prevent the tablet and punches from sticking in the die. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. Enteric formulations are often used to protect an active ingredient from the strongly acidic contents of the stomach and to delay disintegration and absorption in the gastrointestinal tract. Such formulations are created by coating a solid dosage form with a film of a polymer that is insoluble in acid environments, and soluble in basic environments. Tablets are often coated with sugar as a flavor and sealant.

[0210] In certain embodiments, the composition provided herein is a granule. In certain embodiments, the granule includes about 1-100 %w / w Compound 1; about 0.01-5.0% w / w of Compound 2; about 10- 85% w / w of bulking agent; and about 1-30 %w / w stabilizer and about 1-10 %w / w disintegrant.

[0211] In certain embodiments, the granule includes about 1-100 %w / w Compound 1; about 0.01-5.0% w / w of Compound 2; about 10-85% w / w of mannitol, about 1-30 %w / w poloxamer (such as poloxamer- 188) and about 1-10 %w / w disintegrant.

[0212] In certain embodiments, the granule includes about 1-100 %w / w Compound 1; about 0.1-5.0% w / w of Compound 2; about 10-85% w / w of mannitol, about 1-30 %w / w sodium lauryl sulfate and about 1-10 %w / w disintegrant.

[0213] In certain embodiments, the granule is in the dosage form of tablets, capsules, or sachets.

[0214] In certain embodiments, the composition provided herein is a tablet. In certain embodiments, the tablet includes about 1.0-50.0 %w / w of the Compound 1, about 0.1-5.0 %w / w of the Compound 2, about 3.0-5.0 %w / w of the hydroxypropyl cellulose, about 10.0-20.0 %w / w of the sodium lauryl sulfate, about 45.0-60.0 %w / w of the lactose monohydrate, about 15-20 %w / w of the microcrystalline cellulose, about 5-8 %w / w of croscarmellose sodium, about 0.1-1.0 %w / w of the magnesium stearate.

[0215] In certain embodiments, the tablet includes about 10.0 %w / w of the Compound 1, about 0.1-5.0 %w / w of the Compound 2, about 3.0 %w / w of the hydroxypropyl cellulose, about 10.0 %w / w of the sodium lauryl sulfate, about 53.0 %w / w of the lactose monohydrate, about 17.5 %w / w of the microcrystalline cellulose, 6 %w / w of the croscarmellose sodium, about 0.5 %w / w of the magnesium stearate.

[0216] In certain embodiments, the tablet includes about 1.0-50.0 %w / w of the Compound 1, about 0.01- 5.0 %w / w of the Compound 2, about 3.0-5.0 %w / w of the hydroxypropyl cellulose, about 10.0-20.0%w / w of the sodium lauryl sulfate, about 20.0-50.0 %w / w of the mannitol, about 5-8 %w / w of the croscarmellose sodium, about 1.0-2.0 %w / w of the magnesium stearate.

[0217] In certain embodiments, the tablet includes about 40.0 %w / w of the Compound 1, about 0.01-1.0 %w / w of the Compound 2, about 3.0 %w / w of the hydroxypropyl cellulose, about 20.0 %w / w of the sodium lauryl sulfate, about 30.0 %w / w of the mannitol, about 6 %w / w of the croscarmellose sodium, about 1.0 %w / w of the magnesium stearate.

[0218] In certain embodiments, the composition provided herein is a capsule. In certain embodiments, the capsule includes about 15-25 %w / w of the Compound 1, about 0.01-5.0 %w / w of the Compound 2, about 4.0-4.5 %w / w of the poloxamer-188, about 0.3-0.6 %w / w of the sodium lauryl sulfate, about 50-80 %w / w of the mannitol, about 2.0-4.0 %w / w of the croscarmellose sodium, about 0.1-1.0 %w / w of the magnesium stearate.

[0219] In certain embodiments, the capsule includes about 21.82 %w / w of the Compound 1, about 0.1- 1.5 %w / w of the Compound 2, about 4.16 %w / w of the poloxamer-188, about 0.42 %w / w of the sodium lauryl sulfate, about 70.11 %w / w of the mannitol, about 3.0 %w / w of the croscarmellose sodium, about 0.5 %w / w of the magnesium stearate.

[0220] In certain embodiments, the capsule further includes about 15-30 %w / w of a size 00 HPMC capsule. In certain embodiments, the size 00 HPMC capsule is present in an amount of about 23.27 %w / w. Methods of Treatment, Dosing and Treatment Regimens

[0221] In some embodiments, a mammal treated with a composition provided herein as described herein has a disease or disorder. In some embodiments, the disease or condition is selected from the group consisting of cardiovascular diseases, fibrosis, neurological disorders, type I hypersensitivity disorders, chronic and acute liver diseases, lung diseases, renal diseases, diabetes, obesity, and cancer. In some embodiments, the cancer is a hormone-related cancer. In some embodiments, the hormone-related cancer is breast cancer, endometrial cancer, ovarian cancer, prostate cancer, testicular cancer, thyroid cancer or osteosarcoma. In some embodiments, the hormone-related cancer is metastatic castration resistant prostate cancer. In some embodiments, the hormone-related cancer is breast cancer.

[0222] The term “cancer” as used herein, refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias and lymphomas) at any stage of the disease with or without metastases.

[0223] In some embodiments, the A2B adenosine receptor antagonists described herein (e.g., Compound 1, or a pharmaceutically acceptable salt or solvate thereof) are used as monotherapy in the treatment of cancer (e.g., carcinomas, sarcomas, benign tumors, primary tumors, tumor metastases, solid tumors, non- solid tumors, blood tumors, leukemias and lymphomas, hyperproliferative disorders, and / or primary and / or metastatic tumors as described herein).

[0224] Provided herein is a method for treating a cancer in a mammal, the method comprising administering to the mammal a composition provided herein as described herein, wherein the cancer is selected from bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, gastric cancer, rectal cancer, urothelial cancer, testis cancer, cervical cancer, head and neck cancer, and skin cancer. In some embodiments, the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the prodrug of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, has a structure described herein. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a lymphoma, a sarcoma, prostate cancer, or breast cancer.

[0225] In some embodiments, the composition provided herein containing the A2Badenosine receptor antagonists described herein is used alone or in combination with other agents in the treatment of solid tumors. A solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are carcinomas, sarcomas, and lymphomas.

[0226] Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, renal cell carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.

[0227] Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0228] Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias; c) chronic lymphocytic leukemias (CLL), including B-cell CLL, T-cell CLL prolymphocyte leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts). Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; and the like.

[0229] Benign tumors include, e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.

[0230] Primary and metastatic tumors include, e.g., lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain; kidney cancers; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs.

[0231] In one aspect, a composition provided herein containing an A2Badenosine receptor antagonist described herein, or a pharmaceutically acceptable salt or solvate thereof, reduces, ameliorates or inhibits immunosuppression and cell proliferation associated with cancers.

[0232] Provided herein are composition provided herein containing A2B adenosine receptor antagonists that are useful for treating one or more diseases or disorders associated with or would benefit from modulation of A2Badenosine receptor activity.

[0233] In some embodiments, described herein are methods for treating a disease or disorder, wherein the disease or disorder is cancer, or a hyperproliferative disorder.

[0234] In one embodiment, the composition provided herein described herein are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of A2B adenosine receptor activity. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of composition provided herein that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0235] In certain embodiments, the composition provided herein containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a mammal already suffering from a disease or condition, in anamount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the mammal’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0236] In prophylactic applications, composition provided herein containing the compounds described herein are administered to a mammal susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the mammal’s state of health, weight, and the like. When used in mammals, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal’s health status and response to the drugs, and the judgment of a healthcare professional. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a composition provided herein comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0237] In certain embodiments wherein the mammal’s condition does not improve, upon the discretion of a healthcare professional the administration of the composition provided herein are administered chronically, that is, for an extended period of time, including throughout the duration of the mammal’s life in order to ameliorate or otherwise control or limit the symptoms of the mammal’s disease or condition.

