RU2775232C1 - Pharmaceutical compositions - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to the field of medicine, namely to a pharmaceutical composition in solid dosage form containing: (a) from 1 mg to 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) 50 mg to 175 mg microcrystalline cellulose; (c) 6 mg to 15 mg croscarmellose sodium; and (d) 0.5 mg to about 2.5 mg magnesium stearate.

EFFECT: invention provides for the creation of a stable pharmaceutical composition.

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Description

Link to related applications

[0001] This application claims priority under U.S. Provisional Application No. 62/423,124, filed November 16, 2016, and U.S. Provisional Application No. 62/545,857, filed August 15, 2017, which are incorporated herein in their entirety. document through a link.

Background of the Invention

[0002] Monoacylglycerol lipase (MAGL) is an enzyme responsible for the hydrolysis of 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 an inhibitor of MAGL.

Brief summary of the present invention

[0003] Provided herein are pharmaceutical compositions in solid dosage form containing 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. According to one aspect, the present document describes a pharmaceutical composition in solid dosage form, containing:

(a) about 1 mg to about 60 mg 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 polymer carrier;

(c) about 0.2 mg to about 10 mg of a surfactant; as well as

(d) 0.2 mg to 10 mg glidant.

[0004] In some embodiments, the pharmaceutical composition contains from about 10 mg to about 150 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 14 mg to about 85 mg of a polymeric carrier. In some embodiments, the polymeric carrier is selected from polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone K17 (PVP K17), polyvinylpyrrolidone K12 (PVP K12), polyvinylpyrrolidone/vinyl acetate (PVPVA 64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), and methyl methacrylate polymers (Eudragit polymers). In some embodiments, the polymeric carrier is polyvinylpyrrolidone K30 (PVP K30). In some embodiments, the polymeric carrier is polyvinylpyrrolidone/vinyl acetate (PVPVA 64). In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 4 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from 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, ethylene oxide-propylene oxide copolymers, 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 composition contains from about 0.2 mg to about 4 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 2 mg of glidant. In some embodiments, the glidant is silicon dioxide or talc. In some embodiments, the glidant is silica. In some embodiments, the pharmaceutical composition 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 composition contains from about 0.1 mg to about 5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from 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, sorbitan-sorbitol solution, castor oil, diacetylated monoglycerides, dibutyl sebacate, 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 an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 400 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 200 mg of an excipient. In some embodiments, the excipient is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, siliconized 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 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.

[0005] According to some embodiments, a pharmaceutical composition in a solid dosage form is described herein, comprising:

(a) about 1 mg to about 60 mg 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 excipient;

(c) about 3 mg to about 150 mg disintegrant; as well as

(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 an excipient. In some embodiments, the pharmaceutical formulation further comprises about 50 mg to about 175 mg of an excipient. In some embodiments, the excipient is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, siliconized 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 composition 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.

[0006] In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 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. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 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. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is the free base. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is the hydrochloride . In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a fumarate .

[0007] Additionally provided herein is a pharmaceutical formulation in 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) hydrochloride) piperazine-1-carboxylate;

(b) about 14 mg to about 72.5 mg of polyvinylpyrrolidone K30 (PVP K30);

(c) about 2 mg to about 13 mg 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 silica;

(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; as well as

(i) about 0.3 mg to about 1.5 mg sodium stearyl fumarate.

[0008] Additionally provided herein is a pharmaceutical formulation in 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) hydrochloride) piperazine-1-carboxylate;

(b) from about 17 mg to about 85 mg of polyvinylpyrrolidone/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 silica;

(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; as well as

(h) about 0.3 mg to about 1.5 mg sodium stearyl fumarate.

[0009] Additionally, 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) hydrochloride) piperazine-1-carboxylate;

(b) about 14 mg to about 72.5 mg of polyvinylpyrrolidone K30 (PVP K30);

(c) about 1 mg to about 13 mg 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 silica;

(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; as well as

(i) about 0.3 mg to about 1.5 mg sodium stearyl fumarate; as well as

j) about 2 mg to about 10 mg of Opadry AMB II Beige.

[0010] Additionally, 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 ;

(b) about 72.1 mg of polyvinylpyrrolidone K30 (PVP K30);

(c) about 12.9 mg PEG-400;

(d) about 2 mg polysorbate 80 (Tween 80);

(e) about 2 mg of silicon dioxide;

(f) about 1 mg potassium dihydrogen phosphate;

(g) about 168.5 mg of microcrystalline cellulose;

(h) about 30 mg of crospovidone; as well as

(i) about 1.5 mg sodium stearyl fumarate.

[0011] Additionally provided herein is a pharmaceutical formulation in 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)piperazin-1 hydrochloride -carboxylate;

(b) about 72.1 mg of polyvinylpyrrolidone K30 (PVP K30);

(c) about 12.9 mg PEG-400;

(d) about 2 mg polysorbate 80 (Tween 80);

(e) about 2 mg of silicon dioxide;

(f) about 1 mg potassium dihydrogen phosphate;

(g) about 168.5 mg of microcrystalline cellulose;

(h) about 30 mg of crospovidone; as well as

(i) about 1.5 mg sodium stearyl fumarate.

[0012] Additionally provided herein is a pharmaceutical formulation in 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 ;

(b) about 85 mg of polyvinylpyrrolidone/vinyl acetate (PVPVA 64);

(c) about 2 mg polysorbate 80 (Tween 80);

(d) about 2 mg of silicon dioxide;

(e) about 1 mg potassium dihydrogen phosphate;

(f) about 168.5 mg of microcrystalline cellulose;

(g) about 30 mg of crospovidone; as well as

(h) about 1.5 mg sodium stearyl fumarate.

[0013] Additionally, 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)piperazin-1 hydrochloride -carboxylate;

(b) about 156 mg of microcrystalline cellulose;

(c) about 10 mg of croscarmellose sodium; as well as

(d) about 1.7 mg of magnesium stearate.

[0014] Additionally provided herein is a pharmaceutical formulation in 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)piperazin-1 hydrochloride -carboxylate;

(b) about 147 mg of microcrystalline cellulose;

(c) about 10.2 mg of croscarmellose sodium; as well as

(d) about 1.7 mg of magnesium stearate.

[0015] Additionally provided herein is a pharmaceutical formulation in 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)piperazin-1 hydrochloride -carboxylate;

(b) about 104 mg of microcrystalline cellulose;

(c) about 10 mg of croscarmellose sodium; as well as

(d) about 1.7 mg of magnesium stearate.

[0016] Additionally provided herein is a pharmaceutical formulation in 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)piperazin-1 hydrochloride -carboxylate;

(b) about 15.1 mg of polyvinylpyrrolidone K30 (PVP K30);

(c) about 1.6 mg PEG-400;

(d) about 0.4 mg polysorbate 80 (Tween 80);

(e) about 0.4 mg silica;

(f) about 0.4 mg potassium dihydrogen phosphate;

(g) about 121.7 mg of microcrystalline cellulose;

(h) about 7.5 mg of croscarmellose sodium;

(i) about 0.8 mg sodium stearyl fumarate; as well as

j) about 6.0 mg of Opadry AMB II beige.

[0017] In some embodiments, the solid dosage form is selected from powder, tablet, bite-disintegrating tablet, chewable tablet, capsule tablet, capsule, gelatin capsule, effervescent powder, fast disintegrating tablet, anti-abuse tablet, modified release tablet, capsule tablet modified release capsule, modified release capsule and powdered aqueous suspension. 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 the film coat. In some embodiments, the pharmaceutical formulation further comprises about 4 mg to about 8 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 2 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 3 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 4 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 5 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 6 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 7 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 8 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 9 mg of the film coat. In some embodiments, the pharmaceutical formulation further comprises about 10 mg of the film coat. In some embodiments, the film shell is Opadry AMB II Beige. In some embodiments, the solid dosage form is a capsule-shaped tablet. In some embodiments, the solid dosage form is a capsule. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salt is crystalline. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salt is amorphous. In some embodiments, the pharmaceutical formulation is made by a hot melt extrusion process. In some embodiments, the pharmaceutical composition is made by a spray drying (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.

[0018] According to another aspect, provided herein is a method for treating pain in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain.

[0019] In another aspect, provided herein is a method for treating epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optic nerve (NMO), Tourette's syndrome, Alzheimer's disease, or abdominal pain associated with irritable bowel syndrome in a patient in need thereof, comprising administering to a patient in need thereof, a therapeutically effective amount of a pharmaceutical composition described herein.

Detailed description of the present invention

Certain terminology

[0020] Singular forms include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "drug" includes a reference to one or more such drugs, and a reference to "an excipient" includes a reference to one or more such excipients. When ranges are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when applied to a number or numerical range means that the specified number or numerical range is approximate within experimental variability (or within the statistical error of the experiment), and thus the number or numerical range varies from 1% to 15% of the specified number or numeric range.

