Solid dosage forms and administration regimens comprising (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

Abstract

Provided is a solid dispersion of (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (Compound 1) as defined herein, or a pharma- ceutically acceptable salt thereof, and a tablet containing the solid dispersion, for treating pain.Also disclosed herein is Compound 1 or a pharma- ceutically acceptable salt thereof for use in a method for treating pain.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 196,933, filed June 4, 2021, U.S. Provisional Application No. 63 / 196,937, filed June 4, 2021, U.S. Provisional Application No. 63 / 285,197, filed December 2, 2021, and U.S. Provisional Application No. 63 / 285,201, filed December 2, 2021, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy humans and animals to avoid tissue damage and prevent further damage to damaged tissue. Managing both acute and chronic pain in clinical settings remains a significant unmet need. In addition to acute pain, there are many conditions in which chronic pain persists beyond its protective role (neuropathic pain), and patients would benefit from pain inhibition. Neuropathic pain is a form of chronic pain caused by sensory nerve damage (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): pp. 681-688). Neuropathic pain can be divided into two categories: pain caused by general metabolic damage to nerves and pain caused by specific nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Specific nerve injury indications include nerve entrapment injuries, such as post-amputation pain, post-operative nerve injury pain, and neuropathic back pain. Neuropathic pain is a leading cause or disorder worldwide, adversely affecting patient sleep, mood, and function. Clin. Ther. 2018 40(6):p.828-49.

[0003] Current pain therapies suffer from poor efficacy and a high risk of adverse events (AEs). For example, lidocaine (a nonselective sodium channel blocker) can effectively reduce pain, but its usefulness is limited by significant side effects when given at the dose levels required for pain relief. Opioid pain medications have a high abuse liability and frequently lead to deaths due to overdose. Furthermore, opioid-induced hyperalgesia also limits the long-term use of opioids. Opioid-induced hyperalgesia is routinely encountered in clinical practice and poses significant challenges in pain management.

[0004] Antidepressants and anticonvulsants remain first-line treatments for neuropathic pain, despite not being designated for such purposes. Their use is often limited by significant side effects or inadequate pain relief. Clinical development has demonstrated a significant lack of recent advances and innovations in new medications for treating both acute and chronic pain. Over the past decade, most approved analgesics for the treatment of neuropathic pain act on either the serotonin-norepinephrine system (e.g., the serotonin-norepinephrine reuptake inhibitor duloxetine) or voltage-gated calcium channels (e.g., gabapentin and pregabalin). Given the limited treatment options for pain, coupled with an awareness of the increasing risks and relative effectiveness of current standard treatments, the development of analgesics that target specific pathophysiological mechanisms with improved efficacy and safety profiles is essential for better pain management and patient health outcomes.

[0005] Voltage-gated sodium channels (Na V ) is involved in pain signaling. VNav1.8 is a biological mediator of electrical signaling and mediates the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, and cardiac muscle cells). Support for the critical and central role of Nav in pain signaling comes from (1) evaluation of the role Nav plays in normal physiology, (2) pathologies resulting from mutations in the Nav1.8 gene (SCN10A), (3) preclinical work in animal models, and (4) the pharmacological effects of known Nav1.8 modulators. Furthermore, because Nav1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., dorsal root ganglia), Nav1.8 inhibitors are unlikely to be associated with the side effects commonly observed with other sodium channel modulators and the abuse liability associated with opioid therapy. Therefore, targeting the biology underlying pain through selective Nav1.8 inhibition represents a novel approach to analgesic development that may address the urgent unmet need for safe and effective acute and chronic pain therapies (Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Nav1.8). V 1.8 Sodium Channels. Mol. Interv., 2007.7(4):pp.192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), pp.1849-64(2008), Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), pp.50-56(2008). Na plays a key role in the initiation and propagation of neuronal signals. V Because of the role played by Na VAntagonists that reduce current can prevent or reduce nerve signaling, V It has been thought that these channels are likely to reduce pain under conditions of high excitability (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7(2), p. 144-58 (2008)). Several clinically useful analgesics are known to be sodium-gated. V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants, which block pain by inhibiting channels and have been shown to be effective in reducing pain, have also been suggested to act by blocking sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na + currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008)).

[0006] Na V form a subfamily of the voltage-gated ion channel superfamily and V 1.1~Na V It contains nine isoforms, designated 1.1 and 1.9. The tissue localization of the nine isoforms varies. V 1.4 is the major sodium channel in skeletal muscle and is the Na V 1.5 is the major sodium channel in cardiac myocytes. VNav1.7, Nav1.8, and Nav1.9 are mainly localized in the peripheral nervous system, while Na V Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but they differ in the details of their voltage dependence and kinetic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397 (2005)). At the time of their discovery, Na V The 1.8 channel was identified as a likely target for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562):pp. 257-62). Subsequently, Na V 1.8 has been shown to be a carrier of sodium currents that sustain action potential firing in small DRG neurons, supporting its potential as a target for multiple indications or across multiple pain types (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current). + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V1.8 is involved in spontaneous firing in injured neurons, which leads to neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + Channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6, Jarvis,MF,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.USA,2007.104(20):p.8520-5, Joshi,SK,et al.,Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic,but not post-operative,pain states.Pain,2006.123(1-2):pp.75-82, Lai, J., et al.,Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel,Na V 1.8.Pain,2002.95(1-2):p.143-52, Dong,XW,et al.,Small interfering RNA-mediated selective knockdown of Na( V)1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats.Neuroscience,2007.146(2):p.812-21, Huang, HL, et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves.Mol.Pain,2008.4:p.33, Black, JA, et al. al.,Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas.Ann.Neurol.,2008.64(6):p.644-53, Coward,K.,et al.,Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states.Pain,2000.85(1-2):p.41-50, Yiangou,Y.,et al.,SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves.FEBS Lett.,2000.467(2-3):p.249-52, Ruangsri,S.,et al.,Relationship of axonal voltage-gated sodium channel 1.8(Na V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats.J.Biol.Chem.286(46):p.39836-47). Na V The small DRG neurons in which Na1.8 is expressed contain nociceptors involved in pain signaling.V 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na + Current, TTX-resistant Na + current, and Ca2 + current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is required for rapid repetitive action on nociceptors and for spontaneous activity of injured neurons (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study.J.Neurophysiol.106(6):p.3173-84, Renganathan, M., TRCummins, and SGWaxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons.J.Neurophysiol.,2001.86(2):p.629-40, Roza,C.,et al.,The tetrodotoxin-resistant Na + Channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): pp. 921-926. In depolarized or damaged DRG neurons, Na V1.8 appears to be a driver of hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21):p.8245-50). In some animal pain models, Na V The 1.8 mRNA expression level indicates an increase in DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt2): pp. 359-75; Strickland, IT, et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6). [Prior art documents] [Non-patent literature]

[0007]

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[0008] In one aspect, the present disclosure provides a method of treating or lessening the severity of pain in a subject, comprising administering to the subject a compound of formula: [ka] or a pharmaceutically acceptable salt thereof in an amount of about 10 mg to about 300 mg per day.

[0009] In yet another aspect, the present disclosure relates to methods of treating or lessening the severity of various diseases, illnesses, disorders, or conditions in a subject, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmias, by administering Compound 1, a pharmaceutically acceptable salt, or a pharmaceutical composition to the subject.

[0010] In one aspect, the present disclosure relates to a solid dispersion comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one polymer.

[0011] In one embodiment, Compound 1 is substantially amorphous.

[0012] In one aspect, the present disclosure relates to a pharmaceutical composition comprising Compound 1 and at least one polymer.

[0013] In another embodiment, the pharmaceutical composition further comprises at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows an XRPD pattern characteristic of Compound 1, Form A. [Figure 2] 1 shows a TGA thermogram profile of Compound 1, Form A. [Figure 3] 1 shows a DSC thermogram profile of Compound 1, Form A. [Figure 4] 1 shows an XRPD pattern characteristic of Compound 1, Form B. [Figure 5] 1 shows the solid-state 13C NMR spectral characteristics of Compound 1, Form B. [Figure 6] 1 shows the solid-state 19F NMR spectral characteristics of Compound 1, Form B. [Figure 7] 1 shows a TGA thermogram profile of Compound 1, Form B. [Figure 8] 1 shows a DSC thermogram profile of Compound 1, Form B. [Figure 9] 1 shows the IR spectral characteristics of Compound 1, Form B. [Figure 10] 1 shows the thermal ellipsoid plot characteristics of Compound 1, Form B. [Figure 11] 1 shows the XRPD pattern of a spray-dried dispersion of Compound 1 in Example 3. [Figure 12A] 1 shows the XRPD pattern of the SDD tablet composition of Example 3 over the range of about 3° to about 40° 2θ. [Figure 12B] 1 shows the XRPD pattern of the SDD tablet composition of Example 3 over the range of about 14° to about 16° 2θ. [Figure 13A] 1 shows the solid-state 19F NMR spectral characteristics of the SDD tablet composition of Example 3. [Figure 13B] 1 shows the solid-state 13C NMR spectral characteristics of the powder of the SDD tablet composition of Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Further, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0016] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the positions of its molecules. The molecules in an amorphous solid are generally arranged randomly, without a clearly defined arrangement. An amorphous solid is generally isotropic, i.e., exhibits similar properties in all directions, and does not have a distinct melting point. For example, an amorphous material is a solid material that does not have a sharp, characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) are seen in its XRPD pattern.

[0017] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order in the position of its molecules. For example, a substantially amorphous material has less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity). The term "substantially amorphous" includes materials that have no crystallinity (0%).

[0018] As used herein, the term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed in discrete units throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary greatly (e.g., colloidal particles from nanometer dimensions to several microns in size). Generally, the dispersed phase can be a solid, liquid, or gas. In solid dispersions, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can contain a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion contains a polymer that constitutes the dispersed phase, and the drug constitutes the continuous phase. In other embodiments, a solid dispersion contains a drug that constitutes the dispersed phase, and the polymer constitutes the continuous phase.

[0019] As used herein, the prefix "rac-" when used in reference to a chiral compound refers to a racemic mixture of the compound. In compounds bearing the "rac-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound.

[0020] As used herein, the prefix "rel-", when used in reference to a chiral compound, refers to a single enantiomer of unknown absolute configuration. In compounds bearing the "rel-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound. If the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some instances, the absolute configurations of some stereocenters are known, while only the relative configurations of other stereocenters are known. In these instances, stereochemical designators associated with stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while stereochemical designators associated with stereocenters of unknown absolute configuration are not. Unmarked stereochemical designators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters relative to other stereocenters of unknown absolute configuration, but not necessarily relative stereochemistry to stereocenters of known absolute configuration.

[0021] As used herein, the term "Compound 1," as well as structures and chemical names corresponding to "Compound 1," refer to a collection of molecules having the same chemical structure, i.e., a structure corresponding to "Compound 1," except that there may be isotopic variation among the constituent atoms of the molecule. The term "Compound 1" includes a collection of molecules regardless of the purity of a given sample containing such a collection of molecules. Thus, the term "Compound 1" includes such a collection of molecules in pure form or in a mixture (e.g., a solution, suspension, or colloid) with one or more other substances.

[0022] In this specification and claims, unless otherwise specified, any atom in Compound 1 that is not specifically designated as a particular isotope is meant to represent any stable isotope of the specified element. In the examples, when an atom is not specifically designated as a particular isotope, no effort was made to enrich that atom in a particular isotope, and thus, one of skill in the art would understand that such atom was likely present in approximately the natural abundance isotopic composition of the specified element.

[0023] As used herein, the term "compound 1a" refers to the compound having the chemical name: 2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)pyridine 1-oxide.