[0238] In certain embodiments wherein a mammal’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0239] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the mammal requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0240] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0241] In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 100 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 25 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 10 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 5 mg / kg per body weight. In some of these embodiments, the dose relates to mg / kg per body weight of Compound 1. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0242] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the composition provided herein, including further embodiments in which (i) the compound is administered once a day; or (ii) the composition provided herein is administered to the mammal multiple times over the span of one day.

[0243] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the composition provided herein, including further embodiments in which (i) the composition provided herein is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the composition provided herein is administered to the mammal every 8 hours; (iv) the composition provided herein is administered to the mammal every 12 hours; (v) the composition provided herein is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the composition provided herein is temporarily suspended or the dose of the composition provided herein being administered is temporarily reduced; at the end of the drug holiday,dosing of the composition provided herein is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0244] In certain instances, it is appropriate to administer composition provided herein described herein, in combination with one or more other therapeutic agents. In certain embodiments, the therapeutic agents comprise one or more anti-cancer agents.

[0245] In one embodiment, the therapeutic effectiveness of one of the compositions provided herein described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compositions provided herein described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0246] In one specific embodiment, a composition provided herein described herein is co-administered with a second therapeutic agent, wherein the composition provided herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0247] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[0248] In certain embodiments, different therapeutically-effective dosages of the compounds in the composition provided herein disclosed herein will be utilized in formulating pharmaceutical composition and / or in treatment regimens when the composition provided herein disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention / treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a composition provided herein described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a composition provided herein described herein and the second agent being used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment further includesperiodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0249] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0250] For combination therapies described herein, dosages of the co-administered composition provided herein vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the composition provided herein provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[0251] In combination therapies, the multiple therapeutic agents (one of which is the composition provided herein described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0252] The composition provided herein described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the formulation containing a compound varies. Thus, in one embodiment, the composition provided herein described herein is used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the composition provided herein is administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a composition provided herein described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

[0253] In some embodiments, a composition provided herein described herein is administered in combination with chemotherapy, radiation therapy, monoclonal antibodies, or combinations thereof.

[0254] Chemotherapy includes the use of anti-cancer agents.Hormone Deprivation Agents

[0255] In some embodiments, the antiandrogen is selected from the group consisting of flutamide, hydroxyflutamide, bicalutamide, enzalutamide, nilutamide, apalutamide, darolutamide, seviteronel, zanoterone, proxalutamide, cimetidine, ketoconazole, and topilutamide. In some embodiments, the antiandrogen is selected from the group consisting of abiraterone, canrenone, chlormadinone, cyproterone, delmadinone, dienogest, drospirenone, medrogestone, megestrol, nomegestrol, osaterone, oxendolone, potassium canrenoate, and spironolactone. In some embodiments, the antiandrogen is selected from the group consisting of aminoglutethimide, ketoconazole, or abiraterone acetate, finasteride, and dutasteride. In some embodiments, the antiandrogen is selected from the group consisting of leuprorelin, goserelin, triptorelin, histrelin, degarelix, relugolix and cetrorelix. In some embodiments, the antiandrogen is enzalutamide, darolutamide, apalutamide, or abiraterone. In some embodiments, the antiandrogen is enzalutamide.

[0256] In another aspect, the composition provided herein containing the A2Badenosine receptor antagonist (e.g. the Compound 1), or a pharmaceutically acceptable salt or solvate thereof is administered to the subject in need thereof along with a hormone deprivation agent. In some embodiments, the hormone deprivation agent is an antiandrogen. In some embodiments, the hormone deprivation agent is a selective estrogen receptor modulator (SERM).

[0257] In some embodiments, the hormone deprivation agent is an antiandrogen. The antiandrogen may be an androgen receptor antagonist, an androgen synthesis inhibitor, or an antigonadotropin.

[0258] In some embodiments, the hormone deprivation agent is an androgen receptor antagonist. The androgen receptor antagonists include steroidal antagonists and nonsteroidal antagonists.

[0259] In some embodiments, the androgen receptor antagonist is a steroidal antagonist. For example, the androgen receptor antagonist may be 7α-thioprogesterone, 7α-thiospironolactone, 7α- thiomethylspironolactone, 11α-hydroxyprogesterone, 15β-hydroxycyproterone acetate, abiraterone, abiraterone acetate, allyltestosterone, benorterone, BOMT, canrenoic acid, canrenone, chlormadinone acetate, clascoterone, clometerone, cyproheptadine, cyproterone, cyproterone acetate, delanterone, delmadinone acetate, dicirenone, dienogest, drospirenone, DU-41165 (6-fluoro-16-methylene-17α- acetoxy-δ6-retroprogesterone), edogestrone, EM-4350 (from Endoceutics), EM-5854 (4-Fluoro-17β- hydroxy-17α-[(1-oxidopyridin-1-ium-4-yl)methyl]estra-1,3,5(10)-triene-3-carbonitrile), EM-5855 (from Endoceutics), EM-6537 (from Endoceutics), epitestosterone, galeterone, guggulsterone, ludaterone, medrogestone, megestrol acetate, mespirenone, metogest, mexrenone, mifepristone, nomegestrol acetate, nordinone, osaterone, osaterone acetate, oxendolone, potassium canrenoate, promegestone, prorenone, rosterolone, RU-15328 (from Roussel Uclaf), SC-5233 (spirolactone), spironolactone, spirorenone, spiroxasone, topterone, trimegestone, trimethyltrienolone (R-2956), zanoterone, or allylestrenol.

[0260] In some embodiments, the androgen receptor antagonist is a nonsteroidal antagonist. For example, the androgen receptor antagonist may be 5N-bicalutamide, AA560 (N-2-chloromethyl-2- hydroxypropionyl)-3, 4, 5-trichloroaniline), antarlides, arabilin, apalutamide, atraric acid, AZD-3514 (CAS No.: 1240299-33-5), bakuchiol, BAY-1024767 (1273068-71-5), bicalutamide, bisphenols (e.g., BADGE (5,5-dimethyl-3,7-dioxa-1,9(2)-bis(oxirana)-4,6(2,4)-dibenzenanonaphane), BFDGE (bis[4- (glycidyloxy)phenyl]methane), bisphenol A (4,4’-(propane-2,2-diyl)diphenol), bisphenol F (4,4’- methylenediphenol), bisphenol S (4,4’-Sulfonyldiphenol)), BMS-501949 (from Bristol Myers Squibb), BMS-570511 (from Bristol Myers Squibb), BMS-641988 (CAS No.: 1093276-09-5), CH5137291 (from Chugai Pharmaceutical), cimetidine, cioteronel, cyanonilutamide, darolutamide, DDT (via metabolite p,p’-DDE), dieldrin, DIMP, endosulfan, enzalutamide, EPI-001 (CAS No.: 227947-06-0), EPI-7386 (from ESSA Pharmaceuticals), fenarimol, flutamide, hydroxyflutamide, inocoterone, inocoterone acetate, ketoconazole, ketodarolutamide, lavender oil, LG-105 (from Ligand Pharmaceuticals), LG-120907 (1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline), LGD-1331 (from Ligand Pharmaceuticals), linuron, methiocarb, N-butylbenzenesulfonamide, N-desmethylapalutamide, N- desmethylenzalutamide, nilutamide, ONC1-13B ((R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-4-oxo-2- thioxo-7-oxa-1,3-diazaspiro[4.4]nonan-1-yl)-2-fluoro-N-methylbenzamide), pentomone, PF-998425 (CAS No. : 1076225-27-8), phenothrin, prochloraz, procymidone, proxalutamide, ralaniten (EPI-002), ralaniten acetate (EPI-506), RD-162 (CAS No.: 915087-27-3), rezvilutamide, Ro 2-7239 (2-acetyl-7-oxo- l, 2,3,4,4α,4β,5,6,7,9,10,10α-dodecahydrophenanthrene), Ro 5-2537 (2-(l-ethinyl-l-hydroxyethyl)-7-oxo- l,2,3,4,4α,4β,5,6,7,9,10,10α-dodecahydrophenanthrene), RU-22930 (2-methyl-4-[4-nitro-3- (trifluoromethyl)phenyl]-1,2,4-oxadiazinan-3-one), RU-56187 (CAS No.143782-25-6), RU-57073 (4-[3- (2-hydroxyethyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile), RU-58642 (CAS No.143782-63-2), RU-58841 (4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxo-1- imidazolidinyl]-2-(trifluoromethyl)benzonitrile), seviteronel, thalidomide, topilutamide (fluridil), valproic acid, vinclozolin, YM-580 ((+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6- (trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide), YM-92088 (4-[4-cyano-(3- trifluoromethyl)phenyl]-N-(4-fluorophenyl)piperazine-1-carboxamide), YM-175735 (trans-N-4-[4-cyano- 3-(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide).