[0021] As used herein, the terms "composition" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms "composition" and "composition" may be used to refer to a mixture of one or more active agents with a carrier or other excipients.

[0022] The terms "active agent", "active pharmaceutical agent", "drug", "active ingredient" and variants thereof are used interchangeably to refer to an agent or substance that has a measurable intended or selected physiological activity when administered to a subject in a significant or effective quantity.

[0023] The compound described herein 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- the carboxylate, or a pharmaceutically acceptable salt thereof, is a MAGL inhibitor compound. The term 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 refers to to a connection with the following structure:

или его фармацевтически приемлемой соли. Согласно некоторым вариантам осуществления 1,1,1,3,3,3-гексафторпропан-2-ил-4-(2-(пирролидин-1-ил)-4-(трифторметил)бензил)пиперазин-1-карбоксилат или его фармацевтически приемлемая соль является кристаллической. Согласно некоторым вариантам осуществления 1,1,1,3,3,3-гексафторпропан-2-ил-4-(2-(пирролидин-1-ил)-4-(трифторметил)бензил)пиперазин-1-карбоксилат или его фармацевтически приемлемая соль является аморфной.

or a pharmaceutically acceptable salt thereof. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salt is crystalline. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salt is amorphous.

[0024] The term "pharmaceutically acceptable salt" refers to the salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate that does not cause significant irritation to the mammal to which it is administered and does not substantially abolish the biological activity and properties of the compound. A wide range of pharmaceutically acceptable salts is formed from 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate and includes:

- acid addition salts formed by the reaction of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate with an organic acid, which includes aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxylalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. and includes, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like;

- acid addition salts formed by the reaction of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate with an inorganic acid, which includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, and the like.

[0025] In some embodiments of the pharmaceutical formulations described herein, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl )piperazine-1-carboxylate is in free base form. In some embodiments of the pharmaceutical formulations described herein, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine 1-carboxylate is a salt. In some embodiments of the pharmaceutical formulations described herein, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine 1-carboxylate is a hydrochloride. In some embodiments of the pharmaceutical formulations described herein, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine 1-carboxylate is a fumarate.

[0026] It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition forms (solvates). Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol , methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, without limitation, Class 3 solvent(s). Categories of solvents are defined, for example, at the International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C (R3)" (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its pharmaceutically acceptable salts are conveniently obtained or formed during the processes described herein. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate solvates are anhydrous . In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salts exist in unsolvated form. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salts exist in unsolvated form and are anhydrous.

[0027] In still other embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- the carboxylate, or a pharmaceutically acceptable salt thereof, is prepared in a variety of forms including, but not limited to, amorphous phase, crystalline forms, milled forms, and nanoparticles. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salt is amorphous. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt is amorphous and anhydrous. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salt is crystalline. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically acceptable salt is crystalline and anhydrous.

[0028] While not intended to be limited by any particular theory, some solid forms have physical properties (eg, stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. Moreover, without being bound by any particular theory, some solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, disintegration, stickiness, solubility, water absorption, electrical properties, thermal properties, solid state reactivity, physical stability and chemical stability) affecting particular processes (e.g. yield, filtration, washing, drying, milling, mixing, tabletting, flow, dissolution, formulation, and lyophilization) that make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using specific analytical chemistry techniques, including solid phase analytical methods (eg, x-ray diffraction, microscopy, spectroscopy, and thermal analysis) as described herein and known in the art.

[0029] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of an agent or compound administered that will relieve one or more symptoms of the disease or condition being treated to some extent. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound described herein necessary to provide a clinically significant reduction in disease. An appropriate "effective" amount in any individual case may be determined using methods such as dose escalation studies.

Pharmaceutical formulations

[0030] Pharmaceutical compositions described herein 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate contain 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its pharmaceutically acceptable a salt; and at least one pharmaceutically acceptable excipient in a solid dosage form. In some embodiments, the pharmaceutical formulations described herein comprise 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 and at least one pharmaceutically acceptable excipient in a solid dosage form, wherein the solid dosage form is selected from powder, tablet, bite-disintegrating tablet, chewable tablet, caplet, capsule, gelatin capsule, effervescent powder, fast disintegrating tablet, anti-abuse tablet, modified release tablet, modified release capsule tablet, modified release capsule and powder-derived aqueous suspension. In some embodiments, the pharmaceutical formulations described herein comprise 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 and at least one pharmaceutically acceptable excipient in a solid dosage form, the solid dosage form being a tablet. In some embodiments, the pharmaceutical formulations described herein comprise 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 and at least one pharmaceutically acceptable excipient in a solid dosage form, the solid dosage form being a capsule-shaped tablet. In some embodiments, the pharmaceutical formulations described herein comprise 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 and at least one pharmaceutically acceptable excipient in a solid dosage form, the solid dosage form being a capsule.

[0031] In some embodiments, a pharmaceutical composition in solid dosage form is provided, comprising:

(a) about 1 mg to about 60 mg 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 polymer carrier;

(c) about 0.2 mg to about 10 mg of a surfactant; as well as

(d) about 0.2 mg to about 10 mg of glidant.

[0032] In some embodiments described herein, the polymeric carrier is selected from polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone K17 (PVP K17), polyvinylpyrrolidone K12 (PVP K12), inylpyrrolidone/vinyl acetate (PVPVA 64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetylsuccinate (HPMC AS) and methyl methacrylate polymers (Eudragit polymers). In some embodiments, the polymeric carrier is polyvinylpyrrolidone K30 (PVP K30). In some embodiments described herein, the polymeric carrier is polyvinylpyrrolidone K17 (PVP K17). In some embodiments described herein, the polymeric carrier is polyvinylpyrrolidone/vinyl acetate (PVPVA 64). In some embodiments described herein, the polymeric carrier is hydroxypropyl methylcellulose (HPMC). In some embodiments described herein, the polymeric carrier is hydroxypropyl methylcellulose acetylsuccinate (HPMC AS). In some embodiments described herein, the carrier polymer is methyl methacrylate polymers (Eudragit polymers). In some embodiments, the pharmaceutical composition contains from about 5 mg to about 425 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 5 mg to about 350 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 5 mg to about 300 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 5 mg to about 250 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 5 mg to about 200 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 5 mg to about 175 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 5 mg to about 150 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 150 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 125 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 100 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 95 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 90 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 12 mg to about 90 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 85 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 12 mg to about 85 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 12 mg to about 80 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 14 mg to about 80 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 12 mg to about 75 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 14 mg to about 75 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 5 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 10 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 11 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 12 mg of a polymeric carrier. In some embodiments, the pharmaceutical formulation contains about 13 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 14 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 15 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 16 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 17 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 18 mg of a polymeric carrier. In some embodiments, the pharmaceutical formulation contains about 19 mg of a polymeric carrier. In some embodiments, the pharmaceutical formulation contains about 20 mg of a polymeric carrier. In some embodiments, the pharmaceutical formulation contains about 25 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 30 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 35 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 40 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 45 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 50 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 55 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 60 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 65 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 70 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 75 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 80 mg of a polymeric carrier. In some embodiments, the pharmaceutical formulation contains about 85 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 90 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 95 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains about 100 mg of a polymeric carrier. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 90 mg of a polymeric carrier, wherein the polymeric carrier is polyvinylpyrrolidone K30 (PVP K30). In some embodiments, the pharmaceutical composition contains from about 10 mg to about 90 mg of a polymeric carrier, wherein the polymeric carrier is polyvinylpyrrolidone K17 (PVP K17). In some embodiments, the pharmaceutical composition contains from about 10 mg to about 90 mg of a polymeric carrier, wherein the polymeric carrier is polyvinylpyrrolidone K12 (PVP K12). In some embodiments, the pharmaceutical formulation contains from about 10 mg to about 90 mg of a polymeric carrier, the polymeric carrier being polyvinylpyrrolidone/vinyl acetate (PVPVA 64). In some embodiments, the pharmaceutical formulation contains from about 10 mg to about 90 mg of a polymeric carrier, wherein the polymeric carrier is hydroxypropyl methylcellulose (HPMC). In some embodiments, the pharmaceutical formulation contains from about 10 mg to about 90 mg of a polymeric carrier, wherein the polymeric carrier is hydroxypropyl methylcellulose acetylsuccinate (HPMC AS). In some embodiments, the pharmaceutical formulation contains from about 10 mg to about 90 mg of a polymeric carrier, wherein the polymeric carrier is methyl methacrylate polymers (Eudragit polymers).