[0024] As used herein, the term "stable," when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes whose decay mode is not identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0025] As used herein, "H" refers to hydrogen and any stable isotope of hydrogen, i.e. 1 H and D. In examples where an atom is designated as "H," no attempt has been made to enrich the atom in a particular isotope of hydrogen, and one of skill in the art will understand that such hydrogen atom is likely to be present in approximately the natural abundance isotopic composition of hydrogen.

[0026] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, comprises each constituent atom in about the natural abundance isotopic composition of the specified element.

[0027] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, contains one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the specified element (isotopically labeled compound or salt). Examples of stable isotopes that are commercially available and suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, e.g., 2 H, 13C. 15 N, 18 O. 17 O, and 31 Examples include, but are not limited to, P.

[0028] The terms "Compound 1" and "a pharmaceutically acceptable salt thereof" include Compound 1 and any pharmaceutically acceptable salt thereof in any form, including any solid form thereof (including any amorphous or crystalline form thereof), any solvate, hydrate, or co-crystal form thereof, and any solution or suspension thereof.

[0029] As used herein, the term "about" includes a specific amount value or a range encompassing a specific amount that would be recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that resulting from a specific amount. The term "about" can refer to an acceptable error for a specific value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the term "about" means within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In some embodiments, the term "about" means within 20% of a given value or range. In some embodiments, the term "about" means within 15% of a given value or range. In some embodiments, the term "about" means within 10% of a given value or range. In some embodiments, the term "about" means within 5% of a given value or range. In some embodiments, the term "about" means within 1% of a given value or range. In some embodiments, the term "about" means within 0.5% of a given value or range.

[0030] The term "subject" or "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0031] As used herein, the term "amount," when referring to the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject, refers to the mass of an equimolar amount of (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, regardless of the actual mass of any salt, solvate, hydrate, or co-crystal form that may be administered.

[0032] In certain embodiments, an "effective amount" of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is an amount effective to treat or lessen the severity of one or more of the conditions listed herein.

[0033] As used herein, and unless otherwise specified, the terms "per day" and "total daily dose," when referring to the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject, refer to the amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject during at least one 24-hour period during the course of treatment. Unless otherwise specified, it will be understood that Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject in different amounts on one or more other days during the course of treatment.

[0034] As used herein, the term "day 1" refers to the first 24 hours during which Compound 1, or a pharmaceutically acceptable salt thereof, is administered during a course of treatment.

[0035] As used herein, the term "course of treatment," when referring to Compound 1, or a pharmaceutically acceptable salt thereof, refers to the administration of one or more doses of the compound or salt during a period distinct from any earlier or later administration of the compound or salt. Typically, Compound 1 and any metabolites thereof are substantially eliminated from the subject's systemic circulation during the course of treatment.

[0036] As used herein, when referring to the administration of Compound 1, or a pharmaceutically acceptable salt thereof, the term "dose" refers to an amount of the compound or salt administered at a discrete time period, separate from other amounts of the compound or salt that may be administered on the same day or at other times during the course of treatment. When a dose is administered orally, the dose may be administered in a single tablet, capsule, or other oral dosage form, or in multiple such dosage forms.

[0037] As used herein, the term "initial dose" refers to the first dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered on a given day or in a given course of treatment, as the context indicates.

[0038] As used herein, the term "subsequent dose" refers to any dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered after the initial dose on a given day or during a given course of treatment, as the context indicates.

[0039] As used herein, the term "baseline pain score" refers to a subject's pain score, such as a score on an 11-point numeric pain rating scale or a verbal categorical rating scale, before starting a course of treatment with Compound 1, or a pharmaceutically acceptable salt thereof.

[0040] As used herein, the term "11-point numeric pain rating scale" refers to a pain rating scale in which a subject rates their pain intensity on a scale of 0 to 10, with a score of 0 indicating no pain and a score of 10 indicating the worst pain intensity imaginable.

[0041] As used herein, the term "verbal categorical rating scale" refers to a pain rating scale in which subjects rate their pain intensity as none, mild, moderate, or severe.

[0042] As used herein, the term "adverse event" is defined as any untoward medical occurrence in a subject during a study, the event not necessarily having a causal relationship to treatment. This includes a new-onset event or a worsening of an existing condition (e.g., an increase in its severity or frequency).

[0043] As used herein, an abnormal trial assessment is considered "clinically significant" if the subject has one or more of the following: concomitant signs or symptoms related to the abnormal trial assessment, further diagnostic testing or medical / surgical intervention, a change in the dose of study drug, or withdrawal from the study. The determination of whether a trial assessment result is clinically significant is made by the investigator.

[0044] Medical Use of Compound 1 or a Pharmaceutically Acceptable Salt Thereof In one aspect, the present disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof.

[0045] In another aspect, the present disclosure relates to the use of Compound 1, or a pharmaceutically acceptable salt thereof, in a method for treating or reducing the severity of pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject.

[0046] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject.

[0047] Dosage schedule Compound 1, or a pharmaceutically acceptable salt thereof, may be administered in any amount appropriate to treat or reduce the severity of pain in a subject. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 20 mg to 5000 mg per day, or 20 mg to 4500 mg per day, or 20 mg to 4000 mg per day, or 20 mg to 3500 mg per day, or 20 mg to 3000 mg per day, or 20 mg to 2500 mg per day, or 20 mg to 2000 mg per day, or 20 mg to 1500 mg per day, or 20 mg to 1000 mg per day, or 20 mg to 800 mg per day, or 20 mg to 700 mg per day, or 20 mg to 3000 mg per day. mg to 600mg, or 20mg to 500mg per day, or 20mg to 450mg per day, or 20mg to 400mg per day, or 20mg to 350mg per day, or 20mg to 300mg per day, or 20mg to 250mg per day, or 20mg to 200mg per day, or 20mg to 150mg per day, or 20mg to 30mg per day, or 90mg to 120mg per day, or 100mg to 5000mg per day, or 100mg to 4500mg per day, or 100mg to 4000mg per day , or 100mg to 3500mg per day, or 100mg to 3000mg per day, or 100mg to 2500mg per day, or 100mg to 2000mg per day, or 100mg to 1500mg per day, or 100mg to 1000mg per day, or 100mg to 800mg per day, or 100mg to 600mg per day, or 100mg to 500mg per day, or 100mg to 400mg per day, or 100mg to 300mg per day, or 100mg to 200mg per day, or 100mg per day g to 150mg, or 60mg to 2500mg per day, or 60mg to 2400mg per day, or 60mg to 2300mg per day, or 60mg to 2200mg per day, or 60mg to 2100mg per day, or 60mg to 2000mg per day, or 60mg to 1900mg per day, or 60mg to 1800mg per day, or 60mg to 1700mg per day, or 60mg to 1200mg per day, or 60mg to 800mg per day, or about 60mg per day, or 60mg to 700mg per day,Or it is administered in an amount of 60 mg to 600 mg per day, or 60 mg to 500 mg per day, or 60 mg to 300 mg per day, or 60 mg to 200 mg per day, or 60 mg to 150 mg per day, or 60 mg to 90 mg per day, or about 10 mg, or about 20 mg per day, or about 23 mg per day, or about 30 mg per day, or about 46 mg per day, or about 50 mg per day, or about 60 mg per day, or about 69 mg per day, or about 70 mg per day, or about 90 mg per day, or about 100 mg per day, or about 150 mg per day, or about 200 mg per day.

[0048] Compound 1, or a pharmaceutically acceptable salt thereof, when administered on multiple days may be administered in the same or different amounts each day.

[0049] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in different amounts on day 1 and after day 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 10 mg to 3000 mg, or 10 mg to 2000 mg, or 10 mg to 1000 mg, or 10 mg to 500 mg, or 10 mg to 400 mg, or 10 mg to 350 mg, or 10 mg to 300 mg, or 10 mg to 250 mg, or 10 mg to 200 mg, or about 100 mg, or about 150 mg, or about 120 mg, or about 90 mg, or is administered in an amount of about 30 mg, and after day 1 in an amount of 10 mg to 2000 mg per day, or 10 mg to 1500 mg per day, or 10 mg to 1000 mg per day, or 10 mg to 500 mg per day, or 10 mg to 400 mg per day, or 10 mg to 300 mg per day, or 20 mg to 100 mg per day, or about 20 mg per day, or about 60 mg per day, or about 100 mg per day, or about 30 mg per day, or about 20 mg per day, or about 50 mg per day.

[0050] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 100 mg, or 150 mg, or 20 mg, or about 30 mg, or about 60 mg, or about 90 mg on day 1.

[0051] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 100 mg per day, or 150 mg per day, or 50 mg per day, or 30 mg per day, or 60 mg per day, or 10 mg per day, or about 20 mg per day.

[0052] Compound 1, or a pharmaceutically acceptable salt thereof, may be administered in any number of doses per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a single dose per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a single dose of 10 mg to 500 mg, or 10 mg to 400 mg, or 10 mg to 300 mg, or 10 mg to 260 mg, or 10 mg to 200 mg, or 10 mg to 150 mg, or 10 mg to 100 mg, or 10 mg, or 20 mg, or 30 mg per day, or 60 mg per day, or 90 mg per day, or 100 mg per day, or 120 mg per day, or 150 mg per day.

[0053] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in two doses per day.

[0054] When administered on multiple days, Compound 1 or a pharmaceutically acceptable salt thereof may be administered at the same or different doses each day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at the same dose on day 1 and after day 1.

[0055] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in two doses (i.e., an initial dose and a subsequent dose) on day 1. The amounts of the initial dose and the subsequent doses may be the same or different.

[0056] In some embodiments, the initial dose and subsequent doses are the same. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in two doses of 10 mg to 1000 mg per day, or 10 mg to 500 mg, or 10 mg to 400 mg, or 10 mg to 300 mg, or 10 mg to 200 mg, or about 100 mg.

[0057] In some embodiments, the initial dose is larger than subsequent doses on day 1. In some embodiments, the initial dose is 5 mg to 2000 mg, or 10 mg to 1000 mg, or 10 mg to 200 mg, or 10 mg to 150 mg, or 10 mg to 100 mg, or 20 mg to 150 mg, or 20 mg to 100 mg, or about 250 mg, or about 200 mg, or about 150 mg, or about 100 mg, or about 90 mg, or about 60 mg, or about 30 mg, or about 20 mg, or about 10 mg.

[0058] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in two doses per day (i.e., an initial dose and a subsequent dose) after day 1. The amounts of the initial dose and the subsequent doses may be the same or different. In some embodiments, the initial dose and the subsequent doses are the same after day 1.

[0059] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in two doses of 10-100 mg per day after day 1, or in two doses of 10 mg-200 mg, or in two doses of 10 mg-250 mg, or in two doses of 10 mg-300 mg, or in two doses of 10 mg-350 mg, or in two doses of 10 mg, or in two doses of 30 mg, or in two doses of 50 mg.

[0060] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg every 12 to 30 hours.

[0061] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 23 mg every 12 to 30 hours.

[0062] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg every 12 to 30 hours.

[0063] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 46 mg every 12 to 30 hours.

[0064] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg every 12 to 30 hours.

[0065] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 69 mg every 12 to 30 hours.

[0066] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70 mg every 12 to 30 hours.

[0067] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg every 24 hours.

[0068] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 23 mg every 24 hours.

[0069] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 46 mg every 24 hours.

[0070] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60 mg every 24 hours.

[0071] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 69 mg every 24 hours.

[0072] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70 mg every 24 hours.

[0073] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg every 24 hours.

[0074] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in one or more doses totaling about 100 mg every 24 hours.

[0075] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily at a dose of about 10 mg.

[0076] In some embodiments, about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day (bid).