[0261] In some embodiments, the androgen receptor antagonist is one of enzalutamide, darolutamide, apalutamide, and abiraterone. In an exemplary embodiment, the androgen receptor antagonist is enzalutamide.

[0262] In some embodiments, hormone deprivation agent is an androgen synthesis inhibitor. For example, the hormone deprivation agent may be aminoglutethimide, ketoconazole, or abiraterone acetate,alone or in combination with a glucocorticoid like prednisone. In some embodiments, the hormone deprivation agent is a 5α-Reductase inhibitor, such as finasteride and dutasteride.

[0263] In some embodiments, hormone deprivation agent is an antigonadotropin. For example, the hormone deprivation agent may be LHRH modulators. The LHRH modulator may be an LHRH agonist, such as leuprorelin (leuprolide), triptorelin, histrelin, and goserelin. Alternatively, the LHRH modulator may be an LHRH antagonist, such as degarelix, relugolix, and cetrorelix. For another example, the hormone deprivation agent may be estrogens, such as estradiol, estradiol esters like estradiol valerate, estradiol undecylate, and polyestradiol phosphate, conjugated estrogens, ethinylestradiol, diethylstilbestrol, and bifluranol. For yet another example, the hormone deprivation agent may be progestogen, such as chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and oxendolone.

[0264] In some embodiments, the hormone-deprivation agent is administered to a cancer patient in need thereof as part of a hormone therapy. In some embodiments, a pharmaceutically acceptable salt or solvate of the hormone-deprivation agent is administered in place of the hormone-deprivation agent. In some embodiments, a prodrug of the hormone-deprivation agent or a pharmaceutically acceptable salt or solvate thereof is administered in place of the hormone-deprivation agent. Immune checkpoint inhibitors

[0265] In some embodiments, a compound described herein (i.e. a A2B adenosine receptor antagonist), or a pharmaceutically acceptable salt thereof, is administered in combination with an immune checkpoint inhibitor. In some embodiments, immune checkpoint inhibitors include, but are not limited to, anti-PD-1, anti-PD-L1, or anti-ligand 2 of programmed cell death protein 1 (PD-L2) agents / inhibitors. In some embodiments, immune checkpoint inhibitors include, but are not limited to anti-PD-1, anti-PD-L1, or anti-ligand 2 of programmed cell death protein 1 (PD-L2) antibodies.

[0266] As used herein, “PD-1” or “PD1” refers to the Programmed Death 1 (PD-1) receptor. Other names include programmed cell death protein 1 and CD279 (cluster of differentiation 279). PD-1 has two ligands, PD-L1 and PD-L2. In some embodiments, targeting PD-1 restores immune function in the tumor microenvironment.

[0267] As used herein, “PD-L1” or “PDL1” refers to the programmed death ligand 1 (PD-L1).

[0268] As used herein, “PD-L2” or “PDL2” refers to the programmed death ligand 2 (PD-L2).

[0269] In some embodiments, the anti-PD-1 or anti-PDL-1 agent is an antibody, a peptide, a small molecule or a nucleic acid.

[0270] In some embodiments, a compound described herein (i.e. a A2Badenosine receptor antagonist), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD-1 or anti-PD-L1 agent. In some embodiments, the anti-PD-1 agent is an anti-PD-1 antibody. In some embodiments, the anti-PD-L1 agent is an anti-PD-L1 antibody.

[0271] In some embodiments, the anti PD-l agent for use in combination with a compound described herein (i.e. a A2Badenosine receptor antagonist), or a pharmaceutically acceptable salt thereof, is nivolumab, pembrolizumab, atezolizumab, durvalumab, pidilizumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI- 754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN- 2034, CSIOOI, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, BGB-108, SHR-1210, PDR-001, PF-06801591, STI-1110, mDX-400, Spartalizumab (PDR001), Camrelizumab (SHR1210), Sintilimab (IBI308), Tislelizumab (BGB-A317), Toripalimab (JS 001), Dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680).

[0272] In some embodiments, the anti PD-l agent is an anti PD-l antibody.

[0273] “Anti-PD-1 antibody” refers to an antibody directed towards programmed death protein 1 (PD1). In some embodiments, an anti-PD-1 antibody binds an epitope of PD-1 which blocks the binding of PD-1 to any one or more of its putative ligands. In some embodiments, an anti-PD1 antibody binds an epitope of a PD-1 protein which blocks the binding of PD-1 to PD-L1 and / or PD-L2.

[0274] Exemplary anti-PD-l antibodies include but are not limited to: nivolumab / MDX-l106 / BMS- 9300 / ONO1152, a fully human lgG4 anti-PD-l monoclonal antibody; pidilizumab (MDV9300 / CT-011), a humanized lgGl monoclonal antibody; pembrolizumab (MK-3475 / pembrolizumab / lambrolizumab), a humanized monoclonal IgG4 antibody; durvalumab (MEDI-4736) and atezolizumab.

[0275] In some embodiments, the anti-PD-1 antibody is nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck), cemiplimab (Libtayo), labrolizumab (Merck), or BGB-A317.

[0276] In some embodiments, the anti-PD1 antibody is an antibody set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546, 8,709,417, or WO2014 / 179664.

[0277] The terms “antibody” and “antibodies” as used herein is inclusive of all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, that may be appropriate for the medical uses disclosed herein. The antibodies may be monoclonal or polyclonal and may be of any species of origin, including, for example, mouse, rat, rabbit, horse, or human. Antibody fragments that retain specific binding to the protein or epitope, for example, PD-L1 or PD-1, bound by the antibody used in the present disclosure are included within the scope of the term “antibody.” The antibodies may be chimeric or humanized, particularly when they are used for therapeutic purposes. Antibodies and antibody fragments may be obtained or prepared using various methods.

[0278] In some embodiments, the anti PD-l agent for use in combination with a compound described herein (i.e. a A2Badenosine receptor antagonist), or a pharmaceutically acceptable salt thereof, is atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX- 072, BMS-936559, KN035, CK-301 (Checkpoint Therapeutics), AUNP12, CA-170 (Aurigene / Curis), MEDI4736, MSB0010718C, MDX 1105-01, and BMS-986189.

[0279] In some embodiments, the anti PD-Ll agent is an anti PD-Ll antibody.

[0280] “Anti-PD-L1 antibody” refers to an antibody directed towards programmed death ligand 1 (PD- L1).

[0281] Anti-PD-Ll antibodies for use in combination with a compound described herein (i.e. a A2B adenosine receptor antagonist), or a pharmaceutically acceptable salt thereof, include: avelumab; BMS- 936559, a fully human IgG4 antibody; atezolizumab (MPDL3280A / RG-7446), a human monoclonal antibody; MEDI4736; MSB0010718C, and MDX 1105-01.

[0282] In some embodiments, the anti-PD-L1 antibody is avelumab (Bavencio®, Merck KGA / Pfizer), durvalumab (AstraZeneca) and atezolizumab (TECENTRIQ®, Roche).

[0283] Additional exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos.8,217,149, 8,383,796, 8,552,154 and 8,617,546.