[0033] In some embodiments, the surfactant is selected from polysorbates, polaxomers, bile salts, glyceryl monostearate, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, ethylene oxide-propylene oxide copolymers, and d-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS). In some embodiments, the surfactant is a polysorbate. In some embodiments, the surfactant is polysorbate 80 (Tween 80). In some embodiments, the surfactant is a polaxomer. In some embodiments, the surfactant is a bile salt. In some embodiments, the surfactant is glyceryl monostearate. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the surfactant is sorbitan monooleate. In some embodiments, the surfactant is polyoxyethylene sorbitan monooleate. In some embodiments, the surfactant is an ethylene oxide copolymer. In some embodiments, the surfactant is a propylene oxide copolymer. In some embodiments, the surfactant is d-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS). In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 8 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 7 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 6 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 4 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 4 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 3.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 3 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 4 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 3.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 3 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 2.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 2 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 1.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 1 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.2 mg of a surfactant. In some embodiments, the pharmaceutical formulation contains about 0.25 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.3 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.35 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.4 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.45 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.6 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.7 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.8 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 0.9 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.1 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.2 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.3 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.4 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.6 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.7 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.8 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 1.9 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 2 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 2.25 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 2.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 2.75 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 3 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 3.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 4 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 4.5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 5 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 6 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 7 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 8 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 9 mg of a surfactant. In some embodiments, the pharmaceutical composition contains about 10 mg of a surfactant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 5 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 4 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 3 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2.5 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 4 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 3 mg of a surfactant, the surfactant being Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical formulation contains from about 0.4 mg to about 2.5 mg of a surfactant, wherein the surfactant is Polysorbate 80 (Tween 80). In some embodiments, the pharmaceutical formulation contains from about 0.4 mg to about 2 mg of surfactant, the surfactant being Polysorbate 80 (Tween 80).

[0034] In some embodiments, the glidant is silica or talc. In some embodiments, the glidant is talc. In some embodiments, the glidant is silica. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 8 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 7 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 6 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 4 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 to about 2.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 4 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 3.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 3 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 4 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 3.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 3 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 2.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 2 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 1.5 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 1 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.2 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.25 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.3 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.35 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.4 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.45 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.5 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.6 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.7 mg of glidant. In some embodiments, the pharmaceutical formulation contains about 0.8 mg of glidant. In some embodiments, the pharmaceutical composition contains about 0.9 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.1 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.2 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.3 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.4 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.5 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.6 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.7 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.8 mg of glidant. In some embodiments, the pharmaceutical composition contains about 1.9 mg of glidant. In some embodiments, the pharmaceutical composition contains about 2 mg of glidant. In some embodiments, the pharmaceutical composition contains about 2.25 mg of glidant. In some embodiments, the pharmaceutical composition contains about 2.5 mg of glidant. In some embodiments, the pharmaceutical composition contains about 2.75 mg of glidant. In some embodiments, the pharmaceutical composition contains about 3 mg of glidant. In some embodiments, the pharmaceutical composition contains about 3.5 mg of glidant. In some embodiments, the pharmaceutical composition contains about 4 mg of glidant. In some embodiments, the pharmaceutical composition contains about 4.5 mg of glidant. In some embodiments, the pharmaceutical composition contains about 5 mg of glidant. In some embodiments, the pharmaceutical composition contains about 6 mg of glidant. In some embodiments, the pharmaceutical composition contains about 7 mg of glidant. In some embodiments, the pharmaceutical composition contains about 8 mg of glidant. In some embodiments, the pharmaceutical composition contains about 9 mg of glidant. In some embodiments, the pharmaceutical composition contains about 10 mg of glidant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 5 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 4 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains about 0.2 mg to about 3 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains about 0.2 mg to about 2.5 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 2 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains from about 0.4 mg to about 4 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains from about 0.4 mg to about 3 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains from about 0.4 mg to about 2.5 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical formulation contains from about 0.4 mg to about 2 mg of glidant, where the glidant is silica. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 5 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 4 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical formulation contains about 0.2 mg to about 3 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical formulation contains from about 0.2 mg to about 2.5 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical formulation contains about 0.2 mg to about 2 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 4 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical formulation contains about 0.4 mg to about 3 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 2.5 mg of glidant, where the glidant is talc. In some embodiments, the pharmaceutical composition contains from about 0.4 mg to about 2 mg of glidant, where the glidant is talc.

[0035] In some embodiments, the pharmaceutical formulation further comprises a buffer. In some embodiments, the pharmaceutical formulation further comprises a buffer selected from acetates, carbonates, phosphates, citrates, and glutamates. In some embodiments, the pharmaceutical formulation further comprises an acetate buffer. In some embodiments, the pharmaceutical formulation further comprises a carbonate buffer. In some embodiments, the pharmaceutical formulation further comprises a phosphate buffer. In some embodiments, the pharmaceutical formulation further comprises a citrate buffer. In some embodiments, the pharmaceutical formulation further comprises a glutamate buffer. In some embodiments, the pharmaceutical composition 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 further comprises a buffer selected from potassium dihydrogen phosphate, sodium bicarbonate, magnesium carbonate, and sodium citrate. In some embodiments, the pharmaceutical composition 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 further comprises sodium dihydrogen phosphate, dipotassium monohydrogen phosphate, and disodium monohydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises dipotassium monohydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises disodium monohydrogen phosphate.

[0036] In some embodiments, the pharmaceutical formulation further comprises potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.1 mg to about 5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.1 mg to about 4.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.1 mg to about 4 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.1 mg to about 3.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.1 mg to about 3 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.1 mg to about 2.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises from about 0.1 mg to about 2 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises from about 0.1 mg to about 1.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.1 mg to about 1 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 0.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 4 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 3.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 3 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 2.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 2 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 1.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 1 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises from about 0.2 mg to about 0.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.15 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.25 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.35 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.4 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.45 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.55 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.6 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.65 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.7 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.75 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.8 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 0.85 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.9 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 0.95 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 1 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 1.25 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 1.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 1.75 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 2 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 2.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 3 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 3.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 4 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical formulation further comprises about 4.5 mg of potassium dihydrogen phosphate. In some embodiments, the pharmaceutical composition further comprises about 5 mg of potassium dihydrogen phosphate.

[0037] In some embodiments, the pharmaceutical formulation further comprises sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 4.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 4 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 3.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 3 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 2.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 2 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 1.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 1 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 0.5 mg sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 4 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 0.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 0.1 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 0.15 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 0.25 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.35 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 0.4 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.45 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.55 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.6 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.65 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.7 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.75 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.8 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 0.85 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.9 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.95 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 1 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 1.25 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 1.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 1.75 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 2 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 2.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 3 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 3.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 4 mg of sodium bicarbonate. In some embodiments, the pharmaceutical composition further comprises about 4.5 mg of sodium bicarbonate. In some embodiments, the pharmaceutical formulation further comprises about 5 mg of sodium bicarbonate.

[0038] In some embodiments, the pharmaceutical formulation further comprises magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 5 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 4.5 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 4 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 3.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 3 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 2.5 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 2 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 1.5 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 1 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 0.5 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 4 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1.5 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 0.5 mg magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.15 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.25 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.35 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.4 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 0.45 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 0.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.55 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 0.6 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 0.65 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 0.7 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.75 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.8 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.85 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.9 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 0.95 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 1 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 1.25 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 1.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 1.75 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 2 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 2.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 3 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 3.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 4 mg of magnesium carbonate. In some embodiments, the pharmaceutical formulation further comprises about 4.5 mg of magnesium carbonate. In some embodiments, the pharmaceutical composition further comprises about 5 mg of magnesium carbonate.

[0039] In some embodiments, the pharmaceutical formulation further comprises sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 4.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 4 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 3.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 3 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 2.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 2 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 1.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 1 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 0.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 4 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 0.5 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.1 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.15 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.2 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.25 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.3 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.35 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.4 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.45 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.5 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.55 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.6 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.65 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.7 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.75 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.8 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 0.85 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.9 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 0.95 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 1 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 1.25 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 1.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 1.75 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 2 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 2.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 3 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 3.5 mg of sodium citrate. In some embodiments, the pharmaceutical composition further comprises about 4 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 4.5 mg of sodium citrate. In some embodiments, the pharmaceutical formulation further comprises about 5 mg of sodium citrate.