[0077] In some embodiments, about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours (q12h).

[0078] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg every 18 to 30 hours.

[0079] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg to about 150 mg every 21 to 27 hours.

[0080] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg to about 100 mg every 21 to 27 hours.

[0081] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 21 to 27 hours at a dose of 23 mg, 46 mg, 50 mg, 60 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or 125 mg.

[0082] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 75 mg to 125 mg every 21 to 27 hours.

[0083] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 80 mg to 100 mg every 21 to 27 hours.

[0084] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily at a dose of about 10 mg (20 mg daily).

[0085] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg every 6 to 18 hours.

[0086] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg every 9 to 15 hours.

[0087] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

[0088] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 70 mg every 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg every 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 20 mg every 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30 mg every 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 40 mg every 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg every 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 60 mg every 12 hours. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 70 mg every 12 hours.

[0089] In some embodiments, Compound 1 is administered every 12 hours at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

[0090] In some embodiments, Compound 1 is administered at a dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 70 mg every 12 hours. In some embodiments, Compound 1 is administered at a dose of 10 mg every 12 hours. In some embodiments, Compound 1 is administered at a dose of 20 mg every 12 hours. In some embodiments, Compound 1 is administered at a dose of 30 mg every 12 hours. In some embodiments, Compound 1 is administered at a dose of 40 mg every 12 hours. In some embodiments, Compound 1 is administered at a dose of 50 mg every 12 hours. In some embodiments, Compound 1 is administered at a dose of 60 mg every 12 hours. In some embodiments, Compound 1 is administered at a dose of 70 mg every 12 hours.

[0091] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg every 12 hours.

[0092] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily at a dose of about 30 mg (60 mg daily).

[0093] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg every 6 to 18 hours.

[0094] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg every 9 to 15 hours.

[0095] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg every 12 hours (q12h).

[0096] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 6 to 18 hours following an initial dose of about 20 mg and subsequent doses of about 10 mg.

[0097] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 9 to 15 hours following an initial dose of about 20 mg and subsequent doses of about 10 mg.

[0098] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours following an initial dose of about 20 mg and subsequent doses of about 10 mg.

[0099] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg every 12 hours, followed by an initial dose of about 20 mg and subsequent doses of about 10 mg.

[0100] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg every 12 hours, followed by an initial dose of 20 mg and subsequent doses of 10 mg.

[0101] In some embodiments, Compound 1 is administered at a dose of about 10 mg every 12 hours, followed by an initial dose of about 20 mg and subsequent doses of about 10 mg.

[0102] In some embodiments, Compound 1 is administered at a dose of 10 mg every 12 hours, followed by an initial dose of 20 mg and subsequent doses of 10 mg.

[0103] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of about 10 mg every 12 hours, followed by an initial dose of about 20 mg and subsequent doses of about 10 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0104] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of 10 mg every 12 hours, followed by an initial dose of 20 mg and subsequent doses of 10 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0105] In some embodiments, Compound 1 is administered in doses of 10 mg every 12 hours, followed by an initial dose of about 20 mg and subsequent doses of about 10 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0106] In some embodiments, Compound 1 is administered in doses of 10 mg every 12 hours, followed by an initial dose of 20 mg and subsequent doses of 10 mg, with the subsequent doses administered 12 hours after the initial dose.

[0107] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg every 12 hours, followed by an initial dose of about 40 mg and subsequent doses of about 20 mg.

[0108] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 20 mg every 12 hours, followed by an initial dose of 40 mg and subsequent doses of 20 mg.

[0109] In some embodiments, Compound 1 is administered at a dose of about 20 mg every 12 hours, followed by an initial dose of about 40 mg and subsequent doses of about 20 mg.

[0110] In some embodiments, Compound 1 is administered at a dose of 20 mg every 12 hours, followed by an initial dose of 40 mg and subsequent doses of 20 mg.

[0111] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of about 20 mg every 12 hours, followed by an initial dose of about 40 mg and subsequent doses of about 20 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0112] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 20 mg every 12 hours, followed by an initial dose of 40 mg and subsequent doses of 20 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0113] In some embodiments, Compound 1 is administered at doses of about 20 mg every 12 hours, followed by an initial dose of about 40 mg and subsequent doses of about 20 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0114] In some embodiments, Compound 1 is administered at a dose of 20 mg every 12 hours, followed by an initial dose of 40 mg and subsequent doses of 20 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0115] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 6 to 18 hours following an initial dose of about 60 mg and subsequent doses of about 30 mg.

[0116] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 9 to 15 hours following an initial dose of about 60 mg and subsequent doses of about 30 mg.

[0117] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours following an initial dose of about 60 mg and subsequent doses of about 30 mg.

[0118] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg every 12 hours, followed by an initial dose of about 60 mg and subsequent doses of about 30 mg.

[0119] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30 mg every 12 hours, followed by an initial dose of 60 mg and subsequent doses of 30 mg.

[0120] In some embodiments, Compound 1 is administered at a dose of about 30 mg every 12 hours, followed by an initial dose of about 60 mg and subsequent doses of about 30 mg.

[0121] In some embodiments, Compound 1 is administered at a dose of 30 mg every 12 hours, followed by an initial dose of 60 mg and subsequent doses of 30 mg.

[0122] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of about 30 mg every 12 hours, followed by an initial dose of about 60 mg and subsequent doses of about 30 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0123] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30 mg every 12 hours, followed by an initial dose of 60 mg and subsequent doses of 30 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0124] In some embodiments, Compound 1 is administered at doses of about 30 mg every 12 hours, followed by an initial dose of about 60 mg and subsequent doses of about 30 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0125] In some embodiments, Compound 1 is administered at a dose of 30 mg every 12 hours, followed by an initial dose of 60 mg and subsequent doses of 30 mg, with the subsequent doses administered 12 hours after the initial dose.

[0126] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40 mg every 12 hours, followed by an initial dose of about 80 mg and subsequent doses of about 40 mg.

[0127] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 40 mg every 12 hours, followed by an initial dose of 80 mg and subsequent doses of 40 mg.

[0128] In some embodiments, Compound 1 is administered at a dose of about 40 mg every 12 hours, followed by an initial dose of about 80 mg and subsequent doses of about 40 mg.

[0129] In some embodiments, Compound 1 is administered at a dose of 40 mg every 12 hours, followed by an initial dose of 80 mg and subsequent doses of 40 mg.

[0130] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of about 40 mg every 12 hours, followed by an initial dose of about 80 mg and subsequent doses of about 40 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0131] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 40 mg every 12 hours, followed by an initial dose of 80 mg and subsequent doses of 40 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0132] In some embodiments, Compound 1 is administered at doses of about 40 mg every 12 hours, followed by an initial dose of about 80 mg and subsequent doses of about 40 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0133] In some embodiments, Compound 1 is administered at a dose of 40 mg every 12 hours, followed by an initial dose of 80 mg and subsequent doses of 40 mg, with the subsequent doses administered 12 hours after the initial dose.

[0134] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 6 to 18 hours following an initial dose of about 100 mg and subsequent doses of about 50 mg.

[0135] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 9 to 15 hours following an initial dose of about 100 mg and subsequent doses of about 50 mg.

[0136] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours following an initial dose of about 100 mg and subsequent doses of about 50 mg.

[0137] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg every 12 hours, followed by an initial dose of about 100 mg and subsequent doses of about 50 mg.

[0138] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg every 12 hours, followed by an initial dose of 100 mg and subsequent doses of 50 mg.

[0139] In some embodiments, Compound 1 is administered at a dose of about 50 mg every 12 hours, followed by an initial dose of about 100 mg and subsequent doses of about 50 mg.

[0140] In some embodiments, Compound 1 is administered at a dose of 50 mg every 12 hours, followed by an initial dose of 100 mg and subsequent doses of 50 mg.

[0141] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of about 50 mg every 12 hours, followed by an initial dose of about 100 mg and subsequent doses of about 50 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0142] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg every 12 hours, followed by an initial dose of 100 mg and subsequent doses of 50 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0143] In some embodiments, Compound 1 is administered in doses of about 50 mg every 12 hours, followed by an initial dose of about 100 mg and subsequent doses of about 50 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0144] In some embodiments, Compound 1 is administered in doses of 50 mg every 12 hours, followed by an initial dose of 100 mg and subsequent doses of 50 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0145] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60 mg every 12 hours, followed by an initial dose of about 120 mg and subsequent doses of about 60 mg.

[0146] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 60 mg every 12 hours, followed by an initial dose of 120 mg and subsequent doses of 60 mg.

[0147] In some embodiments, Compound 1 is administered at a dose of about 60 mg every 12 hours, followed by an initial dose of about 120 mg and subsequent doses of about 60 mg.

[0148] In some embodiments, Compound 1 is administered at a dose of 60 mg every 12 hours, followed by an initial dose of 120 mg and subsequent doses of 60 mg.

[0149] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at doses of about 60 mg every 12 hours, followed by an initial dose of about 120 mg and subsequent doses of about 60 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0150] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 60 mg every 12 hours, followed by an initial dose of 120 mg and subsequent doses of 60 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0151] In some embodiments, Compound 1 is administered at doses of about 60 mg every 12 hours, followed by an initial dose of about 120 mg and subsequent doses of about 60 mg, with the subsequent doses administered 12 hours after the initial dose.

[0152] In some embodiments, Compound 1 is administered at a dose of 60 mg every 12 hours, followed by an initial dose of 120 mg and subsequent doses of 60 mg, with the subsequent doses administered 12 hours after the initial dose.

[0153] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70 mg every 12 hours, followed by an initial dose of about 140 mg and subsequent doses of about 70 mg.

[0154] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 70 mg every 12 hours, followed by an initial dose of 140 mg and subsequent doses of 70 mg.

[0155] In some embodiments, Compound 1 is administered at a dose of about 70 mg every 12 hours, followed by an initial dose of about 140 mg and subsequent doses of about 70 mg.

[0156] In some embodiments, Compound 1 is administered at a dose of 70 mg every 12 hours, followed by an initial dose of 140 mg and subsequent doses of 70 mg.

[0157] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at doses of about 70 mg every 12 hours, followed by an initial dose of about 140 mg and subsequent doses of about 70 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0158] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 70 mg every 12 hours, followed by an initial dose of 140 mg and subsequent doses of 70 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0159] In some embodiments, Compound 1 is administered at doses of about 70 mg every 12 hours, followed by an initial dose of about 140 mg and subsequent doses of about 70 mg, with the subsequent doses being administered 12 hours after the initial dose.

[0160] In some embodiments, Compound 1 is administered at a dose of 70 mg every 12 hours, followed by an initial dose of 140 mg and subsequent doses of 70 mg, with the subsequent doses administered 12 hours after the initial dose.

[0161] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg to about 100 mg, or once daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or 1 to 6 weeks.

[0162] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg every 18 to 30 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0163] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 23 mg every 18 to 30 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0164] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 46 mg every 18 to 30 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0165] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg every 18 to 30 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0166] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 69 mg every 18 to 30 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0167] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70 mg every 18 to 30 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0168] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg every 21 to 27 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0169] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg every 24 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0170] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg once daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0171] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg every 18 to 30 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0172] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg every 21 to 27 hours for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0173] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of 50 mg twice daily, followed by an initial dose of 100 mg and subsequent doses of 50 mg, with the subsequent doses being administered about 12 hours after the initial dose.

[0174] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30 mg twice daily, followed by an initial dose of 60 mg and subsequent doses of 30 mg, with the subsequent doses being administered about 12 hours after the initial dose.

[0175] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of 10 mg twice daily, followed by an initial dose of 20 mg and subsequent doses of 10 mg, with the subsequent doses being administered about 12 hours after the initial dose.

