WO2020219867A1

WO2020219867A1 - Pyridone amide co-crystal compositions for the treatment of pain

Info

Publication number: WO2020219867A1
Application number: PCT/US2020/029798
Authority: WO
Inventors: Mark Allen COSTELLO
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 2019-04-25
Filing date: 2020-04-24
Publication date: 2020-10-29

Abstract

Described herein is a pyridone amide sodium channel inhibitor 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, co-crystals thereof, pharmaceutical compositions thereof, and methods for manufacturing and administering the compositions for the treatment of various types of pain.

Description

PYRIDONE AMIDE CO-CRYSTAL COMPOSITIONS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application Serial No.62/838,546 filed April 25, 2019, the entire contents of which is incorporated herein by reference. TECHNICAL FIELD

[0001] Described herein is a pyridone amide sodium channel inhibitor 2-(4-fluoro-2- methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, co-crystals thereof, pharmaceutical compositions thereof, and methods for manufacturing and administering the compositions for the treatment of various types of pain. BACKGROUND

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless, there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves. Dieleman et al., Incidence rates and treatment of neuropathic pain conditions in the general population, Pain 137(3): 681-688 (2008). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve, and pain caused by a discrete nerve injury. The metabolic neuropathies include post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

[0003] Voltage-gated sodium channels (Na_Vs) play a critical role in pain signaling. Na_Vs are key biological mediators of electrical signaling, as they are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g., neurons, skeletal myocytes, and cardiac myocytes). The evidence for the role of these channels in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents all point to the central role of NaVs in pain sensation. Rush and Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels, Mol. Interv. 7(4): 192-195 (2007); England, Voltage-gated sodium channels: the search for subtype-selective analgesics, Expert Opin. Investig. Drugs 17(12): 1849-1864 (2008); Krafte and Bannon, Sodium channels and nociception: recent concepts and therapeutic opportunities, Curr. Opin. Pharmacol. 8(1): 50-56 (2008). NaVs are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g., neurons, skeletal myocytes, cardiac myocytes), and thus are critical for the initiation of signaling in those cells. Hille and Bertil, Ion Channels of Excitable Membranes, 3^rd ed. (Sinauer Associates, Inc., Sunderland, MA, 2001). Because of the role NaVs play in the initiation and propagation of neuronal signals, antagonists that reduce Na_V currents can prevent or reduce neural signaling and Na_V channels have long been considered likely targets to reduce pain in conditions where hyper-excitability is observed. Chahine et al., Voltage-gated sodium channels in neurological disorders, CNS Neurol. Disord. Drug Targets 7(2): 144-158 (2008). Several clinically useful analgesics have been identified as inhibitors of Na_V channels. The local anesthetic drugs such as lidocaine block pain by inhibiting NaV channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition. Soderpalm, Anticonvulsants: aspects of their mechanisms of action, Eur. J. Pain 6 (Suppl A): 3-9 (2002); Wang et al., Block of persistent late Na⁺ currents by antidepressant sertraline and paroxetine, J. Membr. Biol.222 (2):79- 90 (2008).

[0004] The NaVs form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms designated NaV1.1–NaV1.9. The tissue localizations of the nine isoforms vary greatly. Na_V1.4 is the primary sodium channel of skeletal muscle, and Na_V1.5 is primary sodium channel of cardiac myocytes. Navs 1.7, 1.8, and 1.9 are primarily localized to the peripheral nervous system, while NaVs 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior. Catterall et al., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage- gated sodium channels, Pharmacol. Rev.57(4): 397 (2005).