[0040] In some embodiments, the pharmaceutical formulation further comprises 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, sorbitan-sorbitol solution, castor oil, diacetylated monoglycerides, dibutyl sebacate, and diethyl phthalate. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is triethyl citrate. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is triacetin. In some embodiments, the pharmaceutical composition further comprises a plasticizer, wherein the plasticizer is acetyltributyl citrate. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is acetyl triethyl citrate. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is stearic acid. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is glycerol. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is polyethylene glycol. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, wherein the plasticizer is polyethylene glycol monomethyl ether. In some embodiments, the pharmaceutical composition further comprises a plasticizer, where the plasticizer is propylene glycol. In some embodiments, the pharmaceutical composition further comprises a plasticizer, wherein the plasticizer is a sorbitan-sorbitol solution. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is castor oil. In some embodiments, the pharmaceutical composition further comprises a plasticizer, wherein the plasticizer is diacetylated monoglycerides. In some embodiments, the pharmaceutical formulation further comprises a plasticizer, where the plasticizer is dibutyl sebacate. In some embodiments, the pharmaceutical composition further comprises a plasticizer, where the plasticizer is diethyl phthalate. In some embodiments, the pharmaceutical composition further comprises from about 1 mg to about 65 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises from about 1 mg to about 60 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises from about 1 mg to about 55 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises from about 1 mg to about 50 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises from about 1 mg to about 45 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises from about 1 mg to about 40 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 35 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 1 mg to about 25 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 20 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 15 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 10 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 2 mg to about 30 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 2 mg to about 25 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 2 mg to about 20 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 pharmaceutical formulation further comprises about 2 mg to about 10 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1.5 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises about 2 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 2.5 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 3 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 3.5 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 4 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 4.5 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 5 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 5.5 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 6 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 6.5 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 7 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises about 7.5 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises about 8 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 8.5 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 9 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 10 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 11 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises about 12 mg of a plasticizer. In some embodiments, the pharmaceutical composition further comprises about 13 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 14 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 15 mg of a plasticizer. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 65 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 60 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 55 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 50 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 45 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 40 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 35 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 30 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 25 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 20 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical composition further comprises about 1 mg to about 15 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 1 mg to about 10 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 2 mg to about 30 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical composition further comprises about 2 mg to about 25 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical formulation further comprises about 2 mg to about 20 mg of a plasticizer, where the plasticizer is PEG-400. In some embodiments, the pharmaceutical composition further comprises from about 2 mg to about 15 mg of a plasticizer, wherein the plasticizer is PEG-400. In some embodiments, the pharmaceutical composition further comprises from about 2 mg to about 10 mg of a plasticizer, wherein the plasticizer is PEG 400 .

[0041] In some embodiments, the pharmaceutical formulation further comprises an excipient. In some embodiments, the excipient is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, siliconized microcrystalline cellulose, starch, and pregelatinized starch (starch 1500). In some embodiments, the filler is lactose. In some embodiments, the filler is mannitol. In some embodiments, the filler is dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler is siliconized microcrystalline cellulose. In some embodiments, the filler is starch. In some embodiments, the bulking agent is pregelatinized starch (starch 1500). In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 850 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 800 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 750 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 700 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 650 mg of an excipient. In some embodiments, the pharmaceutical composition further comprises about 15 mg to about 600 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 550 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 500 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 450 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 15 mg to about 400 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 400 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 350 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 300 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 275 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 250 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 225 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 20 mg to about 200 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 25 mg to about 300 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 25 mg to about 275 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 25 mg to about 250 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 25 mg to about 225 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 25 mg to about 200 mg of an excipient. In some embodiments, the excipient is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, siliconized microcrystalline cellulose, starch, and pregelatinized starch (starch 1500). In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 300 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 275 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 250 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 225 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 200 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 175 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg to about 150 mg of an excipient. In some embodiments, the pharmaceutical formulation further comprises about 30 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 35 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 40 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 45 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 50 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 55 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 60 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 65 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 70 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 75 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 80 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 85 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 90 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 95 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 100 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 105 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 110 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 115 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 120 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 125 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 130 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 135 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 140 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 145 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 150 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 155 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 160 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 165 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 170 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 175 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 180 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 185 mg of excipient. In some embodiments, the pharmaceutical formulation further comprises about 190 mg of excipient. In some embodiments, the pharmaceutical composition further comprises about 195 mg of excipient. In some embodiments, the pharmaceutical composition further comprises about 200 mg of excipient.

[0042] In some embodiments, the pharmaceutical formulation further comprises a disintegrant. In some embodiments, the disintegrant is selected from corn starch, potato starch, microcrystalline cellulose, methylcellulose, sodium croscarmellose, sodium starch glycolate, povidone, crospovidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, alginic acid, sodium alginate, agar, guar, carob, karaya, pectin, tragacanth, bentonite, citrus pulp and sodium lauryl sulfate. In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, hydroxypropyl cellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is polyvinyl alcohol. In some embodiments, the disintegrant is hydroxypropyl cellulose. In some embodiments, the disintegrant is hypromellose. In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 150 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 125 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 100 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 75 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 60 mg of a disintegrant. In some embodiments, the pharmaceutical composition further comprises about 3 mg to about 50 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 4 mg to about 60 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 4 mg to about 55 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 4 mg to about 50 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 5 mg to about 45 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 40 mg of a disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 35 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 30 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 pharmaceutical formulation further comprises about 5 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 6 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 7 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 8 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 9 mg of disintegrant. In some embodiments, the pharmaceutical composition further comprises about 10 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 12 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 15 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 20 mg of disintegrant. In some embodiments, the pharmaceutical composition further comprises about 25 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 30 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 35 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 40 mg of disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 150 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical composition further comprises about 3 mg to about 100 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 75 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 60 mg of a disintegrant, the disintegrant being crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 50 mg of a disintegrant, the disintegrant being crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 40 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 35 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 30 mg of a disintegrant, the disintegrant being crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 30 mg of a disintegrant, the disintegrant being crospovidone. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 100 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 75 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 3 mg to about 60 mg of a disintegrant, wherein the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 50 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 40 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 35 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 30 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation further comprises about 5 mg to about 30 mg of a disintegrant, the disintegrant being croscarmellose sodium.

[0043] In some embodiments, the pharmaceutical formulation further comprises a lubricant. In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, and sodium stearyl fumarate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. 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 0.1 mg to about 8 mg of a lubricant. In some embodiments, the pharmaceutical composition further comprises about 0.1 mg to about 6 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 5 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg to about 4 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 10 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 8 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 7 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 6 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 5 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 0.2 mg to about 3.5 mg of a lubricant. In some embodiments, the pharmaceutical composition further comprises about 0.2 mg to about 3 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2.5 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1.5 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 3 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 2.5 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 2 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 pharmaceutical formulation further comprises about 0.3 mg to about 1 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.1 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.15 mg of a lubricant. In some embodiments, the pharmaceutical composition further comprises about 0.2 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.25 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.35 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.4 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.45 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.5 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.6 mg of a lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.7 mg of lubricant. In some embodiments, the pharmaceutical composition further comprises about 0.8 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.9 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1 mg of lubricant. In some embodiments, the pharmaceutical composition further comprises about 1.1 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.2 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.3 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.4 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.5 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.6 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.7 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.8 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 1.9 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 2 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 2.5 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 3 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 4 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 5 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 6 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 7 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 8 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 9 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 10 mg of lubricant. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 10 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition further comprises about 0.2 mg to about 4 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2.5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1.5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 4 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 3 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 2.5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 2 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 1.5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 1 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 10 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 5 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 4 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 3 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical composition further comprises about 0.2 mg to about 2.5 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 2 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.2 mg to about 1.5 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical composition further comprises about 0.2 mg to about 1 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 4 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 3 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 2.5 mg of a lubricant, the lubricant being magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 2 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 1.5 mg of lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical formulation further comprises about 0.3 mg to about 1 mg of lubricant. substances, and the lubricant is magnesium stearate.

[0044] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is in free base form. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 60 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 55 mg of free base 1,1,1,3; 3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 50 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 45 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 40 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 35 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 30 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 25 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 20 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 15 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 10 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 2 mg to about 30 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 2 mg to about 25 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 2 mg to about 20 mg of free base 1,1,1,3; 3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 2 mg to about 15 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 1 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) free base benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 2 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) free base benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 3 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 3.5 mg 1 free base of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl )benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 4 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) free base benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 5 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 6 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 7 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 8 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 9 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 16 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 17 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 18 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 19 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 30 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 40 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 55 mg 1 free base of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl )piperazine-1-carboxylate. According to some embodiments, the pharmaceutical composition contains about 60 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)- 4-(trifluoromethyl)benzyl)piperazine-1-carboxylate.

[0045] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is in the form of a pharmaceutically acceptable salt. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is the hydrochloride 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains 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. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 55 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 40 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl )benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl hydrochloride )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl hydrochloride )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl hydrochloride )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl hydrochloride )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 8 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 9 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 16 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 17 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 18 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 19 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate In some embodiments, the pharmaceutical formulation contains about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride )benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 40 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 55 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. According to some embodiments, the pharmaceutical formulation contains about 60 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate.

[0046] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate. In some embodiments, the pharmaceutical formulation contains 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. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 55 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 40 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 8 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 9 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 16 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 17 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 18 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 19 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 40 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 55 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. According to some embodiments, the pharmaceutical composition contains about 60 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate.