[0176] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in doses of 30 mg twice daily, followed by an initial dose of 90 mg and subsequent doses of 30 mg, with the subsequent doses being administered about 12 hours after the initial dose.

[0177] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, or about 80 mg every 24 hours (q24h). In some embodiments, a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, or about 80 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily (qd). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered every 24 hours (q24h) at a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 43 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, or 80 mg. In some embodiments, a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 43 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, or 80 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily (qd).

[0178] In some embodiments, Compound 1 is administered every 24 hours (q24h) at a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, or about 80 mg. In some embodiments, a dose of Compound 1 of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, or about 80 mg is administered once daily (qd). In some embodiments, Compound 1 is administered every 24 hours (q24h) at a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 43 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, or 80 mg. In some embodiments, a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 43 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, or 80 mg of Compound 1 is administered once daily (qd).

[0179] Compound 1, or a pharmaceutically acceptable salt thereof, may be administered in any form, including any solid form (including any amorphous or crystalline form), any solvate, hydrate, or co-crystal form, or any solution or suspension of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered in Form B. In some embodiments, Compound 1 is administered in a pharmaceutical composition prepared by mixing Form B with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, Form B has a Cu K molar mass of 4.4, 15.2, 16.4, 18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5, 24.2, 24.8, 26.3, 29.6, 30.1, and 31.3 when the XRPD is collected from about 4 to about 40 degrees two-theta (2θ). αForm B is characterized by an X-ray powder diffraction pattern (XRPD) containing at least three approximate peak positions (degrees 2-theta + 0.2) when measured using radioactive radiation. In some embodiments, Form B has Cu K peaks selected from the group consisting of 19.3, 22.2, 23.5, 26.3, and 30.1 when the XRPD is collected from about 4 to about 40 degrees 2-theta (2θ). α Form B is characterized by an X-ray powder diffraction pattern (XRPD) containing at least three approximate peak positions (degrees 2-theta +0.2) when measured using radioactive radiation. In some embodiments, Form B has a CuK structure substantially similar to that shown in FIG. α It is characterized by an X-ray powder diffraction pattern (XRPD) measured using radiation.

[0180] In some embodiments, the method includes administering to the subject Compound 1 (i.e., as the free acid (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide) in a non-salt form.

[0181] Compound 1, or a pharmaceutically acceptable salt thereof, may be administered by any route known in the art. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0182] Compound 1, or a pharmaceutically acceptable salt thereof, can be administered for any number of days necessary or desirable to treat or reduce the severity of a subject's pain, which may depend on the type of pain the subject is experiencing. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least 2 days. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or for 1 to 6 weeks.

[0183] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg once daily to a subject. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 23 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 45 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 46 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 50 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 60 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 69 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 70 mg once daily.In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 75 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 90 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 100 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 110 mg once daily. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject once daily at a dose of about 125 mg.

[0184] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject once daily a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg of Compound 1. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject once daily a dose of 23 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 45 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 46 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 50 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 60 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily a dose of 69 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily a dose of 70 mg of Compound 1, or a pharmaceutically acceptable salt thereof.In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 75 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 90 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 100 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 110 mg once daily. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 125 mg once daily.

[0185] In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg of Compound 1. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily a dose of about 23 mg of Compound 1. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 45 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 46 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 50 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 60 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 69 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily at a dose of about 70 mg Compound 1. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily at a dose of about 75 mg Compound 1.In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 90 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 100 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 110 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of about 125 mg.

[0186] In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 23 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 45 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 46 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 50 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 60 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 69 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject once daily at a dose of 70 mg. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily at a dose of 75 mg Compound 1. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily at a dose of 90 mg Compound 1.In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily at a dose of 100 mg Compound 1. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily at a dose of 110 mg Compound 1. In another aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, comprising administering to the subject once daily at a dose of 125 mg Compound 1.

[0187] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 23 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 45 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 46 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 50 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 60 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 69 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 70 mg.In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 75 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 90 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 100 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 110 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 125 mg.

[0188] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 23 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 45 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 46 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 50 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 60 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 69 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 70 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 75 mg.In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 90 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 100 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 110 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of 125 mg.

[0189] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 23 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of about 45 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of about 46 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of about 50 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of about 60 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of about 69 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 70 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 75 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 90 mg.In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 100 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 110 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of about 125 mg.

[0190] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 23 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 45 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 46 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 50 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 60 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 69 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering Compound 1 to the subject at a total daily dose of 70 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of 75 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of 90 mg.In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of 100 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of 110 mg. In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound 1 at a total daily dose of 125 mg.

[0191] Indications Compound 1, or a pharmaceutically acceptable salt thereof, can be administered to a subject to treat or lessen the severity of any type of pain known in the art.

[0192] In some embodiments, the present disclosure provides a method for the treatment of acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, status epilepticus, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, post-herpetic pain in a subject. Menstrual pain, diabetic neuropathy, glenoid pain, sciatica, back pain, non-specific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post-stroke central neuropathic pain), whipflash-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, Systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, degenerative / peristaltic pain, radiculopathy, premolar joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spongiform myositis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylodiscitis, spondylolisthesis, chemotherapy-induced The present invention relates to a method for treating or lessening the severity of oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorders, painful joint arthroplasty, non-cardiac chest pain, vulvar pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0193] In another embodiment, the present disclosure provides a method for the treatment of femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, and / or hereditary neuropathy in a subject. Pathologies, peripheral nerve injury, painful neuromas, ectopic proximal and distal drainage, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic post-operative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom pain (e.g., after removal of lower limb, upper limb, breast), intractable pain, acute pain, acute post-operative pain, acute musculoskeletal pain, arthralgia, mechanical low back pain, neck pain, tendonitis, injury pain, exercise pain, acute visceral pain Nephritis, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, kidney stone pain, acute obstetric pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, achromatopsia, venous pain, Guillain-Barré pain, painful leg and toe movements, Haglund's syndrome and urinary bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina pectoris-induced pain, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0194] In yet another embodiment, the disclosure features a method of treating or lessening the severity of acute pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the acute pain comprises acute post-operative pain.

[0195] In yet another embodiment, the disclosure features a method for treating or lessening the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0196] In yet another embodiment, the disclosure features a method for treating or lessening the severity of bunionectomy pain in a subject, the method comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0197] In yet another embodiment, the disclosure features a method for treating or reducing the severity of herniorrhaphy pain in a subject, the method comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0198] In yet another embodiment, the disclosure features a method of treating or lessening the severity of abdominoplasty pain in a subject, the method comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0199] In yet another embodiment, the disclosure features a method of treating or lessening the severity of visceral pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the visceral pain includes abdominoplasty visceral pain.

[0200] In yet another embodiment, the disclosure features a method of treating or lessening the severity of a neurodegenerative disease in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0201] In another embodiment, the present disclosure provides a method for the treatment of acute pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, status epilepticus, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, glenoid pain, The present invention features a method for treating or lessening the severity of sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0202] Patient population Compound 1, or a pharmaceutically acceptable salt thereof, can be administered to a subject with pain of any severity to treat or reduce the severity of the pain.

[0203] In some embodiments, the subject has a baseline pain score of at least 4 on an 11-point numeric pain rating scale prior to administration of Compound 1, or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the subject has a baseline pain level of moderate or severe on a verbal categorical rating scale prior to administration of Compound 1, or a pharmaceutically acceptable salt thereof.

[0205] Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use - Patent application In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of pain in a subject, according to the methods described herein (including any embodiments thereof).

[0206] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

[0207] In another aspect, the disclosure relates to Compound 1 for use in a method for treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject twice daily at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

[0208] In another aspect, the disclosure relates to Compound 1 for use in a method for treating or reducing the severity of pain in a subject, comprising administering Compound 1 to the subject twice daily at a dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, or 75 mg.

[0209] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, comprising administering to the subject a daily dose of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0210] In another aspect, the disclosure relates to Compound 1 for use in a method for treating or lessening the severity of pain in a subject, comprising administering to the subject a daily dose of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0211] In another aspect, the disclosure relates to Compound 1 for use in a method for treating or lessening the severity of pain in a subject, comprising administering to the subject a daily dose of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0212] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, comprising administering to the subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg of Compound 1. In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, comprising administering to the subject twice daily at a dose of 10 mg, about 30 mg, or about 50 mg of Compound 1.

[0213] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the method comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0214] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0215] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0216] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of intestinal pain in a subject, according to the methods described herein (including any embodiment thereof).

[0217] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0218] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, the method comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0219] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to the subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0220] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0221] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, according to the methods described herein (including any embodiment thereof).

[0222] In another aspect, the present disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0223] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of neuropathic pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0224] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0225] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0226] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, according to the methods described herein (including any embodiments thereof).

[0227] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of idiopathic small fiber neuropathy in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0228] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of idiopathic small fiber neuropathy in a subject, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0229] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of idiopathic small fiber neuropathy in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to the subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0230] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg on day 1, and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0231] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of diabetic peripheral neuropathy in a subject, according to the methods described herein (including any embodiment thereof).

[0232] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of diabetic peripheral neuropathy in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject once daily at a dose of about 23 mg, about 46 mg, about 50 mg, about 69 mg, or about 70 mg.

[0233] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of diabetic peripheral neuropathy in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg, about 30 mg, about 50 mg, or about 130 mg.

[0234] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of diabetic peripheral neuropathy in a subject, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof twice daily at a dose of about 10 mg, about 30 mg, about 50 mg, or about 130 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0235] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of diabetic peripheral neuropathy in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to the subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0236] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of diabetic peripheral neuropathy in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg on day 1, and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0237] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of musculoskeletal pain in a subject, according to the methods described herein (including any embodiments thereof).

[0238] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0239] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0240] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to the subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0241] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0242] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, according to the methods described herein (including any embodiments thereof).

[0243] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of osteoarthritis pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0244] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of osteoarthritis pain in a subject, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0245] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of osteoarthritis pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to the subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0246] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal osteoarthritis pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0247] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of acute pain in a subject, according to the methods described herein (including any embodiment thereof).

[0248] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0249] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of acute pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0250] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0251] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0252] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of inflammatory pain in a subject, according to the methods described herein (including any embodiment thereof).

[0253] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0254] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0255] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0256] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0257] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of cancer pain in a subject, according to the methods described herein (including any embodiments thereof).

[0258] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of cancer pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0259] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of cancer pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0260] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of cancer pain in a subject, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to the subject twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0261] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of cancer pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0262] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, according to the methods described herein (including any embodiments thereof).

[0263] In another aspect, the present disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of idiopathic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0264] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of idiopathic pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0265] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of idiopathic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to the subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0266] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of idiopathic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0267] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of postoperative pain in a subject, according to the methods described herein (including any embodiments thereof).

[0268] In another aspect, the present disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0269] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0270] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to the subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0271] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0272] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of visceral pain in a subject, according to the methods described herein (including any embodiments thereof).

[0273] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg.

[0274] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10 mg, about 30 mg, or about 50 mg for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0275] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to the subject twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0276] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily after day 1.

[0277] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration to a subject once daily at a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 23 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 60 mg.In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 70 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of about 125 mg.

[0278] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, once daily to a subject at a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 23 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 60 mg.In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 69 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 70 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 125 mg.

[0279] In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 23 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 60 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 69 mg.In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 70 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject once daily at a dose of about 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to the subject once daily at a dose of about 110 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to the subject once daily at a dose of about 125 mg of Compound 1.

[0280] In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to a subject once daily at a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to a subject once daily at a dose of 23 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 60 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to the subject once daily at a dose of 69 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to the subject once daily at a dose of 70 mg of Compound 1.In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject once daily at a dose of 125 mg.