[0005] Immediately upon their discovery, Nav1.8 channels were identified as likely targets for analgesia. Akopian et al., A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons, Nature 379(6562): 257-262 (1996). Since then, NaV1.8 has been shown to be the most significant carrier of the sodium current that maintains action potential firing in small dorsal root ganglia (DRG) neurons. Blair and 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.22(23): 10277-10290 (2002). NaV1.8 is essential for spontaneous firing in damaged neurons, like those that drive neuropathic pain. Roza et al., The tetrodotoxin-resistant Na⁺ channel Na_V1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice, J. Physiol.550(Pt 3): 921-926 (2003); Jarvis et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat, Proc. Natl. Acad. Sci. USA 104(20): 8520-8525 (2007); Joshi et al., Involvement of the TTX-resistant sodium channel Na_V1.8 in inflammatory and neuropathic, but not post-operative, pain states, Pain 123(1-2): 75-82 (2006); Lai et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na_V1.8, Pain 95(1-2): 143-152 (2002); Dong et al., Small interfering RNA-mediated selective knockdown of Na_V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats, Neuroscience 146(2): 812-821 (2007); Huang et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves, Mol. Pain 4: 33 (2008); Black et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas, Ann. Neurol. 64(6): 644-653 (2008); Coward et al., Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states, Pain 85(1-2): 41-50 (2000); Yiangou et al., SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves, FEBS Lett.467(2-3): 249-252 (2000); Ruangsri et al., Relationship of axonal voltage-gated sodium channel 1.8 (Na_V1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats, J. Biol. Chem.286(46): 39836-39847 (2011). The small DRG neurons, where NaV1.8 is expressed, include the nociceptors critical for pain signaling. NaV1.8 is the primary channel that mediates large amplitude action potentials in small neurons of the dorsal root ganglia. Blair and 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.22(23): 10277- 10290 (2002). NaV1.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. Choi and Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study, J. Neurophysiol.106(6): 3173- 3184 (2011); Renganathan et al., Contribution of NaV1.8 sodium channels to action potential electrogenesis in DRG neurons, J. Neurophysiol. 86(2): 629-640 (2001); Roza et al., The tetrodotoxin-resistant Na⁺ channel Na_V1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice, J. Physiol. 550(Pt 3): 921-926 (2003). In depolarized or damaged DRG neurons, NaV1.8 appears to be the primary driver of hyper-excitability. Rush et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons, Proc. Natl. Acad. Sci. USA 103(21): 8245-8250 (2006). In some animal pain models, NaV1.8 mRNA expression levels have been shown to increase in the DRG. Sun et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats, Brain 135(2): 359-375 (2012); Strickland et al., Changes in the expression of Na_V1.7, Na_V1.8 and Na_V1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain, Eur. J. Pain 12(5): 564-72 (2008); Qiu et al., Increased expression of tetrodotoxin-resistant sodium channels Na_V1.8 and Na_V1.9 within dorsal root ganglia in a rat model of bone cancer pain, Neurosci. Lett.512(2): 61-6 (2012).

[0006] The primary drawback to some known NaV inhibitors is their poor therapeutic window, and this is likely a consequence of their lack of isoform selectivity. Since NaV1.8 is primarily restricted to the neurons that sense pain, selective Na_V1.8 blockers are unlikely to induce the adverse events common to non-selective NaV blockers. Accordingly, there remains a need to develop additional NaV channel modulators, and preferably those that are highly potent and selective for Na_V 1.8.

[0007] U.S. Patent Application Publication No. 2014/0213616 A1 discloses a pyridone amide compound useful as an inhibitor of NaV1.8 sodium channels and known by the chemical name 2- (4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide. SUMMARY

[0008] One embodiment described herein is a co-crystal comprising Compound 1 _[0009]

(1); and tartaric acid. In one aspect, Compound 1 and tartaric acid are present in a molar ratio of 2:1. In another aspect, the co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one peak selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 degrees 2 theta (2 q) ± 0.2, when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation. In another aspect, the co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peak positions selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 degrees 2 theta (2 q) ± 0.2, when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation. In another aspect, the co- crystal has an XRPD pattern substantially similar to the XRPD pattern of FIG.7. In another aspect, the co-crystal is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 146 °C (±2.0 °C) indicative of dehydration and an endothermic peak at 230 °C (±2.0 °C) indicative of the melting point. In another aspect, the co-crystal has a 1.07% mass loss from ambient temperature to 150 °C in a thermogravimetric analysis. In another aspect, the co-crystal is characterized by an infra-red (IR) spectrum comprising at least three peak positions selected from wavenumbers 1121, 1183, 1336, 1492, 1566, 1651, 1693, 1722, 1740, 3372, or 3338 cm^-1. In another aspect, the co-crystal is characterized by a UV spectrum comprising two maxima at approximately 204 nm and 260 nm. In another aspect, the co-crystal has a ¹H-NMR spectrum substantially similar to the NMR spectrum of FIG.2. In another aspect, the co-crystal has a ¹³C- NMR spectrum substantially similar to the NMR spectrum of FIG.3. In another aspect, the co- crystal is characterized by ¹H- and ¹³C-NMR chemical shifts shown in Table 4 and substantially similar to the NMR spectra of FIG. 2 or 3, respectively when acquired in deuterated dimethyl sulfoxide (DMSO-d6) at 500 MHz (¹H) and 125 MHz (¹³C). In another aspect, the co-crystal is characterized by the ¹⁹F-solid state NMR spectrum substantially similar to that of FIG. 4A; or having the peaks listed in Table 5; or the ¹³C-solid state NMR spectrum substantially similar to that of FIG.4B; or having the peaks listed in Table 6.