[0284] Peptide anti-PD-1 / PD-L1 agents include AUNP12 (a 29-mer peptide by Aurigene and Laboratoires Pierre Fabre), CA-170 (Aurigene / Curis), BMS-986189 (a macrocyclic peptide by BMS). Small molecule anti-PD-1 / PD-L1 agents include those described in WO / 2020 / 086556, WO / 2020 / 014643, WO / 2019 / 204609, WO / 2019 / 160882, WO / 2018 / 195321, WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057455, US20180057486, US20180045142, WO20180044963, WO2018044783, WO2018009505, WO20180044329, WO2017066227, WO2017087777, US20170145025, WO2017079669, W02017070089, US2017107216, WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, WO2017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO2017202273, WO2017202274, WO2017202276, WO2017180769, WO2017118762, W02016041511, WO2016039749, WO2016142835, WO2016142852, WO2016142886, WO2016142894, and WO2016142833. In some embodiments, the small molecule anti-PD-1 / PD-L1 agent is GS-4224. In some embodiments, GS-4224 is administered at about 400 mg to about 1000 mg. In some embodiments, immune checkpoint inhibitors include, and are not limited to, anti-T cell immunoglobulin and anti- immunoreceptor tyrosine-based inhibition motif (ITIM) domain (anti-TIGIT) agents such as BMS-986207, which is an anti-TIGIT monoclonal antibody. In some embodiments, immune checkpoint inhibitors include, and are not limited to, anti- lymphocyte activation gene-3 (anti-LAG3) agents such as relatlimab (BMS). In some embodiments, immune checkpoint inhibitors include, and are not limited to, anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab (Lucentis®) and bevacizumab (Avastin®). EXAMPLES Example 1. Property development of formulation

[0285] In general, the final step in the manufacturing process of the Compound 1 drug substance includes micronization by jet milling. The dried crude Compound 1 is dissolved in ethyl acetate at 55 °C to 65 °C, and the insoluble matter is separated out through filtration. The solution is then warmed to between 40 °C and 50 °C, and the Compound 1 crystal seeds are added. After cooling to 15 °C to 25 °C, n-heptane is added and the mixture is stirred for ~6 hours until the desired purity in the wet cake is reached and the X-ray powder diffraction (XRPD) diffractogram is consistent with the reference standard. The wet cake is then centrifuged, dried and sieved until all residual solvents are sufficiently reduced to meet specifications. The pure Compound 1 is then jet milled until the desired particle size distribution is reached. 1. Jet Milled Tablet Development

[0286] 20 g of Compound 1 was added to jet milling gradually with the injector gas pressure to be 3.5 bar, the grinding gas to be 2.5 bar. The results were shown in Table 1 and 2. Table 1. Characterization of raw and jet milled Compound 1

[0287] Table 2 shows the HPLC overlay and impurities for the jet milling product. Table 2. HPLC overlay and impurities for jet milling product1.1 Tablet development of 10% drug load

[0288] Nine tablets were prepared for each formulation by Single-Punch Tablet Press (Table 3). The diameter of tablet was 9 mm. And the hardness tested by Hardness Tester was 50N. Table 3. Tablets formulationDisintegration test in simulated gastric fluid (SGF)

[0289] Disintegration of each formulation were tested in triplicate. When the tablets were disintegrated completely, the time was recorded (Table 4). Table 4. Disintegration time of the tabletsDissolution test in Fed State Simulated Intestinal Fluid FeSSIF (pH 5.0)

[0290] The dissolution profile of each sample was determined in USP Apparatus 2 (Agilent 708-DS) according to the sampling schedule shown in Table 5. All studies used 900 mL of FeSSIF and were carried out at 37±0.5 ℃. Dissolution in the medium was carried out in triplicate (n = 3). At each time point, 5 mL of suspension was automatically sampled and 1.5 mL was taken out for centrifugation at 14000 rpm for 5 min.0.6 mL of clear solution was analyzed by HPLC. The final suspensions were also tested by pH meter.Table 5. Dissolution test in FeSSIF (pH 5.0)Dissolution test in Fasted State Simulated Intestinal Fluid (FaSSIF) (pH 6.5)

[0291] 1 tablet was added into a 40-mL glass vial, and 20 mL of FaSSIF was added to the vial with target API concentration at 1 mg / mL. Then the suspension was stirred magnetically at 37 ºC (200 rpm). Dissolution in the medium was carried out in triplicate (n = 3). At each time point, 500 μL of each suspension was sampled and centrifuged at 14000 rpm for 5 min. Then the supernatants were diluted and analyzed by HPLC. The final suspensions were also tested by pH meter. Results can be found in Table 6- 1 and Table 6-2. Table 6-1. Dissolution test in FaSSIF (pH 6.5)Table 6-2. Dissolution test in FaSSIF (pH 6.5)1.2 Tablet development of 40% drug load

[0292] Seven prototype batches (T1-T7) in combination with the previously manufactured 10 mg tablet formulation were evaluated, and four lead prototype formulations were selected for an in vivo pharmacokinetic (PK) and an accelerated stability study. One formulation was selected to go forward for scale-up and manufacturing of an engineering batch followed by a GMP batch.

[0293] The major processing steps for making tablets consisted of wet granulation, wet milling, drying, milling, blending / lubrication and tableting. 1.2.1 Prototype Tablet Formulation and Process Development

[0294] The formula of T1 (40 mg tablets) had the same composition as that of 10 mg strength with only different tablet weight. It was manufactured at 10% Drug load. All other prototypes had a drug load of 40% and a tablet weight of 100 mg. The amount of sodium lauryl sulfate was kept constant at 20% of the total weight equivalent to 20 mg per tablet.

[0295] Hydroxypropyl Cellulose EXF was selected as the granulation binder and Croscarmellose sodium SD-711 was used throughout as the disintegrant. Three diluents were explored either alone or in combination with each. These diluents include Microcrystalline cellulose, lactose monohydrate and Mannitol 100SD. The grades of diluents were selected to lead to optimum granulation properties such as particle size distribution and flowability and compression properties such as hardness, disintegration and friability. Magnesium stearate and sodium stearyl fumarate were both tested as lubricants and magnesium stearate was selected in the final formulation.

[0296] A summary of prototype formulation compositions is shown in Table 7.Table 7. Summary of prototype formulation compositionsNote: *Purified water acts as a processing aid for the granulation step. It is removed during the granulation drying step.

[0297] A high shear wet granulation process was selected for the manufacture of Compound 140 mg tablets of T1-T7 in order to improve blend uniformity and blend flowability in the tablet press and weight uniformity of the tablet formulation, which consisted of 40% jet milled drug substance. All Compound 1 40 mg Tablets were uncoated.

[0298] The manufacturing process consisted of six steps: 1. The jet milled Compound 1 drug substance and intra-granular excipients were charged into the Glatt TMG bowl. Then, purified water was added to granulate the excipients with the drug substance while applying high shear. At the end of granulation wet massing was applied to ensure batch homogeneity and further strengthening the granules. 2. The wet granules are unloaded from the high shear bowl and passed a Comil U5 using a 156Q screen to ensure that large granules are broken into smaller granules to be efficiently dried in the next step. 3. The wet milled granules are then loaded into a fluid bed dryer or oven and dried until a certain loss on drying value has been reached. 4. The dried granules are then milled using a Comil U5 equipped with a 62 G screen. 5. The milled granules are then blended for a certain number of revolutions with extra granular excipients such as disintegrant and additional filler. This was followed by the addition of a lubricant and subsequent blending for a short duration to ensure proper dispersion of the lubricant. 6. The Blend is then compressed into tablets using a rotary tablet press such as Korsch XL100.

[0299] The wet granulation process parameters, wet milling, drying, dry milling and blending are listed in Table 8. Table 8. Summary of process parameters of T1-T7* The intra-granular material was too sticky and had poor fluidity, which needed to stop and scrape the materials from bowl wall during dry mixing and wet granulation process for several times. In T6 prototype, the color of powder was inhomogeneous after lubrication and blending. In T7 prototype, the material was well granulated and damp after adding 18.7 g purified water and 1 min wet massing. After lubrication and blending, the final blend was uniform in color.