[0047] According to some embodiments, a pharmaceutical composition in a solid dosage form is described herein, 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) hydrochloride) piperazine-1-carboxylate;

(b) about 14 mg to about 72.5 mg of polyvinylpyrrolidone K30 (PVP K30);

(c) about 2 mg to about 13 mg 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 silica;

(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; as well as

(i) about 0.3 mg to about 1.5 mg sodium stearyl fumarate.

[0048] In some embodiments, a pharmaceutical composition in a solid dosage form is described herein, 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) hydrochloride) piperazine-1-carboxylate;

(b) from about 17 mg to about 85 mg of polyvinylpyrrolidone/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 silica;

(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; as well as

(h) about 0.3 mg to about 1.5 mg sodium stearyl fumarate.

[0049] According to some embodiments, a pharmaceutical composition in a solid dosage form is described herein, comprising:

(a) about 1 mg to about 60 mg 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) from about 20 mg to about 400 mg of excipient;

(c) about 3 mg to about 150 mg disintegrant; as well as

(d) about 0.1 mg to about 10 mg of a lubricant.

[0050] In some embodiments, the pharmaceutical formulation contains an excipient. In some embodiments, the excipient is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, siliconized microcrystalline cellulose, starch, and pregelatinized starch (starch 1500). In some embodiments, the filler is lactose. In some embodiments, the filler is mannitol. In some embodiments, the filler is dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler is siliconized microcrystalline cellulose. In some embodiments, the filler is starch. In some embodiments, the bulking agent is pregelatinized starch (starch 1500). In some embodiments, the pharmaceutical composition contains from about 20 mg to about 750 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 700 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 650 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 600 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 550 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 500 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 450 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 400 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 350 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 300 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 275 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 250 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 225 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 20 mg to about 200 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 25 mg to about 300 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 25 mg to about 275 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 25 mg to about 250 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 25 mg to about 225 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 25 mg to about 200 mg of excipient. In some embodiments, the excipient is selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, siliconized microcrystalline cellulose, starch, and pregelatinized starch (starch 1500). In some embodiments, the pharmaceutical composition contains from about 30 mg to about 300 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 30 mg to about 275 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 30 mg to about 250 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 30 mg to about 225 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 30 mg to about 200 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 30 mg to about 175 mg of excipient. In some embodiments, the pharmaceutical composition contains from about 30 mg to about 150 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 30 mg of excipient. In some embodiments, the pharmaceutical composition contains about 35 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 40 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 45 mg of excipient. In some embodiments, the pharmaceutical composition contains about 50 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 55 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 60 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 65 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 70 mg of excipient. In some embodiments, the pharmaceutical composition contains about 75 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 80 mg of excipient. In some embodiments, the pharmaceutical composition contains about 85 mg of excipient. In some embodiments, the pharmaceutical composition contains about 90 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 95 mg of excipient. In some embodiments, the pharmaceutical composition contains about 100 mg of excipient. In some embodiments, the pharmaceutical composition contains about 105 mg of excipient. In some embodiments, the pharmaceutical composition contains about 110 mg of excipient. In some embodiments, the pharmaceutical composition contains about 115 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 120 mg of excipient. In some embodiments, the pharmaceutical composition contains about 125 mg of excipient. In some embodiments, the pharmaceutical composition contains about 130 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 135 mg of excipient. In some embodiments, the pharmaceutical composition contains about 140 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 145 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 150 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 155 mg of excipient. In some embodiments, the pharmaceutical composition contains about 160 mg of excipient. In some embodiments, the pharmaceutical composition contains about 165 mg of excipient. In some embodiments, the pharmaceutical composition contains about 170 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 175 mg of excipient. In some embodiments, the pharmaceutical composition contains about 180 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 185 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 190 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 195 mg of excipient. In some embodiments, the pharmaceutical formulation contains about 200 mg of excipient.

[0051] In some embodiments, the pharmaceutical composition contains a disintegrant. In some embodiments, the disintegrant is selected from corn starch, potato starch, microcrystalline cellulose, methylcellulose, sodium croscarmellose, sodium starch glycolate, povidone, crospovidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, alginic acid, sodium alginate, agar, guar, carob, karaya , pectin, tragacanth, bentonite, citrus pulp and sodium lauryl sulfate. In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, hydroxypropyl cellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is polyvinyl alcohol. In some embodiments, the disintegrant is hydroxypropyl cellulose. In some embodiments, the disintegrant is hypromellose. In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 125 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 100 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 75 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 60 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 50 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 4 mg to about 60 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 4 mg to about 55 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 4 mg to about 50 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 50 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 45 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 40 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 35 mg of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 30 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 6 mg to about 30 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 5 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 6 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 7 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 8 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 9 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 10 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 12 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 15 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 20 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 25 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 30 mg of disintegrant. In some embodiments, the pharmaceutical composition contains about 35 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 40 mg of disintegrant. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 150 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 100 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 75 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 60 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 50 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 40 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 35 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 30 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 30 mg of a disintegrant, where the disintegrant is crospovidone. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 100 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 75 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 3 mg to about 60 mg of a disintegrant, wherein the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 50 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 40 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 35 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 30 mg of a disintegrant, the disintegrant being croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 5 mg to about 30 mg of a disintegrant, the disintegrant being croscarmellose sodium.

[0052] In some embodiments, the pharmaceutical formulation further comprises a lubricant. In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, and sodium stearyl fumarate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.1 mg to about 8 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.1 mg to about 6 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.1 mg to about 5 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.1 mg to about 4 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 8 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 7 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 6 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 5 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 4 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3.5 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2.5 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1.5 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 3 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2.5 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1.5 mg of a lubricant. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1 mg of a lubricant. In some embodiments, the pharmaceutical formulation contains about 0.1 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.15 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.2 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.25 mg of lubricant. In some embodiments, the pharmaceutical composition contains about 0.3 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.35 mg of lubricant. In some embodiments, the pharmaceutical composition contains about 0.4 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.45 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.5 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.6 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.7 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.8 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 0.9 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.1 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.2 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.3 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.4 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.5 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.6 mg of lubricant. In some embodiments, the pharmaceutical composition contains about 1.7 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.8 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 1.9 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 2 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 2.5 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 3 mg of lubricant. In some embodiments, the pharmaceutical composition contains about 4 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 5 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 6 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 7 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 8 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 9 mg of lubricant. In some embodiments, the pharmaceutical formulation contains about 10 mg of lubricant. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 4 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3 mg of a lubricant, wherein the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2.5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2 mg of a lubricant, wherein the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1.5 mg of a lubricant, wherein the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 4 mg of a lubricant, wherein the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 3 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2.5 mg of a lubricant, wherein the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2 mg of a lubricant, wherein the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1.5 mg of a lubricant, the lubricant being sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1 mg of a lubricant, wherein the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 10 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 5 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 4 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 3 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2.5 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 2 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1.5 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.2 mg to about 1 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 4 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 3 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2.5 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 2 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1.5 mg of a lubricant, wherein the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains from about 0.3 mg to about 1 mg of a lubricant, wherein the lubricant is magnesium stearate.

[0053] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate in free base form. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 60 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 55 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 50 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 45 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 40 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 35 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 30 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 25 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 20 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 15 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 1 mg to about 10 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 2 mg to about 30 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 2 mg to about 25 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains from about 2 mg to about 15 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 1 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) free base benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 2 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) free base benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 3 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) free base benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 4 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) free base benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 5 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 6 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 7 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 8 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 9 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 16 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 17 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 18 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 19 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 30 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 40 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition contains about 55 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) free base) piperazine-1-carboxylate. According to some embodiments, the pharmaceutical composition contains about 60 mg of free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4 -(trifluoromethyl)benzyl)piperazine-1-carboxylate.

[0054] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is in the form of a pharmaceutically acceptable salt. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is the hydrochloride 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 60 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 55 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 50 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 45 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 40 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 35 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 25 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 20 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 15 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 10 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 30 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 25 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) hydrochloride benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 1.5 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 2.5 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 3.5 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 4.5 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine hydrochloride -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 5 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 6 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 7 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 8 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 9 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical composition contains about 11 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 13 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 15 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 16 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 17 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 18 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 19 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 20 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 25 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 30 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 35 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 40 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 45 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 50 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate. In some embodiments, the pharmaceutical formulation contains about 55 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1 hydrochloride -carboxylate. According to some embodiments, the pharmaceutical formulation contains about 60 mg of 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) hydrochloride piperazine-1-carboxylate.

[0055] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate. In some embodiments, the pharmaceutical formulation contains 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. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 55 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 40 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 1.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 2.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 3.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 4.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 8 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 9 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 16 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 17 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 18 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 19 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 20 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 25 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 30 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 35 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 40 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 45 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 50 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. In some embodiments, the pharmaceutical formulation contains about 55 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate. According to some embodiments, the pharmaceutical composition contains about 60 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-( trifluoromethyl)benzyl)piperazine-1-carboxylate.