[0010] Another embodiment described herein is a drug substance comprising the Compound 1– tartaric acid co-crystal described herein.

[0011] Another embodiment described herein is a pharmaceutical composition comprising the Compound 1–tartaric acid co-crystal described herein and one or more pharmaceutically acceptable excipients. In one aspect, the composition comprises a tablet pharmaceutical composition. In another aspect, the Compound 1–tartaric acid co-crystal is micronized. In another aspect, the Compound 1–tartaric acid co-crystal has a median volume particle size, D(v,0.5) of about 1–10 mm, 1–5 mm, 1–3 mm, or 2–4 mm. In another aspect, the Compound 1–tartaric acid co- crystal has a median volume particle size, D(v,0.5) of about £ 10 mm, £ 5 mm, £ 4 mm, £ 3 mm, £ 2.5 mm, or £ 2.0 mm. In another aspect, the Compound 1–tartaric acid co-crystal has a median volume particle size, D(v,0.5) of about 2–4 mm. In another aspect, the pharmaceutically acceptable excipients comprise: (a) one or more fillers or diluents; (b) one or more disintegrants; and (c) one or more lubricants. In another aspect, the filler comprises one or more of lactose, lactose monohydrate, glucose, fructose, sucrose, sorbitol, mannitol, dicalcium phosphate dihydrate, cellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, crospovidone, or a combination thereof. In another aspect, the disintegrant comprises one or more of crospovidone, croscarmellose sodium, alginic acid, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof. In another aspect, the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, talc, glyceryl behenate, or a combination thereof. In another aspect, the composition further comprises one or more colorants, flavorings, additional fillers or diluents, additional disintegrants, additional lubricants, binders, glidants, coatings, or other pharmaceutically acceptable excipients. In another aspect, the filler comprises microcrystalline cellulose. In another aspect, the disintegrant comprises croscarmellose sodium. In another aspect, the lubricant comprises magnesium stearate. In another aspect, the composition comprises: (a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 30% to about 70% by mass of one or more fillers or diluents; (c) about 1% to about 10% by mass of one or more disintegrants; and (d) about 0.1% to about 5% by mass of one or more lubricants. In another aspect, the composition comprises: (a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 30% to about 70% by mass of microcrystalline cellulose; (c) about 1% to about 10% by mass of croscarmellose sodium; and (d) about 0.1% to about 5% by mass of magnesium stearate. In another aspect, the composition comprises: (a) about 30% to about 40% by mass of Compound 1–tartaric acid co-crystals; (b) about 50% to about 60% by mass of microcrystalline cellulose; (c) about 3% to about 7% by mass of croscarmellose sodium; and (d) about 1% to about 3% by mass of magnesium stearate. In another aspect, the composition further comprises an intragranular composition and an extragranular composition. In another aspect, the intragranular composition comprises: (a) Compound 1–tartaric acid co-crystals; (b) a filler; (c) a disintegrant; (d) a lubricant; (e) optionally a brittle filler; and (f) optionally a glidant; and the extragranular composition comprises: (g) a filler; (h) a disintegrant; (i) a lubricant; and (j) optionally a glidant. In another aspect, the composition comprises: an intragranular composition comprising: (a) Compound 1–tartaric acid co-crystals; (b) a filler; (c) a disintegrant; and (d) a lubricant; and an extragranular composition comprising: (e) a filler; (f) a disintegrant; and (g) a lubricant. In another aspect, the composition comprises: an intragranular composition comprising: (a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 5% to about 10% of a filler; (c) about 1% to about 5% by mass of a disintegrant; and (d) about 0.2% to about 1% by mass of a lubricant; and an extragranular composition comprising: (e) about 30% to about 60% by mass of a filler; (f) about 1.5% to about 5% by mass of a disintegrant; and (g) about 1% to about 5% by mass of a lubricant. In another aspect, the intragranular composition comprises: (a) Compound 1–tartaric acid co-crystals; (b) microcrystalline cellulose; (c) croscarmellose sodium, and (d) magnesium stearate; and the extragranular composition comprises: (e) microcrystalline cellulose; (f) croscarmellose sodium; and (g) magnesium stearate. In another aspect, the composition comprises: an intragranular composition comprising: (a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 5% to about 10% by mass of microcrystalline cellulose; (c) about 1% to about 5% by mass of croscarmellose sodium; and (d) about 0.2% to about 1% by mass of magnesium stearate; and an extragranular composition comprising: (e) about 30% to about 60% by mass of microcrystalline cellulose; (f) about 1.5% to about 5% by mass of croscarmellose sodium; and (g) about 1% to about 5% by mass of magnesium stearate. In another aspect, the composition comprises: an intragranular composition comprising: (a) about 30% to about 40% by mass of Compound 1–tartaric acid co-crystals; (b) about 6% to about 8% by mass of microcrystalline cellulose; (c) about 1% to about 2% by mass of croscarmellose sodium; and (d) about 0.2% to about 0.8% by mass of magnesium stearate; and an extragranular composition comprising: (e) about 45% to about 55% by mass of microcrystalline cellulose; (f) about 2% to about 4% by mass of croscarmellose sodium; and (g) about 1% to about 3% by mass of magnesium stearate. In another aspect, the composition comprises: an intragranular composition comprising: (a) about 35% by mass of Compound 1–tartaric acid co-crystals; (b) about 7% by mass of microcrystalline cellulose; (c) about 2% by mass of croscarmellose sodium; and (d) about 0.6% by mass of magnesium stearate; and an extragranular composition comprising: (e) about 50% by mass of microcrystalline cellulose; (f) about 3% by mass of croscarmellose sodium; and (g) about 1.5% by mass of magnesium stearate. In another aspect, the composition comprises about 50 mg to about 2000 mg of Compound 1–tartaric acid co-crystals. In another aspect, the composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 750 mg, or about 1000 mg of Compound 1–tartaric acid co-crystals. In another aspect, the composition comprises about 350 mg of Compound 1–tartaric acid co-crystals. In another aspect, the composition comprises about 300 mg of Compound 1 present in Compound 1–tartaric acid co-crystals. In another aspect, the composition is stable for at least 3 months when stored at a temperature up to 30 °C and a relative humidity up to 65%. In another aspect, about 50% of the composition dissolves within about 10 minutes at 37 °C and 75 rpm in a medium of 0.1 N hydrochloric acid and 1.0% w/v sodium dodecyl sulfate (SDS), pH 4.5, using a U.S.P. Apparatus 2. In another aspect, the composition is effective at inhibiting voltage gated sodium channel 1.8. In another aspect, the composition is effective at treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of any type of pain in a subject in need thereof. In another aspect, the composition is effective at treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of any type of pain in a subject in need thereof.