[0300] The physical characteristics of the granules after dry milling and after blending with the extra- granular excipients are summarized in Table 9. The particle size distribution data of granules after dry milling are summarized in Table 10. The particle size distribution data is presented in FIG.1.Table 9. Summary of physical characteristics of T1-T7*Hausner ratio 1.12-1.18 is defined as good flowability per <USP 1174>. Table 10. Summary of particle size distribution of T1-T7 final blends

[0301] All prototype tablets were submitted to the Analytical Team to be tested for water content, Assay and impurities and dissolution. A summary of all analytical data is presented in Table 11. The in-vitro dissolution profiles of T1-T7 tablets are shown in FIG.2.Table 11: Summary of initial test results of T1-T7 tablets

[0302] The test results of T1-T7 tablets were acceptable, however a new impurity was introduced by sodium stearyl fumarate (SSF) in T5 prototype tablets. It was decided to select magnesium stearate in the lead formulation. The difference in impurity profile between T6 and T7 on one side and T1-T5 on the other side was due to the different drug substance batch used in the granulations. On the basis of dissolution, T2, T4 and T6 were selected for further stability testing and pharmacokinetics in dogs. T1 prototype Tablets were used as a benchmark since the same formulation was used for Compound 110 mg Tablets. 1.2.2 Prototype Tablet Accelerated Stability Study

[0303] Four prototype formulations, T1, T2, T4 and T6 entered into an accelerated stability program to help select the lead formulation. In addition one formulation, T6 was packaged with two types of desiccants. Some T6 tablets were packaged with 2 g silica gel desiccant cannister whereas other T6 tablets were packaged with a 3 g molecular sieve desiccant cannister. The prototype tablets were tested after 2, 4 and 8 weeks for appearance, assay and impurities, water content and dissolution. The results were shown in FIG.3A-3E.

[0304] The stability data for all prototypes showed that there is no significant change in dissolution for all four prototypes. The major difference among the four prototypes is the degree of Compound 2 formation. Clearly the formation of Compound 2 is significantly less in T2 and T4 than in T1 and T6. T6 Tablets packaged with 3 g molecular sieve had significantly less Compound 2 than those tablets stored with 2 g silica gel. Based on stability data, T2 and T4 were selected as lead formulations and a 3 g molecular sieve was selected as the desiccant of choice to package the tablets in HDPE bottles.

[0305] 1.2.3 Prototype Tablet Pharmacokinetic (PK) study

[0306] In order to compare the effects of tablet weight, excipient type and proportion and process on the in vivo pharmacokinetics of prototype tablets and to inform the decision to select the lead formulation for the engineering batch, Compound 110 mg tablets engineering batch, T1, T2, T4 and T6 tablets were provided to DMPK group for PK analysis. The results are shown in FIG.4 (panel A-E) and Table 12.Table 12. PK results of 10 mg engineering batch, T1, T2, T4 and T6 tablets

[0307] T1, T2, and T4 had pharmacokinetics that are comparable to Compound 110 mg Tablets.

[0308] From the above data, it can be concluded that (1) Seven prototype formulations were manufactured successfully; (2) All tablets showed good assay and dissolution results, which were within limits and met the product development requirements. 2. Nano-suspension development 2.1 Vehicle screening

[0309] Vehicle screening was conducted in the presence of Compound 1, as shown in Table 13. Table 13. Vehicle screening2.2 Effect of milling time on PSD

[0310] Effect of milling time on particle size D90 and D50 of the F1-F7 nano-suspension in Table 10 (target conc.: 200 mg / mL) are shown in Table 14-1, Table 14-2, and Table 15. Table 14-1. D50 of different milling timeTable 14-2. D90of different milling time

[0311] The D50 and D90 of F2 and F5 in Table 14 were summarized in Table 15 and the X-ray powder diffraction (XRPD) were shown in FIG.5. Table 15. Characterization of F2 & F5 at 216h2.3 Effect of milling time on the purity

[0312] Effect of milling time on the purity of the nano-suspension was shown in Table 16. Table 16. Purity of the nano-suspension over milling time2.4 Effect of the milling beads on PSD

[0313] Comparison of the PSD using 0.2 / 0.5 / 0.8 mm zirconium beads was also conducted.

[0314] The effect of different milling time on particle size D90and D50(target conc.: 200 mg / mL) was shown in Table 17.Table 17-1. D50 of F2 and F5 using 0.2 / 0.5 / 0.8 mm zirconium beadsTable 17-2. D90of F2 and F5 using 0.2 / 0.5 / 0.8 mm zirconium beads2.5 Test of formulations in scale up jet milling

[0316] PM 400 (planetary ball milling) with 2 vehicles & 0.5 mm beads were used in milling tests of F2 and F5 formulations (100 and 200 mg / mL). Results were shown in Table 18-19. Table 18-1. D50 of the F12-F16Table 18-2. D90 of the F12-F16

[0317] The PSD of the F13 and F15 from Table 18 and purity thereof were summarized in Table 19. Table 19. PSD of the F13 and F152.6 Solubility

[0318] Solubility of the F12- F15 nano-suspensions by PM400 was tested and the results were shown in Table 20.Table 20. Solubility of the nano-suspension F12-F15

[0319] Stability of the nano-suspensions at 5 °C & 25 °C were tested at 0, 1 week, 2 weeks, 4 weeks and 8 weeks, and results were summarized in Table 21.

[0320] 60 mg / mL samples were diluted from 200 mg / mL, hence no PSD and XRPD characterization at initial. Table 21-1. Initial Nano-suspension by PM 400Table 21-2.1 week_ Nano-suspension by PM 400Table 21-3.2 weeks_ Nano-suspension by PM 400Table 21-4.4 weeks_ Nano-suspension by PM 400Table 21-5.8 weeks_ Nano-suspension by PM 4002.7 Nano-suspensions for Pharmacokinetic (PK) study

[0321] The nano-suspensions were scale-up jet milled for PK study using PM 400 (planetary ball milling) with 0.5 mm beads (Table 22). Table 22. Concentration of the nano-suspensions jet milled for PK study2.8 Feasibility study to prepare nanosuspension at 200mg / mL

[0322] PM 400 (planetary ball milling) with 0.5 mm beads

[0323] To achieve a final concentration of 200 mg / mL, the nanosuspension was tested using different starting concentrations (Table 23). Table 23. Actual concentration after jet milling from different starting concentration

[0324] When the starting concentration is 240 mg / mL, the actual concentration reached around 200 mg / mL after the jet milling. Thus, the scale-up batch is under preparation with starting concentration of 240 mg / mL.

[0325] The stability at 5 °C & 25 °C after storage of 3 and 5 days were tested, and the results were summarized in Table 24. Table 24-1. Stability of storage of 3 days at 5 °C & 25 °CTable 24-2. Stability of storage of 5 days at 5 °C & 25 °C2.9 Scale up for PK study (Dog & Rat)

[0326] The PSD and concentrations of the nano-suspensions milled are shown in Table 25. No change in XRPD. Table 25. Concentrations of the nano-suspensions jet milled using PM 400 (planetary ball milling) with 0.5 mm beads.Example 2. Formulations

[0327] From the above development, three pharmaceutical formulations for oral administration, Tablet 10 mg, Tablet 40 mg and capsule 120 mg were prepared using Compound 1. The Tablets 10 mg is a round shaped tablet and Compound 1 Tablets 40 mg is a capsule shaped tablet (caplet). Capsules 120 mg is a filled size 00 white Hydroxypropyl methylcellulose (HPMC) capsule.