Synthesis of pharmaceutical formulations

[0056] The pharmaceutical formulations described herein contain 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)-benzyl)- 1-carboxylate or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical compositions described herein are manufactured by a hot melt extrusion process. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt, polymer carrier, surfactant and glidant were uniformly mixed and then extruded at elevated temperature to obtain an amorphous solid dispersion 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. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt, polymer carrier, plasticizer, surfactant and glidant were uniformly mixed and then extruded at an elevated temperature to obtain a solid amorphous dispersion 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. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride, polymeric the carrier, surfactant, glidant and potassium dihydrogen phosphate were uniformly mixed and then extruded at an elevated temperature to obtain a solid amorphous dispersion of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2- (pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. According to some embodiments of the present invention, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride , polymer carrier, plasticizer, surfactant, glidant and potassium dihydrogen phosphate were uniformly mixed and then extruded at elevated temperature to obtain a solid amorphous dispersion of 1,1,1,3,3,3-hexafluoropropan-2-yl-4 hydrochloride -(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, an amorphous solid dispersion 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 is mixed with an excipient, a disintegrant and a lubricant and compressed to form tablets 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.

[0057] In some embodiments, the pharmaceutical formulation contains 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 55 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 50 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 45 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 40 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 35 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 25 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 20 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 15 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 10 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 30 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 25 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 1.5 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 2.5 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 3 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 3.5 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 per tablet. In some embodiments, the pharmaceutical composition contains about 4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 4.5 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 per tablet. In some embodiments, the pharmaceutical formulation contains about 5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 6 mg of 1,1,1,3;3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 8 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 9 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet. In some embodiments, the pharmaceutical formulation contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per tablet.

[0058] In some embodiments, the pharmaceutical formulation contains 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 per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 55 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 50 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 45 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 40 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 35 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 25 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 20 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 15 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 10 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 30 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 25 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 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 per capsule-shaped tablet. In some embodiments, the pharmaceutical formulation contains about 1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 1.5 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, per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 2.5 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, per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 3 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 3.5 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, per capsule tablet. In some embodiments, the pharmaceutical composition contains about 4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 4.5 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, per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 8 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 9 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule tablet. In some embodiments, the pharmaceutical formulation contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof per capsule tablet.

[0059] In some embodiments, the pharmaceutical formulation contains 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 55 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 50 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 45 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 40 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 35 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 30 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 25 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 20 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 15 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg to about 10 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 30 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 25 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 20 mg of 1,1,1,3,3,3-hexafluoropropane 2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 15 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 2 mg to about 10 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 per capsule. In some embodiments, the pharmaceutical formulation contains about 1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 1.5 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, per capsule. In some embodiments, the pharmaceutical formulation contains about 2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 2.5 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, per capsule. In some embodiments, the pharmaceutical formulation contains about 3 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 3.5 mg of 11,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical composition contains about 4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 4.5 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, per capsule. In some embodiments, the pharmaceutical formulation contains about 5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 8 mg of 1,1,1,3;3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 9 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 10 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 11 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 12 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 13 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 14 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule. In some embodiments, the pharmaceutical formulation contains about 15 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate, or a pharmaceutically acceptable salt thereof, per capsule.

Excipients

[0060] Suitable optional excipients for use in the pharmaceutical formulations described herein trifluoromethyl)benzyl)piperazine-1-carboxylate include any commonly used pharmaceutical excipients and are selected based on compatibility with the active pharmaceutical agent and properties of the release profile of the desired dosage form. Adjuvants include, but are not limited to, binders, fillers, flow improvers, disintegrators, lubricants, glidants, polymer carriers, plasticizers, stabilizers, surfactants, and the like. A summary of excipients described herein can be 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, Pennsylvania 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), incorporated herein by reference in their entirety.

[0061] Binders impart adhesive power to solid oral dosage forms: for powdered capsule formulations, they promote the formation of plugs that can be filled in soft or hard capsule shells, and for tablet formulations, they maintain the integrity of the tablet after compression and help to ensure uniform mixing up to the stage compression or filling. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (eg, Methocel®), hydroxypropyl methylcellulose (eg, ^Hypromellose USP Pharmacoat-603, hydroxypropyl methylcellulose acetate stearate (Aqoate HS -LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (eg ^Klucel® ), ethylcellulose (eg ^Ethocel® ) and microcrystalline cellulose (eg ^Avicel® ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugar such as sucrose (eg ^Dipac® ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg ^Xylitab® ), lactose, and natural or synthetic gums such as gum, tragacanth, gatti, isapol husk gum, starch, polyvinylpyrrolidone (eg, Povidone® CL, ^Kollidon® CL, ^{Polyplasdone®} XL-10 and Povidone® K-12), larch ^{arabogolactan} , ^Veegum® , polyethylene glycol, waxes, sodium alginate, and the like. In some embodiments, the binder is hypromellose, hydroxypropylcellulose, or ethylcellulose. In some embodiments, the binder is hypromellose. In some embodiments, the binder is hydroxypropyl cellulose. In some embodiments, the binder is ethylcellulose.

[0062] Fillers or diluents add bulk to a pharmaceutical formulation. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel®; dibasic calcium phosphate; aqueous dicalcium phosphate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinized starch; pressed sugar such as Di-Pac® (Amstar); hydroxypropyl methylcellulose; sucrose-based diluents; confectionery sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrans; hydrolyzed dry matter of cereals; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; sodium chloride; inositol; bentonite, etc. In some embodiments of the pharmaceutical formulations described herein, the excipient is lactose, mannitol, or microcrystalline cellulose. In some embodiments, the filler is lactose. In some embodiments, the filler is mannitol. In some embodiments, the filler is dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler is siliconized microcrystalline cellulose. In some embodiments, the filler is starch. In some embodiments, the bulking agent is pregelatinized starch (starch 1500).

[0063] Glidants improve the flow characteristics of powder mixtures. Such compounds include, for example, colloidal silicon dioxide such as Cab-o-sil®; tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin and micronized amorphous silica (Syloid®) and the like. In some embodiments of the pharmaceutical formulations described herein, the glidant is colloidal silicon dioxide or talc. In some embodiments, the glidant is talc. In some embodiments, the glidant is colloidal silica.

[0064] Lubricants are compounds that prevent, reduce or inhibit the adhesion or friction of materials. Illustrative lubricants include, for example, stearic acid; calcium hydroxide, talc; a hydrocarbon such as mineral oil or a hydrogenated vegetable oil such as hydrogenated soybean oil ( ^Sterotex® ), ^Lubritab® , ^Cutina® ; higher fatty acids and their salts of alkali and alkaline earth metals such as aluminium, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, glycerin, talc, waxes, Stearowet®, boric acid, sodium acetate, leucine, polyethylene glycol or methoxy polyethylene glycol , such as Carbowax™, sodium oleate, glyceryl behenate (Compitrol 888 ^® ), glyceryl palmitostearate (Precirol ^® ), colloidal silicon dioxide such as Syloid™, Carb-O-Sil ^® , starch such as corn starch, silicone oil, surface active substance and the like. Hydrophilic lubricants include, for example, sodium stearyl fumarate (currently sold under the trade name ^PRUV® ), polyethylene glycol (PEG), magnesium lauryl sulfate, sodium lauryl sulfate (SLS), sodium benzoate, sodium chloride, and the like. In some embodiments of the pharmaceutical formulations described herein, the lubricant is magnesium stearate, stearic acid, or sodium stearyl fumarate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate.

[0065] Disintegrants facilitate the breakdown or disintegration of the pharmaceutical formulation after administration. Examples of disintegrants include starch, such as natural starch such as corn starch or potato starch, eg latinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®; cellulose such as wood product, microcrystalline cellulose, e.g. Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia® and Solka-Floc®, methyl cellulose a, croscarmellose or a crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose; cross-linked starch such as sodium starch glycolate; a crosslinked polymer such as crospovidone; cross-linked polyvinylpyrrolidone; an alginate such as alginic acid or an alginic acid salt such as sodium alginate; a clay such as Veegum® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, karaya, pectin or tragacanth; sodium starch glycolate; bentonite; natural sponge; a resin such as a cation exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate combined with starch and the like. In some embodiments of the pharmaceutical formulations described herein, the disintegrant is povidone, crospovidone, hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol. In some embodiments, the disintegrant is polyvinyl alcohol. In some embodiments, the disintegrant is hydroxypropyl cellulose. In some embodiments, the disintegrant is hypromellose. In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone.

[0066] Polymeric carriers include compounds such as polyvinylpyrrolidone, for example, polyvinylpolyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, pouring inylpyrrolidone vinyl acetate (PVPVA 64-AS, hydroxypropyl methylcellulose) and methyl methacrylate polymers (Eudragit polymers), etc. .P.