[0012] Another embodiment described herein is a method for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of any type of pain in a subject in need thereof comprising administering an effective amount of the Compound 1-tartaric acid co-crystal. Another embodiment described herein is a method for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of any type of pain in a subject in need thereof comprising administering an effective amount of any of the compositions described herein. In one aspect, the pain comprises one or more of abdominal pain, abnormal gastrointestinal motility pain, acute herpes zoster pain, acute inflammatory pain, acute intermittent pain, acute musculoskeletal pain, acute obstetric pain, acute pain, acute post-operative pain (e.g., bunionectomy pain; abdominoplasty pain; knee pain from a total knee replacement; hip pain from a total hip replacement; pain from a laminectomy; pain from a hernia repair; or hemorrhoid removal pain), acute tendonitis pain, acute visceral pain, adiposis dolorosa pain, amyotrophic lateral sclerosis pain, angina-induced pain, anti-retroviral therapy induced neuralgia, anxiety pain, appendicitis pain, arrhythmia pain, arthritis pain, ataxia pain, back pain, Behçet’s disease pain, bipolar disorder pain, bladder and urogenital disease pain, bone pain, brachial plexus avulsion injury pain, breakthrough pain, burn pain, burning mouth syndrome pain, bursitis pain, cancer chemotherapy induced neuralgia, cancer pain, cardiac arrhythmia pain, cardiac pain, carpal tunnel syndrome pain, central pain, cerebral ischemia, Cesarean-section pain, Charcot-Marie Tooth neuropathic pain, chemotherapy induced neuropathic pain, chest pain, cholecystitis pain, chronic and acute headache pain, chronic and acute neuropathic pain, chronic arthritis, chronic pain, chronic visceral pain, cluster headache pain, cold pain, complex regional pain syndrome, Crohn’s disease pain, dental pain (e.g., third molar extraction), depression pain, diabetic neuralgia, diabetic neuropathic pain, diabetic peripheral neuropathic pain, drug therapy induced neuralgia, ectopic proximal and distal discharge pain, endometriosis pain, epilepsy pain, erythromelalgia pain, exercise induced angina pain, exercise induced pain, exercise pain, Fabry’s disease pain, femur cancer pain, fibromyalgia pain, general neuralgias, granuloma annulare pain, Guillain-Barre pain, gut pain, Haglund syndrome pain, head pain, headache pain, hereditary sensory neuropathic pain, hernia pain, herpetic neuralgia pain, HIV-associated neuropathic pain, HIV-associated sensory neuropathic pain, hyperactivity bladder pain, hypertension pain, idiopathic pain, idiopathic sensory neuropathic pain, idiopathic small-fiber neuropathic pain, incontinence pain, inflammatory bowel disease pain, inflammatory pain, injury pain, interstitial cystitis (IC) pain, intestinal obstruction pain, intractable pain, irritable bowel syndrome pain, joint pain, labor pain, leprosy pain, lipoidica pain, malignancy pain, mechanical low back pain, migraine pain, Morton’s neuroma pain, movement disorder pain, multiple sclerosis (MS) pain, musculoskeletal pain, myofascial pain syndrome pain, myotonia pain, neck pain, necrobiosis pain, nerve avulsion injury pain, nerve entrapment injury pain, neurodegenerative disorder pain, neuroendocrine disorder pain, neuropathic low back pain, neuropathic pain, nociceptive pain, non-malignant chronic bone pain, orofacial pain, osteoarthritis pain, painful bladder syndrome, painful legs, painful moving toes, painful neuromas, palpitations, pancreatic pain, paroxysmal extreme pain, pathological cough pain, pelvic pain, peripheral nerve injury pain, phantom pain, phlebitic pain, post spinal cord injury pain, post-amputation pain, post-herpetic neuralgia, post-mastectomy pain, post-stroke pain, postsurgical pain, premenstrual pain, prostatitis pain, pruritis pain, psychiatric disorder associated pain, pyelonephritis pain, radicular pain, radiculopathy, radiotherapy-induced neuropathic pain, renal colic pain, rheumatoid arthritis pain, sarcoidosis pain, sciatica pain, severe pain, shingles pain, sickle cell anemia pain, sinusitis pain, spinal cord injury pain, spinal stenosis pain, sports injury pain, stress-induced angina pain, stress-induced pain, stroke pain, temporomandibular joint pain, tendonitis pain, tension headache pain, thalamic pain, tinnitus pain, trauma pain, traumatic brain injury pain, traumatic neuroma, trigeminal autonomic cephalalgia, trigeminal neuralgia, urinary incontinence pain, visceral pain, widespread pain, or other types of pain. In another aspect, the pain comprises chronic and acute neuropathic pain. In another aspect, the pain comprises herpetic neuralgia. In another aspect, the pain comprises idiopathic small-fiber neuropathy. In another aspect, the pain comprises osteoarthritis pain. In another aspect, the pain comprises acute pain. In another aspect, the pain comprises acute post-operative pain. In another aspect, the pain comprises postsurgical pain. In another aspect, the pain comprises bunionectomy pain. In another aspect, the pain comprises abdominoplasty pain. In another aspect, the pain comprises visceral pain.