[0328] Both drug product of tablets (10 mg and 40 mg) are prepared as immediate release tablets using croscarmellose sodium as a disintegrant and sodium lauryl sulfate as a solubilizing agent. All tablets are uncoated. 1. Tablet (10mg and 40mg)

[0329] The quantitative compositions of the Compound 1 Tablets (10 mg and 40 mg) are presented in Table 26. Table 26. Composition of Compound 1 Tablet (10 mg and 40 mg)a Refer to Compound 1 Drug Substance b Magnesium stearate is of vegetable source c The components Lactose Monohydrate and Microcrystalline cellulose are not included in the Compound 140 mg strength tablet. d The component Mannitol is not included in the Compound 110 mg strength tablet

[0330] Compound 1 Tablets are designed to ensure rapid dissolution of Compound 1 Drug Substance. A drug-excipient compatibility study performed for the higher strength tablet was performed with the aim to reduce the water content in the components and hence improve the chemical stability of Compound 1 Drug Substance. This resulted in the replacement of lactose with mannitol and removal of microcrystalline cellulose. Key attributes of both formulations (10 and 40 mg) include: - Croscarmellose sodium as disintegrant to ensure that tablets disintegrate rapidly in the upper gastro-intestinal tract; - Sodium lauryl sulfate as solubilizing agent to ensure that drug substance is sufficiently solubilized by micelles to allow for rapid dissolution and absorption.

[0331] Manufacture of both of the Compound 1 Tablets (10 and 40 mg) is via a high shear wet granulation process followed by blending, lubrication, and tablet compression. The high shear wet granulation process was selected to improve the blend uniformity and flowability of the blend in the tablet press. Container Closure System

[0332] A container closure system that is standard to the industry was selected for Compound 1 Tablets (10 mg and 40 mg). Microbiological Attributes

[0333] Microbiological assessment of the drug product has been monitored according to USP Chapter <1111> Microbiological Examination of Nonsterile Products. Based on the manufacturing process, drug product components, and packaging system which includes desiccant, the risk for microbial contamination and proliferation in Compound 1 Tablets (10 mg and 40 mg) is very low. 2. Capsule (120 mg)

[0334] The capsule (120 mg) is prepared as an immediate release granule formulation that contains nano- milled drug substance (120 mg), poloxamer-188 and sodium lauryl sulfate (stabilizers), mannitol (bulking agent / filler); croscarmellose sodium (disintegrant) and magnesium stearate (lubricant) are extra-granular, the drug product is then filled into size 00 hydroxypropyl methylcellulose (HPMC) capsules.

[0335] The quantitative compositions of the Compound 1 Capsule (120 mg) are presented in Table 27.Table 27. Composition of Compound 1120 mg Capsules.a Refer to Compound 1 Drug Substance b Magnesium stearate is of vegetable source c Refer to the CoA for the Certificate of Analysis for the size 00 white HPMC capsules

[0336] Compound 1 Capsules 120 mg are designed to ensure rapid dissolution of Compound 1 Drug Substance. A drug-excipient compatibility study was performed with the aim of identifying excipients that would cause minimal degradation of the drug substance during the milling step. The formulation of Compound 1 drug substance to produce a granule to fill into a capsule consists of the following: - Poloxamer-188 as a stabilizing agent used during nano-milling to ensure that the nano- suspension is physically stable prior to granulation. - Sodium lauryl sulfate as a stabilizing agent used during nano-milling to ensure that the nano- suspension is physically stable prior to granulation. - Croscarmellose sodium as a disintegrant to ensure that capsules disintegrate rapidly in the upper gastro-intestinal tract. - Mannitol is used as a filler to aid granule formation and was known not to impact chemical stability of the drug substance due to its use in the 40 mg tablet formulation.

[0337] Manufacture of the Compound 1 Capsules 120 mg initially involves a step whereby the drug substance, poloxamer-188 and sodium lauryl sulfate undergo particle size reduction (nanomilling) in anaqueous environment. The nano-suspension produced is combined with additional poloxamer-188, sodium lauryl sulfate and mannitol in a fluid bed granulator and dried. After delumping of granules, blending with croscarmellose sodium, and lubrication with magnesium stearate, the formulated material is filled into capsules. The nano-milling process was selected to ensure that the drug substance particle size (d50) is reduced below 250 nm and that the nano-suspension remains stable prior to granulation. The fluid bed granulation process was selected to create porous granules that have good flowability for capsule filling and meets pharmacopeial (USP 711) dissolution requirements and are comparable to the dissolution of the tablet formulations. Container Closure System

[0338] A container closure system that is standard to the industry was selected for Compound 1 Capsules. Microbiological Attributes

[0339] Microbiological assessment of the drug product has been monitored according to USP Chapter <1111> Microbiological Examination of Nonsterile Products. Based on the manufacturing process, drug product components, and packaging system which includes desiccant, the risk of microbial contamination and proliferation in Compound 1 Capsules is very low. Example 3. Manufacture Process and Analysis 1. Compound 1 Tablets 10 mg and 40 mg

[0340] Typical batch formulas for both Compound 1 Tablets (10 mg and 40 mg) are listed in Table 28.

[0341] For the Compound 1 Tablets (10 mg) the quantities of each component are based on a typical tablet batch size of 150,000 units equivalent to 15,000 g of Compound 1 Tablets. The batch size may be varied to meet clinical demands.

[0342] For the Compound 1 Tablets (40 mg), the quantities of each component are based on a typical tablet batch size of 28,000 units equivalent to 2800 g of Compound 1 Tablets The batch size may be varied to meet clinical demands. Table 28. Typical Batch Formula for Compound 1 Tablets (10 mg and 40 mg)a No overages are included in the formulation. b Purified water acts as a processing aid for the granulation step. It is removed during the granulation drying step. c Magnesium stearate is of vegetable source. 1.1 Description of Manufacture Process and Process Controls

[0343] The manufacturing process for both strengths of Compound 1 Tablets (10 mg and 40 mg) is described by a brief narrative description. The process described below may be reasonably adjusted, while maintaining the same basic production steps, to compensate for different batch sizes and / or equipment characteristics, and / or on the basis of experience of the previous campaigns.

[0344] A high shear wet granulation process was selected for the manufacture of Compound 1 Tablets in order to improve blend uniformity (10 mg strength formulation only) and blend flowability (10 mg and 40 mg strength formulations) in the tablet press and weight uniformity of the tablets which consist of either ~10% or 40% Compound 1 drug substance.

[0345] The Compound 1 Tablet manufacturing process consists of combining the Compound 1 Drug Substance, hydroxypropyl cellulose, microcrystalline cellulose (10 mg strength formulation only), lactose monohydrate (10 mg strength formulation) or mannitol (40 mg strength formulation), sodium lauryl sulfate and croscarmellose sodium, screening the mix and delumping if required with the use of a cone mill. These six materials are then high shear granulated with the addition of purified water. The wet granules may be sized by milling prior to drying in a fluid bed or oven. After the granules are dried, theyare sized by milling. Prescreened croscarmellose sodium is added to the blender to improve tablet disintegration.

[0346] Pre-screened magnesium stearate is added to the blender and blended to complete the blending process. Tablets are compressed using a rotary tablet press using a circular punch for the 10 mg strength formulation and capsule-shaped (caplet) shaped punch for the 40 mg strength formulation. All Compound 1 Tablets are uncoated. 1.2 Control of Critical Steps and Intermediates

[0347] Preliminary controls of critical steps and intermediates used for the production of Compound 1 Tablets (10 mg and 40 mg) are summarized in Table 29. Table 29. Summary of In-process Controls in the production of Compound 1 Tablets2. Compound 1 Capsules 120 mg

[0348] The typical batch formula to produce the nano-suspension is listed in Table 30. The quantities of each component are based on a nano-suspension batch size of approximately 14,200 g. Table 30. Typical Batch Formula for Compound 1 nano-suspensiona No overages are included in the formulation.