[0067] In some embodiments, the pharmaceutical formulations described herein include one or more pH adjusting agents or buffering agents. In some embodiments, the pharmaceutical formulation contains a buffer selected from acetates, carbonates, phosphates, citrates, and glutamates. In some embodiments, the buffer is selected from potassium dihydrogen phosphate, sodium bicarbonate, magnesium carbonate, sodium citrate, sodium dihydrogen phosphate, dipotassium monohydrogen phosphate, and disodium monohydrogen phosphate. In some embodiments, buffers are included in an amount necessary to maintain the pH of the pharmaceutical formulation within an acceptable range.

[0068] In some embodiments, a film coat is applied around the pharmaceutical composition. In some embodiments, the shell of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its The pharmaceutically acceptable salt is an immediate release shell. In some embodiments, the immediate release shell comprises hydroxypropyl methylcellulose (HPMC) with or without a plasticizer, and with or without surfactants and defoamers (clear, pigmented, or colored). In some embodiments, the shell of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its The pharmaceutically acceptable salt is an immediate release shell with a water-retaining barrier. In some embodiments, the film shell is Opadry AMB II Beige. In some embodiments, the immediate release shell with a moisture barrier comprises polyvinyl alcohol (PVA) with or without a plasticizer, with or without surfactants and defoamers (clear, pigmented, or colored). In some embodiments, the compositions are formulated into particles (eg, for administration as a capsule) and some or all of the particles are coated. In some embodiments, the compositions are formulated into particles (eg, for administration as a capsule) and some or all of the particles are microencapsulated. In some embodiments, the compositions are formulated into particles (eg, for administration as a capsule) and some or all of the particles are not microencapsulated or coated.

[0069] In some embodiments, the compositions described herein are delivered using a pulsatile release dosage form. A pulsatile release dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled delay time or at predetermined locations. Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic and polyglycolic acid, polyanhydrides, and polycaprolactone; porous matrices, systems based on non-polymers that are lipids, including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2nd ^Ed ., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd ^Ed ., pp. 751-753 (2002); US Pat. Nos. 4,327,725; 4,624,848; 4,968,509; 5,461,140;

[0070] Stabilizers include compounds such as any antioxidants such as butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol; buffers, acids, etc.

[0071] Surfactants include compounds such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monote arat, ethylene oxide-propylene oxide copolymers, e.g. Pluronic® (BASF), d-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS), etc.

[0072] The above excipients are given as examples only and are not intended to include all possible options. Other suitable classes of adjuvants include colorants, granulating agents, preservatives, defoamers, plasticizers, and the like. In addition, many excipients may have more than one role or function, or may be classified into more than one group; The classifications are only descriptive and are not intended to limit any use of a particular excipient.

Dosage forms

[0073] In some embodiments, the pharmaceutical formulations described herein are 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl )piperazine-1-carboxylate are included in a solid dosage form. The term "solid unit dosage form" means a dosage form intended to be swallowed as a single unit, which is selected from the group consisting of powder, tablet, bite-disintegrating tablet, chewable tablet, caplet, capsule, gelatin capsule, effervescent powder, fast a disintegrating tablet, an abuse prevention tablet, a modified release tablet, a modified release capsule tablet, a modified release capsule, and an aqueous suspension prepared from a powder. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a capsule-shaped tablet. In some embodiments, the solid dosage unit forms are selected from the group consisting of soft capsules or hard capsules of any size or shape. In some embodiments, the solid dosage unit forms are soft capsules of any size or shape. In some embodiments, the solid dosage unit forms are hard capsules of any size or shape. Suitable capsules include, without limitation, spherical or elliptical soft elastic gelatin capsules; hard capsules of starch, cellulose or gelatin, such as Capill® and the like. Suitable capsule sizes include capsule sizes 000, 00EL, 00, 0EL, 0, 1, 2, 3, 4, or 5.

[0074] Self-emulsifying drug delivery systems (SEDDS), as well as self-microemulsifying drug delivery systems (SMEDDS) and self-nanoemulsifying drug delivery systems (SNEDDS) form fine oil-in-water dispersions (emulsion, microemulsion and nanoemulsion, respectively) when diluted with aqueous media or in contact with gastrointestinal fluids. In some embodiments, the pharmaceutical compositions described herein comprise a self-emulsifying drug delivery system. In some embodiments, the pharmaceutical formulations described herein comprise a self-microemulsifiable drug delivery system. In some embodiments, the pharmaceutical formulations described herein comprise a self-nanoemulsifiable drug delivery system.

Ways

[0075] In some embodiments, the pharmaceutical formulations described herein are 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl )piperazine-1-carboxylate modulate MAGL activity. Contemplated methods, for example, include exposing said enzyme to a pharmaceutical formulation as described herein. The ability of the pharmaceutical formulations described herein to modulate or inhibit MAGL is assessed using procedures known in the art and/or described herein. According to another aspect of the present disclosure, methods are provided for treating a disease associated with MAGL expression or activity in a patient.

[0076] Also disclosed herein are methods of treating and/or preventing a disorder such as one or more of acute or chronic pain and neuropathy in a patient in need thereof. The disclosed methods include administering a pharmaceutically effective amount of a pharmaceutical composition described herein.

[0077] According to another embodiment, a method for treating pain in a patient is provided, comprising administering a therapeutically effective amount of a pharmaceutical composition described herein to a patient in need thereof for the treatment of said pain. According to another embodiment, a method for treating neuropathic pain in a patient is provided, comprising administering a therapeutically effective amount of a pharmaceutical composition described herein to a patient in need thereof for treating said neuropathic pain. According to another embodiment, a method for treating inflammatory pain in a patient is provided, comprising administering a therapeutically effective amount of a pharmaceutical composition described herein to a patient in need thereof for treating said inflammatory pain. According to another embodiment, a method is provided for treating complex regional pain syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0078] According to another embodiment, a method of treating a disease or disorder in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein, wherein the disease or disorder is selected from the group consisting of epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optic nerve (NMO), Tourette's syndrome, Alzheimer's disease and abdominal pain associated with irritable bowel syndrome. According to another embodiment, a method for treating epilepsy/seizure disorder in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating multiple sclerosis in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method of treating neuromyelitis optic nerve (NMO) in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method of treating Tourette's syndrome in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method of treating Alzheimer's disease in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method is provided for treating abdominal pain associated with irritable bowel syndrome in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein.

[0079] According to another embodiment, a method is provided for the treatment of acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, vaso-occlusive sickle cell pain crises, spasticity or pain associated with multiple sclerosis, functional pain in the chest, rheumatoid arthritis, osteoarthritis, or functional dyspepsia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating acute pain in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating inflammatory pain in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating cancer pain in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method is provided for treating pain caused by peripheral neuropathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating central pain in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating fibromyalgia in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating migraine in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method is provided for treating vaso-occlusive sickle cell disease crises in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method is provided for treating spasticity or pain associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating functional chest pain in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating rheumatoid arthritis in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating osteoarthritis in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating functional dyspepsia in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0080] In some embodiments, disclosed herein is a method of treating a chronic motor tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, disclosed herein is a method of treating a chronic motor tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0081] In some embodiments, disclosed herein is a method for treating attention deficit hyperactivity disorder (ADHD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, disclosed herein is a method for treating obsessive-compulsive disorder (OCD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0082] According to another embodiment, a method is provided for reducing intraocular pressure (IOP) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. According to another embodiment, a method for treating glaucoma in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0083] According to another embodiment, a method of treating atopic dermatitis in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0084] According to another embodiment, a method of treating pruritus in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0085] According to another embodiment, a method for treating Down's syndrome in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0086] In some embodiments, disclosed herein is a method of synergistically enhancing the activity of an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, disclosed herein is a method of reducing acute side effects associated with an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0087] According to another embodiment, a method of treating dystonia in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0088] In some embodiments, disclosed herein is a method of treating amyotrophic lateral sclerosis (ALS) or ALS-related symptoms in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0089] In some embodiments, disclosed herein is a method for treating arousal in autism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0090] According to another embodiment, a method is provided for treating sleep disturbance or bladder dysfunction associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0091] In some embodiments, disclosed herein is a method of treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0092] In some embodiments, disclosed herein is a method for treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0093] In some embodiments, disclosed herein is a method of improving post-stroke functional outcome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0094] In some embodiments, disclosed herein is a method of treating a traumatic brain injury in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0095] In some embodiments, disclosed herein is a method of treating trigeminal neuralgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, disclosed herein is a method for treating glossopharyngeal neuralgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein.

[0096] The disclosed pharmaceutical compositions are administered to patients (animals and humans) in need of such treatment at dosages that will provide optimal pharmaceutical efficacy. It is understood that the dose required for use in any particular application will vary from patient to patient, not only depending on the particular pharmaceutical composition chosen, but also on the nature of the condition being treated, the age and condition of the patient, concomitant medication or special diet, monitored by the patient and other factors, with the appropriate dosage ultimately left to the discretion of the attending physician.