[0281] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration to a subject at a total daily dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 23 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 60 mg.In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 69 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 70 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of about 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 125 mg.

[0282] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration to a subject at a total daily dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 23 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 60 mg.In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 69 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 70 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 125 mg.

[0283] In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to a subject at a total daily dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to a subject at a total daily dose of about 23 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 60 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 69 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 70 mg.In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of about 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject at a total daily dose of about 125 mg.

[0284] In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration to the subject at a total daily dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration to the subject at a total daily dose of 23 mg of Compound 1. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 46 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 60 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 69 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 70 mg.In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 75 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is formulated for administration to the subject at a total daily dose of 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method for treating or reducing the severity of pain in a subject, wherein Compound 1 is prepared for administration to the subject at a total daily dose of 125 mg.

[0285] In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration of Compound 1 at a dose of about 10 mg, about 15 mg, about 20 mg, about 23 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 69 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg once daily to a subject.

[0286] In another aspect, the disclosure relates to a composition comprising Compound 1 for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is formulated for administration of Compound 1 at a dose of 10 mg, 15 mg, 20 mg, 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 46 mg, 50 mg, 55 mg, 60 mg, 65 mg, 69 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg, or 150 mg once daily to a subject.

[0287] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of chronic pain in a subject, wherein the composition is formulated for administration to a subject once daily at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 140 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 45 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 50 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 60 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 70 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 75 mg.In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 90 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 100 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 110 mg. In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of chronic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject once daily at a dose of 125 mg.

[0288] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0289] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of pain in a subject, the composition being prepared for administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0290] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0291] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0292] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0293] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, the composition being prepared for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0294] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of intestinal pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0295] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0296] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0297] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject, the composition being prepared for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0298] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of neuropathic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0299] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of idiopathic small fiber neuropathy in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0300] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or lessening the severity of idiopathic small fiber neuropathy in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0301] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of small fiber neuropathy in a subject, the composition being prepared for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0302] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0303] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0304] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0305] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to a subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0306] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0307] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of osteoarthritis pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0308] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of osteoarthritis pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0309] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of osteoarthritis pain in a subject, the composition being prepared for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0310] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of osteoarthritis pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0311] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of acute pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0312] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of acute pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0313] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of acute pain in a subject, the composition being prepared for administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0314] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of acute pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0315] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0316] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0317] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, the composition being prepared for administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0318] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of inflammatory pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0319] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of cancer pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0320] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of cancer pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0321] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of cancer pain in a subject, the composition being prepared for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0322] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or reducing the severity of cancer pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0323] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of idiopathic pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0324] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of idiopathic pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0325] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of idiopathic pain in a subject, the composition being prepared for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0326] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of idiopathic pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0327] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0328] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0329] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, the composition being prepared for administration to the subject of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0330] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of postoperative pain in a subject, the composition being formulated for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0331] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0332] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, the composition being formulated for administration to a subject once daily at a dose of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 90 mg, about 100 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks, or between 1 and 6 weeks.

[0333] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, twice daily to a subject at a dose of about 10 mg (20 mg daily), about 30 mg (60 mg daily), or about 50 mg (100 mg daily).

[0334] In another aspect, the disclosure relates to a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, the composition being prepared for administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject at an initial dose of about 20 mg, about 60 mg, or about 100 mg and subsequent doses of about 10 mg, about 30 mg, or about 50 mg on day 1, and two doses of 10 mg, about 30 mg, or 50 mg daily thereafter.

[0335] Drug manufacturing In another aspect, the present disclosure relates to the use of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for treating or reducing the severity of pain in a subject, according to the methods described herein (including any embodiments thereof).

[0336] In yet another aspect, the disclosure provides use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0337] In yet another aspect, the disclosure provides use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0338] In yet another aspect, the disclosure provides a use of Compound 1, a pharmaceutically acceptable salt, or a pharmaceutical composition as described herein for the manufacture of a medicament for use in treating or reducing the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0339] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0340] In yet another aspect, the disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burnt stomatitis syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic neuropathy.

[0341] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain includes osteoarthritis pain.

[0342] In yet another aspect, the present invention provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or dental pain.

[0343] In yet another aspect, the present invention provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0344] In yet another aspect, the present invention provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain.

[0345] In yet another aspect, the present invention provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of idiopathic pain in a subject, wherein idiopathic pain includes rheumatoid arthritis pain.

[0346] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of pathological cough in a subject.

[0347] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of acute pain in a subject. In some aspects, the acute pain includes acute post-operative pain.

[0348] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject.

[0349] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of herniorrhaphy pain in a subject.

[0350] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of bunionectomy pain in a subject.

[0351] In yet another aspect, the present disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of abdominal pain in a subject.

[0352] In yet another aspect, the disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain includes visceral pain due to abdominoplasty.

[0353] In another aspect, the disclosure features Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0354] In yet another aspect, the disclosure provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0355] In another aspect, the present disclosure provides a method for treating acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, status epilepticus, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, glenoid pain, sciatic pain, sciatic nerve ... Provided is Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of muscle pain, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormalities of gastrointestinal motility.

[0356] In another aspect, the present disclosure provides a method for treating femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, genetic Conductive sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal drainage, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, complex regional pain syndrome, phantom pain, intractable pain, acute pain, acute post-operative pain, acute musculoskeletal pain, arthralgia, mechanical low back pain, neck pain, tendonitis, injury pain, exercise pain, acute visceral pain, nephritis, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction , hernia, chest pain, heart pain, pelvic pain, kidney stone pain, acute obstetric pain, labor pain, cesarean section pain, acute inflammatory, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, achromatopsia, venous pain, Guillain-Barre pain, painful leg and toe movements, Haglund's syndrome, red blood cells The present invention provides Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of hypertension pain, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

[0357] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or lessening the severity of trigeminal neuralgia, Botox-treated migraine, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbar plexopathy, intermittent pain from traumatic neuroma, or post-amputation pain in a subject.

[0358] Pharmaceutically acceptable salts, pharmaceutical compositions, dosage forms, and routes of administration pharmaceutically acceptable salts The methods described and claimed herein involve administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject. As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of Compound 1 includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, Compound 1, or an inhibitory active metabolite or residue thereof (e.g., a parent compound of a prodrug). As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0359] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid, salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, and salts formed using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxybenzoates, and the like. Salts derived from suitable bases include alkali metal, alkaline earth metal, and ammonium salts.Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0360] Pharmaceutical Composition In the methods described and claimed herein, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered in the form of a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0361] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" includes any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with Compound 1, or a pharmaceutically acceptable salt thereof, for example, by causing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, and potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salt, or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene polyoxypropylene block polymer, wool fat, sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate, powdered tragacanth, malt, gelatin, tartar Some exemplary materials which may act as pharmaceutically acceptable carriers include, but are not limited to, additives such as cocoa butter and suppository waxes, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol or polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, release agents, coating agents, sweeteners, flavors and fragrances, preservatives, and antioxidants, and the like.

[0362] Dosage form and route of administration The methods described and claimed herein can involve the administration of Compound 1 or a pharmaceutically acceptable salt thereof by any route of administration effective for treating or reducing the severity of one or more of the pain disorders listed herein. Compound 1 or a pharmaceutically acceptable salt thereof can be formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the term "dosage unit form" refers to a physically discrete unit of agent appropriate for the subject to be treated.

[0363] Compound 1, or a pharmaceutically acceptable salt thereof, can be administered to humans and other animals orally, rectally, parenterally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), bucally, as an oral or nasal spray, etc., depending on the condition being treated.

[0364] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to Compound 1 or its pharmaceutically acceptable salt, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0365] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0366] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0367] To prolong the therapeutic effect of Compound 1, it may be desirable to slow the absorption of the compound or its pharmaceutically acceptable salt from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The compound release rate can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0368] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing Compound 1 or a pharmaceutically acceptable salt thereof with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

[0369] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage form, Compound 1 or its pharmaceutically acceptable salt is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) moisture absorbent, such as glycerol, d) disintegrant, such as agar. They are mixed with agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0370] Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules, using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.They can optionally contain emulsifying agents, and can be of a composition that they release the active ingredient only, or in a certain part of the intestinal tract, optionally in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.

[0371] The active compound or salt may also be in microencapsulated form with one or more of the additives mentioned above.Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation technology.In these solid dosage forms, the active compound or salt may be mixed with at least one inert diluent, such as sucrose, lactose, or starch.These dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, dosage forms may also contain buffering agents.

[0372] Dosage forms for topical or transdermal administration of Compound 1 or its pharmaceutically acceptable salts include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0373] Spray-dried dispersions and tablets Spray drying converts liquid feed into a dry particulate form. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air to promote drying of the liquid droplets. For example, a liquid solution containing Compound 1, or a salt thereof, and at least one polymer can be sprayed into a current of warm filtered gas, which evaporates the solvent and carries the dried product to a collector. The evaporated solvent and spent gas can be removed from the collector and sent to a condenser to recover the solvent. For example, commercially available spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray dryers manufactured by Niro) (see US2004 / 0105820, US2003 / 0144257).

[0374] Spray drying techniques and methods can be found in Perry's Chemical Engineering Handbook, 6th Ed., R.H.Perry, D.W. Green & J.O. Maloney, eds.), McGraw-Hill book co. (1984) and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). All three references are incorporated herein by reference in their entirety.

[0375] An additional drying step may be required after spray drying to ensure solvent removal. Other drying techniques include, but are not limited to, tray drying, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying, or biconical vacuum drying (e.g., from about room temperature to about 200°C).

[0376] In some embodiments, the solvent used in spray drying is a volatile solvent. The volatile solvent can have, for example, a boiling point below 100° C. Mixtures of volatile solvents or mixtures of volatile and non-volatile solvents can also be used.

[0377] Exemplary solvents that may be tested include acetone, cyclohexane, dichloromethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HOAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, DCM, and toluene. Exemplary cosolvents include acetone / DMSO, acetone / DMF, acetone / water, MEK / water, THF / water, and dioxane / water. In two-solvent systems, the solvent may be present at about 0.1% to about 99.9%. In some embodiments, water is a co-solvent with acetone, where water is present at about 0.1% to about 15%, e.g., about 9% to about 11%, e.g., about 10%. In some embodiments, water is a co-solvent with MEK, where water is present at about 0.1% to about 15%, e.g., about 9% to about 11%, e.g., about 10%. In some embodiments, the solvent system comprises three solvents. In some embodiments, where amorphous Compound 1 is a component of a solid amorphous dispersion, the solvent dissolves both Compound 1 and at least one polymer. Suitable solvents include those described above, e.g., DCM, water, methanol, IPA, and mixtures thereof. In some embodiments, the solvent comprises DCM and methanol.

[0378] In some embodiments, the at least one polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof.

[0379] In some embodiments, at least one polymer is HPMCAS.

[0380] In some embodiments, at least one polymer is a polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer. Commercially available examples of polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer include SOLUPLUS®.

[0381] In some embodiments, at least one polymer is a compound of Formula I, where n is about 13, m is about 30, and I is about 57. The weight average molecular weight, as determined by gel permeation chromatography, is about 118,000 g / mol. [ka]

[0382] In some embodiments, the solid dispersions disclosed herein comprise at least one polymer and Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 20% to about 50% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 20% to about 45% by weight, or about 20% to about 40% by weight, or about 20% to about 35% by weight, or about 20% to about 30% by weight, or about 22% to about 28% by weight, or about 23% by weight, or about 24% by weight, or about 25% by weight, or about 26% by weight, or about 27% by weight, or about 28% by weight, or about 29% by weight, or about 30% by weight of Compound 1 or a pharmaceutically acceptable salt thereof.