[0349] Typical batch formula for the Compound 1 Capsules 120 mg is listed in Table 31. The quantities of each component of the formulation are based on a typical capsule batch size of 24,000 units equivalent to 13,200 g of the Compound 1 blend filled into size 00 HPMC capsules. The batch size may be varied to meet clinical demands. Table 31. Typical Batch Formula for Compound 1 Capsules 120 mga Added during dilution and mixing step in Description of Manufacturing Process of Compound 1 120 mg Capsules. b Purified water in the nano-suspension is removed during the fluid bed granulation and drying steps. In total 23945.12 g of purified water is added and subsequently removed during fluid bed granulation and drying.cAdded during fluid bed granulation and drying in Description of Manufacturing Process of Compound 1120 mg Capsules. d Magnesium stearate is of vegetable source. e Refer to the CoA for the Certificate of Analysis for the size 00 white HPMC capsules 2.1 Description of Manufacturing Process and Process Controls

[0350] A nano-milling process followed by a fluid bed granulation process were selected for the manufacture of Compound 1 Capsules in order to reduce particle size, enhance dissolution and improve blend flowability in the encapsulation machine and weight uniformity of the blend filled into capsules.

[0351] The Compound 1 capsule manufacturing process consists of combining the Compound 1 Drug Substance, poloxamer-188, sodium lauryl sulfate and purified water to form a suspension. The suspension is then passed through a nano-mill in order to reduce particle size. The resulting nano-suspension is further diluted with purified water, poloxamer-188, sodium lauryl sulfate and mannitol to form a homogeneous suspension. The suspension is then sprayed on top of mannitol particles in a fluid bed to form granules which are subsequently dried in the same machine. The dried granules are then de-lumped and loaded into a blender together with croscarmellose sodium, to improve capsule disintegration, followed by pre-screened magnesium stearate, for lubrication, and blended before the drug blend is filled into size HPMC capsules using an automatic capsule filling machine. 2.2 Control of Critical Steps and Intermediates

[0352] Preliminary controls of critical steps and intermediates used for the production of Compound 1 Capsules 120 mg are summarized in Table 32. Table 32. Summary of In-process Controls in the production of Compound 1120 mg Capsulesa – X is the target weight of the formulation of 550 mg with upper and lower limits within 5% of X, plus the average capsuleweight of 10 capsules gives the in process weight range. The average capsule weight could vary from batch to batch of capsules. b – capsule length is less than or equal to the average lengths of 10 locked capsules and may vary depending on the batch of capsules used. Example 4. Analysis of the formulation 1. Dissolution 1.1 Tablets 10 mg and 40 mg

[0353] Dissolution profile of the drug product is determined using USP Apparatus 2 (Paddle) operated at 50 rpm. The dissolution method utilizes a buffered solution (pH 2.0) with 3.0% sodium lauryl sulfate. The pH of the medium is adjusted using hydrochloric acid. Samples are analyzed by an isocratic reverse-phase UPLC method with UV detection, as detailed in Table 33. Table 33. Dissolution Method Conditions1.2 Capsules 120 mg

[0354] Dissolution profile of the Compound 1 Capsules 120 mg is determined using USP Apparatus 2 (Paddle) operated at 75 rpm. The dissolution method utilizes a buffered solution (pH 2.0) with 3.0% sodium lauryl sulfate, which is pH adjusted with 0.2M hydrochloric acid. Capsules are placed into a sinker prior to introduction to the dissolution vessel. Samples are analyzed by an isocratic reverse-phase UPLC method with UV detection, as detailed in Table 34. Table 34. Dissolution Method Conditions4. Stability 4.1 Tablets 10 mg and 40 mg

[0355] Both strengths of Compound 1 Tablets: 10 mg drug substance formulated with hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate and 40 mg drug substance formulated with hydroxypropyl cellulose, sodium lauryl sulfate, mannitol, croscarmellose sodium and magnesium stearate, were manufactured andpackaged and placed on formal stability at the recommended storage temperature of 5±3 °C, as well as 25 ºC / 60% RH and on accelerated stability at 40 ºC / 75% RH.

[0356] For the 10 mg formulation, after 24 months storage, analytical results remained in specification for the stability batch (10mg) and after 24 months storage, analytical results remained in specification for the clinical batch (10mg) of Compound 1 Tablets 10 mg at the recommended storage temperature of 5±3 °C and at 25 ºC / 60% RH. However, after six months storage under accelerated conditions (40 ºC / 75 % RH), Compound 1 Tablets 10 mg exceeded the acceptance limit of5.0 area% for Compound 2, 5.32% and 5.42%, respectively, which was to be expected as a known degradant.

[0357] In contrast, for the 40 mg formulation, after 24 months storage, the analytical results for the stability of Compound 1 Tablets 40 mg were within specification at the recommended storage temperature of 5±3 °C as well as at 25 ºC / 60% RH and 40 ºC / 75% RH. In addition, the analytical results for the of Compound 1 Tablets 40 mg after 24 months storage were within specification at the recommended storage temperature of 5±3 °C, as well as at 25 ºC / 60% RH and after 6 months storage were within specification at 40 ºC / 75% RH (e.g. all degradant Compound 25.0 area%).

[0358] Comparing the stability results for all temperatures and time points for stability and clinical batches of the 10 mg and 40 mg formulations show that the 40 mg tablets have much better stability than the 10 mg tablets. This could be partially reflected by the results of storage after 6 months at 40 ºC / 75% RH, and in part in the low content of Compound 2 in the 40 mg tablets. The principal degradation pathway of Compound 1 to Compound 2 is via hydrolysis, which is promoted by higher temperatures as seen by the out of specification results for the 10 mg batches under accelerated conditions at 40 ºC / 75% RH at the 6 month time point. There is therefore some evidence of consistent stability behavior, that permits a cautious extrapolation of stability performance between products. The physicochemical properties of the batches will be monitored closely as more stability data is accrued and if this conclusion does not continue to hold true then the Competent Authority will be notified, and the shelf-life extension plans below re-considered.

[0359] For the 10 mg formulation, based on the current available stability data for both the stability batch and the GMP clinical batch a shelf-life of 36 months will be applied to Compound 1 Tablets 10 mg when stored at 5±3 °C in accordance with the shelf-life extension plan.

[0360] For the 40 mg formulation, based on the current available stability data for the GMP clinical batch a shelf life of 36 months will be applied to the Compound 1 Tablets 40 mg when stored at 5±3 °C in accordance with the shelf-life extension plan. The shelf-life will continue to be extended in line with the plan assuming stability results remain in specification at subsequent time points.4.2 Capsules 120 mg

[0361] In addition, Compound 1 Capsules 120 mg strength: 120 mg drug substance formulated with poloxamer 188, sodium lauryl sulfate, mannitol, croscarmellose sodium and magnesium stearate, manufactured and packaged were placed on formal stability at the recommended storage temperature of 5±3 °C, as well as 25 ºC / 60% RH and on accelerated stability at 40 ºC / 75% RH.

[0362] After 12 months storage, the analytical results for the stability batch of Compound 1 Capsules 120 mg were within specification at the recommended storage temperature of 5±3 °C as well as at 25 ºC / 60% RH and after 6 months storage were within specification at 40 ºC / 75% RH (Table 35).

[0363] Table 35-1. Stability report on capsule 120 mg at 5±3 °C / BottleTable 35-1-A. Dissolution Summary of capsule 120 mg at 5±3 °C / BottleTable 35-2. Stability report on capsule 120 mg at 25±2 °C / 60±5% RH / BottleTable 35-2A. Dissolution Summary of capsule 120 mg at 25±2 °C / 60±5% RH / BottleTable 35-3. Stability report on capsule 120 mg at 40±2°C / 75±5%RH / BottleTable 35-3A. Dissolution Summary of capsule 120 mg at 40±2°C / 75±5%RH / Bottle

Claims

CLAIMS 1. A composition comprising: about 1 to about 100 %w / w Compound 1:or pharmaceutically acceptable salt, co-crystal, or solvate thereof; wherein the particle size (D50), measured using a laser diffraction method, of Compound 1 is less than about 5000 nm.

2. The composition of claim 1 further comprising less than about 10% w / w of Compound 2:or a pharmaceutically acceptable salt or solvate thereof.

