BACKGROUND OF THE INVENTION

Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzing endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate based lipid, in the nervous system. 1,1,1,3,3,3-Hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a MAGL inhibitor.

SUMMARY OF THE INVENTION

Provided herein are pharmaceutical formulations in solid dosage form comprising 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof. In one aspect, described herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 1 mg to about 60 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof,(b) about 5 mg to about 425 mg of a polymeric carrier;(c) about 0.2 mg to about 10 mg of a surfactant; and(d) 0.2 mg to about 10 mg of a glidant.

In some embodiments, the pharmaceutical formulation comprises about 10 mg to about 150 mg of the polymeric carrier. In some embodiments, the pharmaceutical formulation comprises about 14 mg to about 85 mg of the polymeric carrier. In some embodiments, the polymeric carrier is selected from polyvinyl pyrrolidone K30 (PVP K30), polyvinyl pyrrolidone K17 (PVP K17), polyvinyl pyrrolidone K12 (PVP K12), polyvinyl pyrrolidone vinyl acetate (PVPVA 64), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose acetylsuccinate (HPMC AS), and methylmethacrylate polymers (Eudragit polymers). In some embodiments, the polymeric carrier is polyvinyl pyrrolidone K30 (PVP K30). In some embodiments, the polymeric carrier is polyvinyl pyrrolidone vinyl acetate (PVPVA 64). In some embodiments, the pharmaceutical formulation comprises about 0.2 mg to about 4 mg of a surfactant. In some embodiments, the pharmaceutical formulation comprises about 0.4 mg to about 2 mg of a surfactant. In some embodiments, the surfactant is selected from polysorbates, polaxomers, bile salts, glyceryl monostearate, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, copolymers of ethylene oxide and propylene oxide, and d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS). In some embodiments, the surfactant is Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical formulation comprises about 0.2 mg to about 4 mg of a glidant. In some embodiments, the pharmaceutical formulation comprises about 0.4 mg to about 2 mg of a glidant. In some embodiments, the glidant is silicon dioxide or talc. In some embodiments, the glidant is silicon dioxide. In some embodiments, the pharmaceutical formulation further comprises a buffer selected from potassium dihydrogen phosphate, sodium bicarbonate, magnesium carbonate, sodium citrate, sodium dihydrogen phosphate, dipotassium monohydrogen phosphate, and disodium monohydrogen phosphate. In some embodiments, the pharmaceutical formulation comprises about 0.1 mg to about 5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation comprises about 0.2 mg to about 2 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 65 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 30 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 2 mg to about 15 mg of a plasticizer. In some embodiments, the plasticizer is selected from PEG 400, triethyl citrate, triacetin, acetyl tributyl citrate, acetyl triethyl citrate, stearic acid, glycerin, polyethylene glycols, polyethylene glycol monomethyl ether, propylene glycol, sorbitol sorbitan solution, castor oil, diacetylated monoglycerides, dibutyl sebacates, and diethyl phthalate. In some embodiments, the plasticizer is PEG 400. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 850 mg of a filler. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 400 mg of a filler. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 200 mg of a filler. In some embodiments, the filler is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500). In some embodiments, the filler is lactose, mannitol, or microcrystalline cellulose. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 150 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 50 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 6 mg to about 30 mg of a disintegrant. In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, hydroxypropyl cellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 10 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 4 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 1.5 mg of a lubricant. In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, and sodium stearyl fumarate. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, described herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 1 mg to about 60 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof;(b) about 20 mg to about 400 mg of a filler;(c) about 3 mg to about 150 mg of a disintegrant; and(d) about 0.1 mg to about 10 mg of a lubricant.
In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 200 mg of a filler. In some embodiments, the pharmaceutical formulation further comprises about 50 mg to about 175 mg of a filler. In some embodiments, the filler is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500). In some embodiments, the filler is lactose, mannitol, or microcrystalline cellulose. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 50 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 25 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 6 mg to about 15 mg of a disintegrant. In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, hydroxypropyl cellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 4 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.5 mg to about 2.5 mg of a lubricant. In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, and sodium stearyl fumarate. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the pharmaceutical formulation comprises about 1 mg to about 30 mg of the 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical formulation comprises about 2 mg to about 15 mg of the 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof. In some embodiments, the 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a free base. In some embodiments, the 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a hydrochloride salt. In some embodiments, the 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a fumarate salt.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 2 mg to about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 14 mg to about 72.5 mg of polyvinyl pyrrolidone K30 (PVP K30);(c) about 2 mg to about 13 mg of PEG 400;(d) about 0.4 mg to about 2 mg of Polysorbate 80 (Tween 80);(e) about 0.4 mg to about 2 mg of silicon dioxide;(f) about 0.2 mg to about 1 mg of potassium dihydrogen phosphate;(g) about 33 mg to about 170 mg of microcrystalline cellulose;(h) about 6 mg to about 30 mg of crospovidone; and(i) about 0.3 mg to about 1.5 mg of sodium stearyl fumarate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 2 mg to about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 17 mg to about 85 mg of polyvinyl pyrrolidone vinyl acetate (PVPVA 64);(c) about 0.4 mg to about 2 mg of Polysorbate 80 (Tween 80);(d) about 0.4 mg to about 2 mg of silicon dioxide;(e) about 0.2 mg to about 1 mg of potassium dihydrogen phosphate;(f) about 33 mg to about 170 mg of microcrystalline cellulose;(g) about 6 mg to about 30 mg of crospovidone; and(h) about 0.3 mg to about 1.5 mg of sodium stearyl fumarate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 2 mg to about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 14 mg to about 72.5 mg of polyvinyl pyrrolidone K30 (PVP K30);(c) about 1 mg to about 13 mg of PEG 400;(d) about 0.4 mg to about 2 mg of Polysorbate 80 (Tween 80);(e) about 0.4 mg to about 2 mg of silicon dioxide;(f) about 0.2 mg to about 1 mg of potassium dihydrogen phosphate;(g) about 33 mg to about 170 mg of microcrystalline cellulose;(h) about 6 mg to about 30 mg of croscarmellose sodium; and(i) about 0.3 mg to about 1.5 mg of sodium stearyl fumarate; and(j) about 2 mg to about 10 mg of Opadry AMB II Beige.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 72.1 mg of polyvinyl pyrrolidone K30 (PVP K30);(c) about 12.9 mg of PEG 400;(d) about 2 mg of Polysorbate 80 (Tween 80);(e) about 2 mg of silicon dioxide;(f) about 1 mg of potassium dihydrogen phosphate;(g) about 168.5 mg of microcrystalline cellulose;(h) about 30 mg of crospovidone; and(i) about 1.5 mg of sodium stearyl fumarate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 10.7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 72.1 mg of polyvinyl pyrrolidone K30 (PVP K30);(c) about 12.9 mg of PEG 400;(d) about 2 mg of Polysorbate 80 (Tween 80);(e) about 2 mg of silicon dioxide;(f) about 1 mg of potassium dihydrogen phosphate;(g) about 168.5 mg of microcrystalline cellulose;(h) about 30 mg of crospovidone; and(i) about 1.5 mg of sodium stearyl fumarate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 85 mg of polyvinyl pyrrolidone vinyl acetate (PVPVA 64);(c) about 2 mg of Polysorbate 80 (Tween 80);(d) about 2 mg of silicon dioxide;(e) about 1 mg of potassium dihydrogen phosphate;(f) about 168.5 mg of microcrystalline cellulose;(g) about 30 mg of crospovidone; and(h) about 1.5 mg of sodium stearyl fumarate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 2.1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 156 mg of microcrystalline cellulose;(c) about 10 mg of croscarmellose sodium; and(d) about 1.7 mg of magnesium stearate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 10.7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 147 mg of microcrystalline cellulose;(c) about 10.2 mg of croscarmellose sodium; and(d) about 1.7 mg of magnesium stearate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 53.6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 104 mg of microcrystalline cellulose;(c) about 10 mg of croscarmellose sodium; and(d) about 1.7 mg of magnesium stearate.