[0383] In some embodiments, the solid dispersion comprises 5% to 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 5% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 10% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 15% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 20% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments, the solid dispersion comprises 5% to 35% by weight of Compound 1. In some embodiments, the solid dispersion comprises 5% to 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 10% to 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 15% to 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 20% to 30% by weight of Compound 1.

[0385] In some embodiments, the solid dispersion comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, or about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 20% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 25% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof.

[0386] In some embodiments, the solid dispersion comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, or about 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 20% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 25% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 35% by weight of Compound 1.

[0387] In some embodiments, the solid dispersion comprises 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 20% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 25% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof.

[0388] In some embodiments, the solid dispersion comprises 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% by weight of Compound 1. In some embodiments, the solid dispersion comprises 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 20% by weight of Compound 1. In some embodiments, the solid dispersion comprises 25% by weight of Compound 1. In some embodiments, the solid dispersion comprises 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 35% by weight of Compound 1.

[0389] In some embodiments, the solid dispersion comprises about 50% to about 80% by weight of polymer, or about 55% to about 80% by weight, or about 60% to about 80% by weight, or about 65% to about 80% by weight, or about 70% to about 80% by weight, or about 71% by weight, or about 72% by weight, or about 73% by weight, or about 74% by weight, or about 75% by weight, or about 76% by weight, or about 77% by weight, or about 78% by weight, or about 79% by weight, or about 80% by weight of polymer.

[0390] In some embodiments, the solid dispersion comprises about 65% to about 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 70% to about 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 70% to about 90% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 70% to about 85% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 70% to about 80% by weight of at least one polymer.

[0391] In some embodiments, the solid dispersion comprises 65% to 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 70% to 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 70% to 90% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 70% to 85% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 70% to 80% by weight of at least one polymer.

[0392] In some embodiments, the solid dispersion comprises about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, or about 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 65% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 70% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 80% by weight of at least one polymer.

[0393] In some embodiments, the solid dispersion comprises 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 65% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 70% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 80% by weight of at least one polymer.

[0394] In some embodiments, the solid dispersion comprises about 65% to about 95% by weight of at least one polymer and about 5% to about 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 70% to about 95% by weight of at least one polymer and about 5% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 70% to about 90% by weight of at least one polymer and about 10% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 70% to about 85% by weight of at least one polymer and about 15% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 70% to about 80% by weight of at least one polymer and about 20% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof.

[0395] In some embodiments, the solid dispersion comprises about 65% to about 95% by weight of at least one polymer and about 5% to about 35% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 70% to about 95% by weight of at least one polymer and about 5% to about 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 70% to about 90% by weight of at least one polymer and about 10% to about 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 70% to about 85% by weight of at least one polymer and about 15% to about 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises about 70% to about 80% by weight of at least one polymer and about 20% to about 30% by weight of Compound 1.

[0396] In some embodiments, the solid dispersion comprises 65% to 95% by weight of at least one polymer and 5% to 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70% to 95% by weight of at least one polymer and 5% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70% to 90% by weight of at least one polymer and 10% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70% to 85% by weight of at least one polymer and 15% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70% to 80% by weight of at least one polymer and 20% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof.

[0397] In some embodiments, the solid dispersion comprises 65% to 95% by weight of at least one polymer and 5% to 35% by weight of Compound 1. In some embodiments, the solid dispersion comprises 70% to 95% by weight of at least one polymer and 5% to 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 70% to 90% by weight of at least one polymer and 10% to 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 70% to 85% by weight of at least one polymer and 15% to 30% by weight of Compound 1. In some embodiments, the solid dispersion comprises 70% to 80% by weight of at least one polymer and 20% to 30% by weight of Compound 1.

[0398] In some embodiments, the solid dispersion comprises about 65% to about 95% by weight of at least one polymer and about 5% to about 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 95% by weight of at least one polymer and about 5% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 90% by weight of at least one polymer and about 10% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 85% by weight of at least one polymer and about 15% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 80% by weight of at least one polymer and about 20% to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous.

[0399] In some embodiments, the solid dispersion comprises about 65% to about 95% by weight of at least one polymer and about 5% to about 35% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 95% by weight of at least one polymer and about 5% to about 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 90% by weight of at least one polymer and about 10% to about 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 85% by weight of at least one polymer and about 15% to about 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises about 70% to about 80% by weight of at least one polymer and about 20% to about 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous.

[0400] In some embodiments, the solid dispersion comprises 65% to 95% by weight of at least one polymer and 5% to 35% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 95% by weight of at least one polymer and 5% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 90% by weight of at least one polymer and 10% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 85% by weight of at least one polymer and 15% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 80% by weight of at least one polymer and 20% to 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous.

[0401] In some embodiments, the solid dispersion comprises 65% to 95% by weight of at least one polymer and 5% to 35% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 95% by weight of at least one polymer and 5% to 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 90% by weight of at least one polymer and 10% to 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 85% by weight of at least one polymer and 15% to 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70% to 80% by weight of at least one polymer and 20% to 30% by weight of Compound 1, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous.

[0402] In some embodiments, the solid dispersion comprises about 25% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, and about 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 25% by weight of Compound 1 and about 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 25% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, and 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 25% by weight of Compound 1 and 75% by weight of at least one polymer.

[0403] In some embodiments, the solid dispersion comprises about 25% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, and about 75% by weight of at least one polymer, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises about 25% by weight of Compound 1 and about 75% by weight of at least one polymer, wherein the at least one polymer is selected from HPMCAS and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and Compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 25% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, and 75% by weight of at least one polymer, wherein the at least one polymer is selected from HPMCAS and polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, and Compound 1, or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some embodiments, the solid dispersion comprises 25% by weight of Compound 1 and 75% by weight of at least one polymer, wherein the at least one polymer is selected from HPMCAS and polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, and Compound 1 is substantially amorphous.

[0404] In some embodiments, Compound 1 in the solid dispersion is substantially amorphous. In some embodiments, Compound 1 in the solid dispersion is amorphous.

[0405] A method for preparing a spray-dried dispersion comprising Compound 1 or a pharmaceutically acceptable salt thereof is provided, the method comprising mixing Compound 1 or a pharmaceutically acceptable salt thereof in a solvent (or mixture of solvents) with at least one polymer.

[0406] The solvent can be any solvent described above, for example, in some embodiments, the solvent comprises a mixture of DCM and methanol.

[0407] In one embodiment, the method further comprises filtering the mixture before extruding it through the nozzle. In one embodiment, the method further comprises applying heat to the mixture as it enters the nozzle. In one embodiment, the nozzle comprises an inlet and an outlet, the inlet being heated to a temperature above the boiling point of the solvent. It is understood that in certain embodiments, the temperature may be below the boiling point of the solvent, for example, under high pressure conditions.

[0408] In one embodiment, the spray dryer is heated to a temperature of about 40°C to about 150°C. In one embodiment, the spray dryer is heated to a temperature of about 40°C to about 60°C, or about 45°C to about 55°C, or about 48°C. In one embodiment, the mixture is forced through a nozzle by pressurized gas. In one embodiment, the pressurized gas comprises molecular nitrogen. At the nozzle, the gas flow can be about 4 kg / hr to about 5 kg / hr.

[0409] In some embodiments, provided herein is a pharmaceutical composition comprising the solid dispersion disclosed herein. In some embodiments, the pharmaceutical composition may comprise one or more additives. Examples of additives include, but are not limited to, fillers, disintegrants, and lubricants.

[0410] Examples of fillers include, but are not limited to, microcrystalline cellulose, lactose monohydrate, mannitol, and mixtures thereof. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler comprises lactose monohydrate. In some embodiments, the filler comprises mannitol. In some embodiments, the filler comprises a mixture of microcrystalline cellulose and lactose monohydrate. In some embodiments, the filler comprises microcrystalline cellulose, and the microcrystalline cellulose is Avicel PhH101. In some embodiments, the filler comprises microcrystalline cellulose, and the microcrystalline cellulose is Avicel PH102. In some embodiments, the filler comprises microcrystalline cellulose, and the microcrystalline cellulose is a combination of Avicel PH101 and Avicel PH102.

[0411] Examples of suitable disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, and mixtures thereof. In some embodiments, the disintegrant comprises croscarmellose sodium. In some embodiments, the disintegrant comprises crospovidone.

[0412] Examples of suitable lubricants include, but are not limited to, sodium stearyl fumarate, magnesium stearate, and mixtures thereof. In some embodiments, the lubricant comprises sodium stearyl fumarate. In some embodiments, the lubricant comprises magnesium stearate.

[0413] In some embodiments, the pharmaceutical composition comprises Compound 1 or a salt thereof, at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant. In some embodiments, the filler comprises microcrystalline cellulose and lactose monohydrate, the disintegrant comprises croscarmellose sodium, and the lubricant comprises sodium stearyl fumarate.

[0414] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising about 72.5% by weight of at least one filler, about 4.5% by weight of at least one disintegrant, and about 3% by weight of at least one lubricant.

[0415] In some embodiments, the pharmaceutical composition comprises about 1 to about 50 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 1 to about 45 mg, or about 1 to about 40 mg, or about 1 to about 35 mg, or about 5 to about 40 mg, or about 5 to about 35 mg, or about 5 to about 30 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 40 mg, or about 50 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 10 mg of Compound 1.

[0416] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60% by weight of a spray-dried dispersion of Compound 1, about 35 to about 55% by weight of at least one filler, about 1 to about 6% by weight of at least one disintegrant, and about 0.5 to about 2% by weight of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60% by weight of a spray-dried dispersion of Compound 1, about 35 to about 55% by weight of at least one filler, about 1 to about 6% by weight of at least one disintegrant, and about 0.5 to about 2% by weight of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 50% by weight of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 wt% spray-dried dispersion of Compound 1, about 35 to about 55 wt% of at least one filler, about 1 to about 6 wt% of at least one disintegrant, about 0.5 to about 2 wt% of at least one lubricant, and about 2 to about 4.5 wt% of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 wt% spray-dried dispersion of Compound 1, about 35 to about 55 wt% of at least one filler, about 1 to about 6 wt% of at least one disintegrant, about 0.5 to about 2 wt% of at least one lubricant, and about 2 to about 4.5 wt% of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 50 wt% of Compound 1.

[0417] In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60 wt% spray-dried dispersion of Compound 1, 35-55 wt% of at least one filler, 1-6 wt% of at least one disintegrant, and 0.5-2 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60 wt% spray-dried dispersion of Compound 1, 35-55 wt% of at least one filler, 1-6 wt% of at least one disintegrant, and 0.5-2 wt% of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 50 wt% of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60 wt% spray-dried dispersion of Compound 1, 35-55 wt% of at least one filler, 1-6 wt% of at least one disintegrant, 0.5-2 wt% of at least one lubricant, and 2-4.5 wt% of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60 wt% spray-dried dispersion of Compound 1, 35-55 wt% of at least one filler, 1-6 wt% of at least one disintegrant, 0.5-2 wt% of at least one lubricant, and 2-4.5 wt% of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 50 wt% of Compound 1.