3. The composition of claim 1 or 2, further comprising about 0.1 to less than about 10% w / w of Compound 2.

4. The composition of any preceding claim, further comprising about 0.1 to less than about 5% w / w of Compound 2.

5. The composition of any preceding claim, wherein the D50 is about 500 to about 5000 nm.

6. The composition of any preceding claim, wherein the D50is about 100 to 500 nm when measured in a suspension.

7. The composition of any preceding claim wherein the D50, measured in a suspension, is less than about 500 nm after storage for one month at temperatures from 0-8 ℃.

8. The composition of any preceding claim, wherein the D50 is from about 100 to about 250 nm.

9. The composition of any preceding claim, wherein the composition has less than about 5.0% w / w water content.

10. The composition of any preceding claim, wherein the composition has less than about 2.5% w / w water content.

11. The composition of any preceding claim, wherein the composition has less than about 1.0 % w / w water content.

12. The composition of any preceding claim, wherein the composition has less than about 0.5% w / w water content.

13. The composition of any preceding claim, further comprising a stabilizer.

14. The composition of claim 13, wherein the stabilizer is present in an amount of about 0.1- 40 %w / w.

15. The composition of claim 13 or 14, wherein the stabilizer comprises surfactant, polymer, or combinations thereof.

16. The composition of claim 15, wherein the stabilizer is a polymer.

17. The composition of claim 16, wherein the polymer is present in an amount of about 0.1 to about 20 %w / w, about 1-10 %w / w, or about 2-6 %w / w.

18. The composition of claim 16 or claim 17, wherein the polymer comprises PVP (Povidone), PVA (Polyvinyl alcohol), PEG (Polyethylene glycol), HPMC (Hypromellose), HPMC-AS (Hydroxypropyl methylcellulose acetate succinate), Eudragit®, HPC (Hydroxypropyl cellulose, approx.50,000–1,250,000 g / mol), HEC (Hydroxyethyl cellulose), methylcellulose (MC, approx.10,000–200,000 g / mol), Plantacare® 2000 (decyl glucoside) and Na alginate chitosan, NaCMC (Carboxymethylcellulose sodium), or any combination thereof.

19. The composition of claim 15, wherein the stabilizer is a surfactant.

20. The composition of claim 19, wherein the surfactant is present in an amount of about 0.1-30% w / w, about 15-30 % w / w, or about 5-15% w / w, or about 2-6% w / w.

21. The composition of claim 19 or claim 20, wherein the stabilizer comprises SD (Docusate sodium), SLS (Sodium lauryl sulfate), Tweens (e.g. Tween 80 or Tween 20), poloxamers (poloxamer 188, poloxamer 338, or poloxamer 407), polysorbates, sorbitan esters, TPGS (D-α-tocopheryl polyethylene glycol succinate), Vitamin E TPGS (VE TPGS), Soluplus®, Sporanox®, gelatin, hydrophobin, cyclodextrins, or any combination thereof.

22. The composition of any one of claims 19-21, wherein the surfactant comprises poloxamer, sodium lauryl sulfate, or any combination thereof.

23. The composition of claim 22, wherein the surfactant is sodium lauryl sulfate and poloxamer.

24. The composition of claim 23, wherein the particle size (D50), measured using a laser diffraction method, of sodium lauryl sulfate and poloxamer is less than about 5000 nm when measured in a suspension, or optionally about 500 to about 5000 nm when measured in a suspension, or optionally about 100 to about 500 nm when measured in a suspension.

25. The composition of claim 23 or 24, wherein the stabilizer comprises about 2-6% w / w of poloxamer 188 and about 0.1-1 % w / w of sodium lauryl sulfate.

26. The composition of any preceding claim, further comprising a bulking agent.

27. The composition of claim 26, wherein the bulking agent is present in an amount of about 10-85% w / w, optionally about 20-50 % w / w, or about 50-80 % w / w.

28. The compound of claim 26 or claim 27, wherein the bulking agent is lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, talc, and combinations thereof.

29. The composition of claim 27 or 28, wherein the bulking agent is mannitol.

30. The composition of any preceding claim, wherein the bulking agent is mannitol and the stabilizers are poloxamer and sodium lauryl sulfate.

31. The composition of claim 30, wherein the mannitol is present in an amount of about 10-85 % w / w, the poloxamer is present in an amount of about 1-30 % w / w, and the sodium lauryl sulfate is present in an amount of about 0.1-20 % w / w.

32. The composition of claim 31, wherein the mannitol is present in an amount of about 50-80 % w / w, the poloxamer is present in an amount of about 2-6 % w / w, and the sodium lauryl sulfate is present in an amount of about 0.1-1 % w / w.

33. The composition of any preceding claim, wherein the bulking agent is mannitol and the stabilizer is sodium lauryl sulfate.

34. The composition of claim 30, wherein the mannitol is present in an amount of about 20-50 % w / w, and the sodium lauryl sulfate is present in an amount of about 15-30% w / w.

35. A composition comprising: about 1 to about 100 %w / w Compound 1:or pharmaceutically acceptable salt, co-crystal, or solvate thereof; wherein the water content is less than about 5.0% w / w.

36. The composition of claim 35, further comprising less than about 10% w / w of Compound 2:or a pharmaceutically acceptable salt or solvate thereof.

37. The composition of claim 35 or 36, wherein the water content is less than about 2.5% w / w, about 1.0 % w / w, or about 0.5% w / w.

38. A capsule comprising the composition of any one of claims 1-37.

39. The capsule of claim 38 comprising about 120 to about 300 mg of Compound 1.

40. A tablet comprising the composition of any one of claims 1-37.

41. The tablet of claim 40 comprising about 120 mg or less of Compound 1.

42. A method of treating a disease or disorder selected from of cardiovascular diseases, fibrosis, neurological disorders, type I hypersensitivity disorders, chronic and acute liver diseases, lung diseases, renal diseases, diabetes, obesity, and cancer, comprising administering to a patient in need thereof the composition of any one of claims 1-37, the capsule of claims 38-39, or the tablet of claims 40-41.

43. The method of claim 42, wherein the disease or disorder is cancer.

44. The method of claim 43, wherein the cancer is a hormone-related cancer.

45. The method of claim 44, wherein the hormone-related cancer is breast cancer, endometrial cancer, ovarian cancer, prostate cancer, testicular cancer, thyroid cancer or osteosarcoma.

46. The method of any one of claims 44-45, wherein the hormone-related cancer is metastatic castration resistant prostate cancer.

47. The method of any one of claims 44-46, wherein the hormone-related cancer is breast cancer.

48. The method of any one of claims 42-47, further comprising a second therapeutic agent.

49. The method of claim 48, wherein the second therapeutic agent comprises at least one antiandrogen or at least one immune checkpoint inhibitor.

50. The method of claim 49, wherein the antiandrogen is selected from the group consisting of flutamide, hydroxyflutamide, bicalutamide, enzalutamide, nilutamide, apalutamide, darolutamide, seviteronel, zanoterone, proxalutamide, cimetidine, ketoconazole, and topilutamide.

51. The method of claim 50, wherein the antiandrogen is selected from the group consisting of abiraterone, canrenone, chlormadinone, cyproterone, delmadinone, dienogest, drospirenone, medrogestone, megestrol, nomegestrol, osaterone, oxendolone, potassium canrenoate, and spironolactone.

52. The method of claim 50, wherein the antiandrogen is selected from the group consisting of aminoglutethimide, ketoconazole, or abiraterone acetate, finasteride, and dutasteride.

53. The method of claim 50, wherein the antiandrogen is selected from the group consisting of leuprorelin, goserelin, triptorelin, histrelin, degarelix, relugolix and cetrorelix.

54. The method of claim 50, wherein the immune checkpoint inhibitor is an anti-PD-1 agent or an anti-PD-L1 agent.

55. The method of claim 54, wherein the anti-PD-1 agent or anti-PD-L1 agent is nivolumab, pembrolizumab, cemiplimab, labrolizumab, avelumab, durvalumab or atezolizumab.

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