Further provided herein is a pharmaceutical formulation in a solid dosage form comprising:(a) about 2.1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride salt;(b) about 15.1 mg of polyvinyl pyrrolidone K30 (PVP K30);(c) about 1.6 mg of PEG 400;(d) about 0.4 mg of Polysorbate 80 (Tween 80);(e) about 0.4 mg of silicon dioxide;(f) about 0.4 mg of potassium dihydrogen phosphate;(g) about 121.7 mg of microcrystalline cellulose;(h) about 7.5 mg of croscarmellose sodium;(i) about 0.8 mg of sodium stearyl fumarate; and(j) about 6.0 mg of Opadry AMB II Beige.

In some embodiments, the solid dosage form is selected from a powder, a tablet, a bite-disintegration tablet, a chewable tablet, a caplet, a capsule, a gelcap, an effervescent powder, a rapid-disintegration tablet, an abuse-deterrent tablet, a modified release tablet, a modified release caplet, a modified release capsule, and an aqueous suspension produced from a powder. In some embodiments, the solid dosage form is a tablet. In some embodiments, the pharmaceutical formulation further comprises about 2 mg to about 10 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 4 mg to about 8 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 2 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 3 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 4 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 5 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 6 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 7 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 8 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 9 mg of a film coating. In some embodiments, the pharmaceutical formulation further comprises about 10 mg of a film coating. In some embodiments, the film coating is Opadry AMB II Beige. In some embodiments, the solid dosage form is a caplet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, the 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, the pharmaceutical formulation is manufactured by a hot melt extrusion process. In some embodiments, the pharmaceutical formulation is manufactured by a sprayed-dried dispersion (SDD) process. In some embodiments, the pharmaceutical formulation comprises a self-emulsifying drug delivery system, a self-microemulsifying drug delivery system, or a self-nanoemulsifying drug delivery system.

In another aspect, provided herein is a method of treating pain in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical formulation described herein. In some embodiments the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain.

In another aspect, provided herein is a method of treating epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optica (NMO), Tourette syndrome, Alzheimer disease, or abdominal pain associated with irritable bowel syndrome in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical formulation described herein.