[0418] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60% by weight of a spray-dried dispersion of Compound 1, about 35 to about 55% by weight of microcrystalline cellulose, about 1 to about 6% by weight of croscarmellose sodium, and about 0.5 to about 2% by weight of magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60% by weight of a spray-dried dispersion of Compound 1, about 35 to about 55% by weight of microcrystalline cellulose, about 1 to about 6% by weight of croscarmellose sodium, and about 0.5 to about 2% by weight of magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50% by weight of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 wt% spray-dried dispersion of Compound 1, about 35 to about 55 wt% microcrystalline cellulose, about 1 to about 6 wt% croscarmellose sodium, about 0.5 to about 2 wt% magnesium stearate, and about 2 to about 4.5 wt% Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 wt% spray-dried dispersion of Compound 1, about 35 to about 55 wt% microcrystalline cellulose, about 1 to about 6 wt% croscarmellose sodium, about 0.5 to about 2 wt% magnesium stearate, and about 2 to about 4.5 wt% Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50 wt% Compound 1.

[0419] In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60% by weight of a spray-dried dispersion of Compound 1, 35-55% by weight of microcrystalline cellulose, 1-6% by weight of croscarmellose sodium, and 0.5-2% by weight of magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60% by weight of a spray-dried dispersion of Compound 1, 35-55% by weight of microcrystalline cellulose, 1-6% by weight of croscarmellose sodium, and 0.5-2% by weight of magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50% by weight of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60% by weight of a spray-dried dispersion of Compound 1, 35-55% by weight of microcrystalline cellulose, 1-6% by weight of croscarmellose sodium, 0.5-2% by weight of magnesium stearate, and 2-4.5% by weight of Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40-60% by weight of a spray-dried dispersion of Compound 1, 35-55% by weight of microcrystalline cellulose, 1-6% by weight of croscarmellose sodium, 0.5-2% by weight of magnesium stearate, and 2-4.5% by weight of Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50% by weight of Compound 1.

[0420] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% of at least one filler, about 1.5 to about 4 wt% of at least one disintegrant, and about 0.75 to about 1.5 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% of at least one filler, about 1.5 to about 4 wt% of at least one disintegrant, and about 0.75 to about 1.5 wt% of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 35 wt% of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% of at least one filler, about 1.5 to about 4 wt% of at least one disintegrant, about 0.75 to about 1.5 wt% of at least one lubricant, and about 2.5 to about 3.5 wt% of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% of at least one filler, about 1.5 to about 4 wt% of at least one disintegrant, about 0.75 to about 1.5 wt% of at least one lubricant, and about 2.5 to about 3.5 wt% of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 35 wt% of Compound 1.

[0421] In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55 wt% spray-dried dispersion of Compound 1, 40-50 wt% of at least one filler, 1.5-4 wt% of at least one disintegrant, and 0.75-1.5 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55 wt% spray-dried dispersion of Compound 1, 40-50 wt% of at least one filler, 1.5-4 wt% of at least one disintegrant, and 0.75-1.5 wt% of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 35 wt% of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55 wt% spray-dried dispersion of Compound 1, 40-50 wt% of at least one filler, 1.5-4 wt% of at least one disintegrant, 0.75-1.5 wt% of at least one lubricant, and 2.5-3.5 wt% of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55 wt% spray-dried dispersion of Compound 1, 40-50 wt% of at least one filler, 1.5-4 wt% of at least one disintegrant, 0.75-1.5 wt% of at least one lubricant, and 2.5-3.5 wt% of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 35 wt% of Compound 1.

[0422] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% microcrystalline cellulose, about 1.5 to about 4 wt% croscarmellose sodium, and about 0.75 to about 1.5 wt% magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% microcrystalline cellulose, about 1.5 to about 4 wt% croscarmellose sodium, and about 0.75 to about 1.5 wt% magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35 wt% Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% microcrystalline cellulose, about 1.5 to about 4 wt% croscarmellose sodium, about 0.75 to about 1.5 wt% magnesium stearate, and about 2.5 to about 3.5 wt% Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 wt% spray-dried dispersion of Compound 1, about 40 to about 50 wt% microcrystalline cellulose, about 1.5 to about 4 wt% croscarmellose sodium, about 0.75 to about 1.5 wt% magnesium stearate, and about 2.5 to about 3.5 wt% Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35 wt% Compound 1.

[0423] In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55% by weight of a spray-dried dispersion of Compound 1, 40-50% by weight of microcrystalline cellulose, 1.5-4% by weight of croscarmellose sodium, and 0.75-1.5% by weight of magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55% by weight of a spray-dried dispersion of Compound 1, 40-50% by weight of microcrystalline cellulose, 1.5-4% by weight of croscarmellose sodium, and 0.75-1.5% by weight of magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35% by weight of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55% by weight of a spray-dried dispersion of Compound 1, 40-50% by weight of microcrystalline cellulose, 1.5-4% by weight of croscarmellose sodium, 0.75-1.5% by weight of magnesium stearate, and 2.5-3.5% by weight of Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45-55% by weight of a spray-dried dispersion of Compound 1, 40-50% by weight of microcrystalline cellulose, 1.5-4% by weight of croscarmellose sodium, 0.75-1.5% by weight of magnesium stearate, and 2.5-3.5% by weight of Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35% by weight of Compound 1.

[0424] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 wt% spray-dried dispersion of Compound 1, about 42.5 to about 47.5 wt% of at least one filler, about 2.5 to about 3.5 wt% of at least one disintegrant, and about 0.75 to about 1.25 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 wt% spray-dried dispersion of Compound 1, about 42.5 to about 47.5 wt% of at least one filler, about 2.5 to about 3.5 wt% of at least one disintegrant, and about 0.75 to about 1.25 wt% of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 30 wt% of Compound 1. Disclosed herein, in some embodiments, is a pharmaceutical composition comprising about 47.5 to about 52.5% by weight of Compound 1 spray-dried dispersion, about 42.5 to about 47.5% by weight of at least one filler, about 2.5 to about 3.5% by weight of at least one disintegrant, about 0.75 to about 1.25% by weight of at least one lubricant, and about 2.75 to about 3.25% by weight of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 wt% spray-dried dispersion of Compound 1, about 42.5 to about 47.5 wt% of at least one filler, about 2.5 to about 3.5 wt% of at least one disintegrant, about 0.75 to about 1.25 wt% of at least one lubricant, and about 2.75 to about 3.25 wt% of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 30 wt% of Compound 1.

[0425] In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-47.5 wt% of at least one filler, 2.5-3.5 wt% of at least one disintegrant, and 0.75-1.25 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-47.5 wt% of at least one filler, 2.5-3.5 wt% of at least one disintegrant, and 0.75-1.25 wt% of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 30 wt% of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-47.5 wt% of at least one filler, 2.5-3.5 wt% of at least one disintegrant, 0.75-1.25 wt% of at least one lubricant, and 2.75-3.25 wt% of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-47.5 wt% of at least one filler, 2.5-3.5 wt% of at least one disintegrant, 0.75-1.25 wt% of at least one lubricant, and 2.75-3.25 wt% of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 20 to about 30 wt% of Compound 1.

[0426] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 wt% spray-dried dispersion of Compound 1, about 42.5 to about 47.5 wt% microcrystalline cellulose, about 2.5 to about 3.5 wt% croscarmellose sodium, and about 0.75 to about 1.25 wt% magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 wt% spray-dried dispersion of Compound 1, about 42.5 to about 47.5 wt% microcrystalline cellulose, about 2.5 to about 3.5 wt% croscarmellose sodium, and about 0.75 to about 1.25 wt% magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 wt% Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 wt% spray-dried dispersion of Compound 1, about 42.5 to about 47.5 wt% microcrystalline cellulose, about 2.5 to about 3.5 wt% croscarmellose sodium, about 0.75 to about 1.25 wt% magnesium stearate, and about 2.75 to about 3.25 wt% Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 wt% spray-dried dispersion of Compound 1, about 42.5 to about 47.5 wt% microcrystalline cellulose, about 2.5 to about 3.5 wt% croscarmellose sodium, about 0.75 to about 1.25 wt% magnesium stearate, and about 2.75 to about 3.25 wt% Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 wt% Compound 1.

[0427] In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-47.5 wt% microcrystalline cellulose, 2.5-3.5 wt% croscarmellose sodium, and 0.75-1.25 wt% magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-47.5 wt% microcrystalline cellulose, 2.5-3.5 wt% croscarmellose sodium, and 0.75-1.25 wt% magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 wt% Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-52.5 wt% microcrystalline cellulose, 2.5-3.5 wt% croscarmellose sodium, 0.75-1.25 wt% magnesium stearate, and 2.75-3.25 wt% Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5-52.5 wt% spray-dried dispersion of Compound 1, 42.5-47.5 wt% microcrystalline cellulose, 2.5-3.5 wt% croscarmellose sodium, 0.75-1.25 wt% magnesium stearate, and 2.75-3.25 wt% Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 wt% Compound 1.

[0428] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5 wt% spray-dried dispersion of Compound 1, about 44.7 wt% of at least one filler, about 2.9 wt% of at least one disintegrant, and about 1 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5 wt% spray-dried dispersion of Compound 1, about 44.7 wt% of at least one filler, about 2.9 wt% of at least one disintegrant, and about 1 wt% of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 25 wt% of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a spray-dried dispersion of Compound 1, about 44.7% by weight of at least one filler, about 2.9% by weight of at least one disintegrant, about 1% by weight of at least one lubricant, and about 2.9% by weight of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and about 25% by weight of Compound 1.

[0429] In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% spray-dried dispersion of Compound 1, 44.7 wt% of at least one filler, 2.9 wt% of at least one disintegrant, and 1 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% spray-dried dispersion of Compound 1, 44.7 wt% of at least one filler, 2.9 wt% of at least one disintegrant, and 1 wt% of at least one lubricant, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and 25 wt% of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% spray-dried dispersion of Compound 1, 44.7 wt% of at least one filler, 2.9 wt% of at least one disintegrant, 1 wt% of at least one lubricant, and 2.9 wt% of at least one coating, wherein the spray-dried dispersion of Compound 1 comprises at least one polymer and 25 wt% of Compound 1.

[0430] In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a spray-dried dispersion of Compound 1, about 44.7% by weight of microcrystalline cellulose, about 2.9% by weight of croscarmellose sodium, and about 1% by weight of magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a spray-dried dispersion of Compound 1, about 44.7% by weight of microcrystalline cellulose, about 2.9% by weight of croscarmellose sodium, and about 1% by weight of magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 25% by weight of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a spray-dried dispersion of Compound 1, about 44.7% by weight of microcrystalline cellulose, about 2.9% by weight of croscarmellose sodium, about 1% by weight of magnesium stearate, and about 2.9% by weight of Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and about 25% by weight of Compound 1.

[0431] In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% spray-dried dispersion of Compound 1, 44.7 wt% microcrystalline cellulose, 2.9 wt% croscarmellose sodium, and 1 wt% magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% spray-dried dispersion of Compound 1, 44.7 wt% microcrystalline cellulose, 2.9 wt% croscarmellose sodium, and 1 wt% of at least one magnesium stearate, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and 25 wt% Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5% by weight spray-dried dispersion of Compound 1, 44.7% by weight microcrystalline cellulose, 2.9% by weight croscarmellose sodium, 1% by weight magnesium stearate, and 2.9% by weight Opadry blue, wherein the spray-dried dispersion of Compound 1 comprises hydroxypropyl methylcellulose acetate succinate and 25% by weight Compound 1.

[0432] In some embodiments, the pharmaceutical compositions described herein can be formulated into tablets. In some embodiments, the tablets comprise Compound 1, or a pharmaceutically acceptable salt thereof, a polymer, a filler, a lubricant, and a disintegrant.

[0433] In some embodiments, the tablet comprises a polymer selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof.

[0434] In some embodiments, the tablet comprises HPMCAS.

[0435] In some embodiments, the tablet comprises about 72.5% by weight of at least one filler, about 4.5% by weight of at least one disintegrant, and about 3% by weight of at least one lubricant.