[0097] While preferred embodiments of the present invention have been shown and described herein, those skilled in the art will appreciate that such embodiments are presented by way of example only. Numerous variations, changes and substitutions will be made by those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of the present invention. It is intended that the following claims define the scope of the present invention and that methods and structures are thus covered within the scope of these claims of the present invention and their equivalents.

EXAMPLES

[0098] The following examples provide exemplary methods for preparing exemplary pharmaceutical formulations piperazine-1-carboxylate. These examples are provided for illustrative purposes only and not to limit the scope of the claims presented herein.

Example 1 Pharmaceutical Composition

[0099] 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride; tablets, 10 mg HCl salt per tablet:

Component mg/unit % Hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-
carboxylate ten 3.33 Polyvinylpyrrolidone K30 (PVP K30) 72.1 24.03 PEG-400 12.9 4.3

Polysorbate 80 (Tween 80) 2 0.67 Silica 2 0.67 Potassium dihydrogen phosphate one 0.33 Microcrystalline cellulose 102 168.5 56.17 Crospovidone thirty ten Sodium fumarate 1.5 0.5 Total: 300 100.00

[00100] 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride; tablets, 10 mg free base per tablet:

Component mg/unit % Hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-
carboxylate 10.72 ¹ 1.4 Polyvinylpyrrolidone K30 (PVP K30) 76 10.1 PEG 400 eight 1.07 Polysorbate 80 (Tween 80) 2 0.27 Silica 2 0.27 Potassium dihydrogen phosphate 2 0.27 Microcrystalline cellulose 102 608.8 81.17 Croscarmellose sodium 37.5 5.0 Sodium fumarate 3.75 0.5 Total: 750.00 100.00

¹ 10.72 mg of the drug substance hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4- (2- (pyrrolidin-1-yl) -4- (trifluoromethyl) benzyl) piperazin-1- carboxylate stoichiometrically equivalent to 10.00 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a free base.

[00101] 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride, polyvinylpyrrolidone K30 (PVP K30), potassium dihydrogen phosphate, PEG-400 and polysorbate 80 (Tween 80) were mixed until a homogeneous mixture was obtained. The mixture was mixed with silica to obtain a free-flowing mixture. The mixture was extruded using a twin screw extruder. The extrudate was then crushed. The ground extrudate was mixed with microcrystalline cellulose 102, crospovidone or croscarmellose sodium and sodium stearyl fumarate to obtain a homogeneous mixture of tablets. The mixture of tablets was compressed into tablets.

Example 2: Pharmaceutical composition

[00102] 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride; tablets, 10 mg HCl salt per tablet:

Component mg/unit % Hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-
(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-carboxylate ten 3.33 Polyvinylpyrrolidone/vinyl acetate (PVPVA 64) 85 28.33 Polysorbate 80 (Tween 80) 2 0.67 Silica 2 0.67 Potassium dihydrogen phosphate one 0.33 Microcrystalline cellulose 102 168.5 56.17 Crospovidone thirty ten Sodium fumarate 1.5 0.5 Total: 300 100.00

[00103] 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride, polyvinylpyrrolidone/ vinyl acetate (PVPVA 64), potassium dihydrogen phosphate and polysorbate 80 (Tween 80) were mixed until a homogeneous mixture was obtained. The mixture was mixed with silica to obtain a free-flowing mixture. The mixture was extruded using a twin screw extruder. The extrudate was then crushed. The crushed extrudate was mixed with microcrystalline cellulose 102, crospovidone and sodium stearyl fumarate to obtain a homogeneous mixture of tablets. The mixture of tablets was compressed into tablets.

Example 3: Pharmaceutical composition

[00104] 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride; capsules, 2, 10 and 50 mg (amount of free base per capsule):

Ingredient Capsule 2 mg Capsule 10 mg Capsule 50 mg % (in
wt. rel.) mg % (in
wt. rel.) mg % (in
wt. rel.) mg 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piper hydrochloride
zine-1-carboxylate 1.26 2.14 ¹ 6.31 10.72 ² 31.53 53.60 ³ microcrystalline
cellulose 91.74 155.9
6 86.69 147.38 61.47 104.5 Croscarmellose sodium 6.00 10.20 6.00 10.20 6.00 10.20 magnesium stearate 1.00 1.70 1.00 1,700 1.00 1,700 Complete filling 100.0 170.0 100.0 170.0 100.0 170.0

¹ 2.14 mg of the drug substance hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4- (2- (pyrrolidin-1-yl) -4- (trifluoromethyl) benzyl) piperazin-1- carboxylate stoichiometrically equivalent to 2.00 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate in the form of a free base;

² 10.72 mg of the drug substance hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4- (2- (pyrrolidin-1-yl) -4- (trifluoromethyl) benzyl) piperazin-1- carboxylate stoichiometrically equivalent to 10.00 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate in the form of a free base;

³ 53.60 mg of the drug substance hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4- (2- (pyrrolidin-1-yl) -4- (trifluoromethyl) benzyl) piperazin-1- carboxylate stoichiometrically equivalent to 50.00 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a free base.

[00105] The following procedure was used to prepare 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-hydrochloride capsules 1-carboxylate:

1. Weighing enough capsules to fill a batch;

2. Weighing of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride, microcrystalline cellulose , croscarmellose sodium and magnesium stearate;

3. Screening each of the following: hydrochloride, 1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate , microcrystalline cellulose and croscarmellose sodium;

4. Transfer of screened materials (1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride , microcrystalline cellulose and croscarmellose sodium) into a blender and mixing the material for 15 minutes;

5. Sifting the magnesium stearate and adding it to the blender in step 4. Mixing the material for 2 minutes;

6. Pour the mixture into each of the orange-red size 2 capsules and check that the capsules are closed.

Example 4: Pharmaceutical composition

[00106] 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride; tablets, 2 mg free base per tablet:

Component mg/unit % Hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-
carboxylate 2.14 ¹ 1.43 Polyvinylpyrrolidone K30 (PVP K30) 15.06 10.04 PEG-400 1.60 1.07 Polysorbate 80 (Tween 80) 0.40 0.27 Silica 0.40 0.27 Potassium dihydrogen phosphate 0.40 0.27 Microcrystalline cellulose 121.70 81.13 Croscarmellose sodium 7.50 5.0 Sodium fumarate 0.75 0.50 Total: 150.00 100.00 Opadry AMB II beige 6.00 4.00 Total: 156.00 104.00

¹ 2.14 mg of the drug substance hydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl- 4- (2- (pyrrolidin-1-yl) -4- (trifluoromethyl) benzyl) piperazin-1- carboxylate stoichiometrically equivalent to 2.00 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a free base.

[00107] 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate hydrochloride, polyvinylpyrrolidone ( PVP K30), PEG-400, potassium dihydrogen phosphate and polysorbate 80 (Tween 80) were mixed until a homogeneous mixture was obtained. The mixture was mixed with silica to obtain a free-flowing mixture. The mixture was extruded using a twin screw extruder. The extrudate was then crushed. The crushed extrudate was mixed with microcrystalline cellulose 102, croscarmellose sodium and sodium stearyl fumarate to obtain a homogeneous mixture of tablets. The mixture of tablets was compressed into tablets. The tablets were coated with Opadry AMB II Beige in a pan.

Claims (23)

1. Pharmaceutical composition in solid dosage form, containing: (a) 1 mg to 60 mg 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate or its pharmaceutically acceptable salt; (b) 50 mg to 175 mg microcrystalline cellulose; (c) 6 mg to 15 mg croscarmellose sodium; as well as (d) 0.5 mg to about 2.5 mg magnesium stearate. 2. The pharmaceutical composition according to claim 1, wherein 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine -1-carboxylate is a hydrochloride. 3. Pharmaceutical composition in solid dosage form according to claim 1, containing: (a) about 2.1 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate; (b) about 156 mg of microcrystalline cellulose; (c) about 10 mg of croscarmellose sodium; as well as (d) about 1.7 mg of magnesium stearate. 4. Pharmaceutical composition in solid dosage form according to claim 1, containing: (a) about 10.7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate; (b) about 147 mg of microcrystalline cellulose; (c) about 10.2 mg of croscarmellose sodium; as well as (d) about 1.7 mg of magnesium stearate. 5. Pharmaceutical composition in solid dosage form according to claim 1, containing: (a) about 53.6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 hydrochloride -carboxylate; (b) about 104 mg of microcrystalline cellulose; (c) about 10 mg of croscarmellose sodium; as well as (d) about 1.7 mg of magnesium stearate. 6. Pharmaceutical composition according to any one of paragraphs. 1-5, wherein the solid dosage form is a tablet. 7. Pharmaceutical composition according to any one of paragraphs. 1-5, in which the solid dosage form is a capsule.