[0436] In some embodiments, the tablet contains about 1 to about 50 mg of Compound 1. In some embodiments, the tablet contains about 1 to about 45 mg, or about 1 to about 40 mg, or about 1 to about 35 mg, or about 5 to about 40 mg, or about 5 to about 35 mg, or about 5 to about 30 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 40 mg, or about 50 mg of Compound 1. In some embodiments, the tablet contains about 10 mg of Compound 1.

[0437] Additional medications It will also be understood that Compound 1, salts, and pharmaceutically acceptable compositions of Compound 1 can be used in combination therapy, i.e., the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired therapies or medical treatments. The specific combination of therapies (therapies or treatments) used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or treatments and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve the desired effect for the same disorder (e.g., a compound of the present invention can be administered simultaneously with another agent used to treat the same disorder) or can achieve a different effect (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known to be appropriate for the disease or condition being treated. For example, exemplary additional therapeutic agents include non-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin, naphthyl alkanes, e.g., nabumetone, oxicams such as piroxicam, para-aminophenol derivatives, e.g., acetaminophen, propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, salicylates, e.g., aspirin, choline magnesium trisalicylate, diflunisal, fenamates such as meclofenamic acid, mefenamic acid, and pyrazoles such as phenylbutazone, or opioid (anesthetic) agonists (co- Examples of suitable analgesic agents include, but are not limited to, morphine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butaphanol, dezocine, nalbuphine, and pentazocine. Additionally, non-drug analgesic approaches can be used in conjunction with the administration of one or more compounds of the present invention. For example, anesthetic (spinal injection, nerve blockade), neurosurgery (neurolysis of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy (physical therapy, orthotic devices, diathermy), or psychology (cognitive-pulmonary, biofeedback, or behavioral) approaches can also be used.Additional suitable therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are incorporated herein by reference.

[0438] In another embodiment, the additional suitable therapeutic agent is selected from the following: (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levorphanol, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butaphanol, nalbuphine, pentazocine, or difelikefalin; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flurbiprofen, ibuprofen (including, but not limited to, intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including, but not limited to, ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac, (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methoherbital, methohexital, pentobarbital, phenobarbital, (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepatate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclidine; (6) sedatives, such as glutethimide, meprobamate, methaqualone, or dichlorphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination preparation of morphine and dextromethorphan, topiramate, NR2B antagonists including neramexane or perzinfotel, such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone, (9) alpha-adrenergic agents such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline; (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline, (11) anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproic acid; (12) Tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazocino[2,lg][l,7]-naphthyridine-6-13-dione (TAK-637), 5-[(2R,3S )-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), a precipitating agent, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S), (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) Coal tar analgesics, especially paracetamol, (16) neuroleptics such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine seruindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindole, epribanaserin, osanetant, rimonabant, meclinabinant, Miraxion®, or sarizotan; (17) Vanilloid receptor agonists (e.g., resinferatoxin or siboamide) or antagonists (e.g., capsazepine, GRC-15300), (18) beta-adrenergic receptor antagonists such as propranolol; (19) Local anesthetics such as mexiletine (20) Corticosteroids such as dexamethasone (21) 5-HT receptor agonists or antagonists, in particular 5-HT receptor antagonists such as eletriptan, sumatriptan, naratriptan, zolitriptan, or rizatriptan. 1B / 1D agonist, (22) 5-HT such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidineethanol (MDL-100907) 2A receptor antagonists, (23) cholinergic (nicotinic) analgesics such as isoprenicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine; (24) Tramadol®, tramadol ER (Ultram ER®), IV tramadol, tapentazole ER (Nucynta®), (25) 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b]indole-l,4-di on (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazin-4-one (wardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7 -one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3- PDE5 inhibitors such as]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; (26) Gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)- alpha-2-delta ligands such as 6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; (27) Cannabinoids such as KHK-6188 (28) Metabolic glutamate subtype 1 receptor (mGluRl) antagonists, (29) Serotonin reuptake inhibitors such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericamine, and trazodone; (30) noradrenaline (norepinephrine) reuptake inhibitors such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivaran®), in particular selective noradrenaline reuptake inhibitors such as reboxetine, in particular (S,S)-reboxetine; (31) Dual serotonin-noradrenaline reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) S-[2-[(l-Iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-Iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-Iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptanoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-S-chloro-S-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile an inducible nitric oxide synthase (iNOS) inhibitor such as (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide; (33) Acetylcholinesterase inhibitors such as donepezil (34) Prostaglandin E2 subtype 4 (EP4) antagonists such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid, (35) Leukotriene B4 antagonists such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870; (36) 5-lipoxygenase inhibitors such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504); (37) Sodium channel blockers such as lidocaine, lidocaine + tetracaine cream (ZRS-201) or eslicarbazepine acetate, (38)XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Bixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112, and WO2011 / 140425 (US2011 / 306607), WO2012 / 106499 (US2012 / 196869), WO2012 / 112743 (US2012245136), WO2012 / 125613 (US2012 / 264749), WO2012 / 116440 (US2014 / 187533), WO2011 / 026240 (US2012 / 220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), WO2020 / 092667 (US2020 / 140411), or CN111217776 (the entire contents of each application are incorporated herein by reference). V 1.7 blockers, (38a) (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4 -dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,...

Claims

1. A composition for use in a method of treating pain or reducing its severity in a subject, comprising Compound 1, 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein the composition is administered to the subject in an amount of about 10 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof per day, and optionally in an amount of about 20 mg to 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof per day. A composition for use, characterized in that it is administered.

2. The composition according to claim 1, wherein the composition is administered in an amount of about 10 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof on the first day, and optionally in an amount of about 20 mg to about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof on the first day, and optionally in an amount of about 20 mg to about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof on the first day, and optionally in an amount of about 60 mg to about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof on the first day, and optionally in an amount of about 100 mg to about 150 mg of Compound 1 or a pharmaceutically acceptable salt thereof on the first day, and optionally after the first day, in an amount of about 5 mg to about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof per day. A composition for use as described in.

3. The composition according to claim 1, wherein the composition is administered in a twice-daily dose, or is administered in a first dose and subsequent doses on the first day, the first dose being larger than the subsequent dose, and optionally the subsequent dose being administered 12 hours after the first dose. A composition for use as described in.

4. The first dose is about 20 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally the first dose is about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof, or optionally the first dose is about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof, or the first dose is about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof. A composition for use as described in claim 3.

5. The subsequent dose is about 10 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof, or the subsequent dose is about 10 mg to about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof, or the subsequent dose is about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof, or the subsequent dose is about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof, or the subsequent dose is about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof, the composition for use according to claim 4.

6. The composition is administered at a dose twice a day after the first day, or at a dose of about 10 mg to 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day after the first day, or at a dose of about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day after the first day, or at a dose of about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day after the first day, or at a dose of about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day after the first day, the composition for use according to claim 5, characterized in that.

7. The composition for use according to claim 6, wherein 12 hours elapse between each administration of the two doses.

8. The composition is an initial dose of 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof, a subsequent dose of 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof 12 hours after the initial dose, and a dose of 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof every 12 hours thereafter, the composition for use according to claim 1, characterized in that.

9. The composition for use according to claim 1, characterized in that the composition is administered in an amount of 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof every 12 hours.

10. The composition for use according to claim 1, characterized in that the composition is administered at a once-daily dose.

11. The composition for use according to claim 10, characterized in that the composition is administered at a once-daily dose of 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

12. The composition for use according to claim 1, characterized in that the composition is administered for at least one week, or at least six weeks, or at least two days.

13. The composition for use according to claim 1, characterized in that the composition is administered orally or intravenously.

14. The composition for use according to claim 1, wherein the pain includes chronic pain, intestinal pain, neuropathic pain, postherpetic neuralgia if necessary, small fiber neuropathy, idiopathic small fiber neuropathy, diabetic neuropathy, or diabetic peripheral neuropathy, musculoskeletal pain, osteoarthritis pain if necessary, acute pain, acute postoperative pain if necessary, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, banionectomy pain if necessary, abdominoplasty pain, or hernia suture pain, or visceral pain, and if necessary, the pain is associated with multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

15. The composition for use according to claim 1, wherein the pain includes trigeminal neuralgia, migraine treated with Botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus disorder, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral nerve neuropathy, meralgia paresthetica, entrapment neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, intermittent pain of traumatic neuroma, or post-amputation pain.

16. The composition for use according to claim 1, wherein the subject experienced a baseline pain score of at least 4 on an 11-point numerical pain assessment scale prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof.

17. The composition for use according to claim 1, wherein the subject experienced a moderate or severe baseline pain level on a verbal categorical assessment scale prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof.

18. The composition for use according to claim 1, wherein Compound 1 is in non-salt form.

19. The composition for use according to claim 1, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after administration of the composition.

20. (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, and At least one polymer, and A solid dispersion comprising

21. Compound 1 or a pharmaceutically acceptable salt thereof, and the polymer is co-spray dried with a solvent, and optionally, the polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof, and optionally, the polymer is HPMCAS, The solid dispersion according to claim 20.

22. The solid dispersion is About 20% to about 50% by weight of Compound 1 or a pharmaceutically acceptable salt thereof, and about 50% to about 80% by weight of the polymer, Optionally about 25% by weight of Compound 1 or a pharmaceutically acceptable salt thereof, and Optionally about 75% by weight of the polymer, The solid dispersion according to claim 21, comprising

23. The solid dispersion according to claim 20, wherein Compound 1 is substantially amorphous.

24. A pharmaceutical composition comprising the solid dispersion according to claim 20, and optionally, the pharmaceutical composition is a tablet.

25. The pharmaceutical composition, wherein the pharmaceutical composition comprises a spray-dried dispersion containing 40 to 60% by weight of Compound 1 or a pharmaceutically acceptable salt thereof, 35 to 55% by weight of at least one filler, 1 to 6% by weight of at least one disintegrant, and 0.5 to 2% by weight of at least one lubricant. The pharmaceutical composition according to claim 24.

26. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition further comprises at least one filler, at least one lubricant, and at least one disintegrant.

27. The filler is selected from microcrystalline cellulose, lactose monohydrate, mannitol, and any combination thereof, Optionally, the disintegrant is selected from croscarmellose sodium, crospovidone, and any combination thereof, Optionally, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, and any combination thereof, Optionally, the filler comprises microcrystalline cellulose and lactose monohydrate, the disintegrant comprises croscarmellose sodium, and the lubricant comprises sodium stearyl fumarate. The pharmaceutical composition according to claim 25.

28. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition comprises from about 1 to about 50 mg, optionally about 10 mg, of Compound 1 or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition comprises 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition wherein a spray-dried dispersion of Compound 1 of 47.5 to 52.5% by weight; microcrystalline cellulose of 42.5 to 47.5% by weight; sodium croscarmellose of 2.5 to 3.5% by weight; and magnesium stearate of 0.75 to 1.25% by weight The pharmaceutical composition according to claim 24.

31. The pharmaceutical composition wherein a spray-dried dispersion comprising 200 mg of a 25% by weight Compound 1 and 75% by weight HPMCAS; 184 mg of microcrystalline cellulose; 12 mg of sodium croscarmellose; and 4 mg of magnesium stearate The pharmaceutical composition according to claim 30, which is a tablet.

32. The composition according to any one of claims 1 to 19 for use, wherein the composition is the pharmaceutical composition according to any one of claims 24 to 31.

33. The composition according to claim 1 for use, characterized in that the composition is administered in an amount of from about 50 mg to about 150 mg of Compound 1 or a pharmaceutically acceptable salt thereof on the first day.

34. The composition according to claim 1 for use, characterized in that the composition is administered in an amount of from about 20 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof on the first day.

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