[0013] Another embodiment described herein is a method for manufacturing a pharmaceutical composition comprising: (a) combining a Compound 1–tartaric acid crystals with one or more fillers or diluents, one or more disintegrants, one or more lubricants, and optionally, one or more first glidants, screening, and blending; (b) combining the blend of (a) with a first screened lubricant and blending; (c) dry granulating and milling the blend of (b); (d) combining the milled blend of (c) with a screened second filler and second disintegrant and blending; (e) combining the blend of (d) with a screened second lubricant, and optionally, a second glidant, and blending; and (f) compressing the blend of (e) into tablets. In one aspect, the filler comprises microcrystalline cellulose; the first and second disintegrant comprises croscarmellose sodium; the first and second lubricant comprises magnesium stearate.

[0014] Another embodiment described herein is a pharmaceutical composition produced by the method described herein. In one aspect, the pharmaceutical composition comprises: an intragranular composition comprising: (a) about 20% to about 50% by mass of Compound 1– tartaric acid co-crystals; (b) about 5% to about 10% by mass of microcrystalline cellulose; (c) about 1% to about 5% by mass of croscarmellose sodium; and (d) about 0.2% to about 1% by mass of magnesium stearate; and an extragranular composition comprising: (e) about 30% to about 60% by mass of microcrystalline cellulose; (f) about 1.5% to about 5% by mass of croscarmellose sodium; and (g) about 1% to about 5% by mass of magnesium stearate. In another aspect, the pharmaceutical composition comprises about 350 mg of Compound 1–tartaric acid co-crystals. In another aspect, the pharmaceutical composition comprises about 300 mg of Compound 1 present in Compound 1–tartaric acid co-crystals. In another aspect, the pharmaceutical composition is effective at treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of pain in a subject in need thereof.

[0015] Another embodiment described herein is a method for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of pain comprising administering to a subject in need thereof an effective amount of the Compound 1-tartaric acid co-crystal. Another embodiment described herein is a method for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of pain comprising administering to a subject in need thereof an effective amount of any of the pharmaceutical compositions described herein.

[0016] Another embodiment described herein is the use of the Compound 1-tartaric acid co-crystal for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of any type of pain in a subject in need thereof. Another embodiment described herein is the use of any of the pharmaceutical compositions described herein for treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of any type of pain in a subject in need thereof.

[0017] Another embodiment described herein is the Compound 1-tartaric acid co-crystal, or a pharmaceutical composition thereof, for use as a medicament. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG.1 shows a high-resolution mass spectroscopy spectrum of Compound 1 obtained from Compound 1–tartaric acid co-crystals (the tartaric acid from the co-crystal dissolved during sample preparation).

[0019] FIG.2 shows a ¹H-NMR spectrum of Compound 1–tartaric acid co-crystals in deuterated dimethyl sulfoxide (DMSO-d6). [0020] FIG.3 shows a ¹³C-NMR spectrum of Compound 1–tartaric acid co-crystals in deuterated dimethyl sulfoxide (DMSO-d6).

[0021] FIG.4 shows solid state NMR spectra. FIG.4A shows a ¹⁹F magic angle spinning spectrum of Compound 1–tartaric acid co-crystals. FIG. 4B shows a ¹³C cross-polarization magic angle spinning spectrum of Compound 1–tartaric acid co-crystals.

[0022] FIG.5 shows an Infra-red (IR) spectrum of Compound 1–tartaric acid co-crystals.

[0023] FIG.6 shows a Ultra-violet (UV) spectrum of Compound 1–tartaric acid co-crystals.

[0024] FIG.7 shows an X-ray powder diffraction (XRPD) spectrum of Compound 1–tartaric acid co-crystals.

[0025] FIG. 8 shows a differential scanning calorimetry (DSC) thermogram of Compound 1– tartaric acid co-crystals.

[0026] FIG. 9 shows a thermogravimetric analysis (TGA) thermogram of Compound 1–tartaric acid co-crystals.

[0027] FIG.10 shows a flow chart for manufacturing tablets containing Compound 1–tartaric acid co-crystals.

DETAILED DESCRIPTION

[0028] Described herein are pyridone amide compositions that inhibit voltage-gated sodium channels. In one embodiment, the pyridone amides inhibit voltage-gated sodium channel 1.8 (NaV1.8).

[0029] The drugs and pharmaceutical compositions of the compounds described herein are characterized by unexpectedly high aqueous solubility. This solubility facilitates administration of higher doses of the drug, resulting in a greater drug load per unit dosage.

[0030] The chemical elements described herein are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, 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 and March, John Wiley & Sons, New York (2001), the contents of each of which are hereby incorporated by reference.

[0031] Combinations of substituents described herein are those combinations that result in the formation of stable or chemically feasible compounds. The term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least 3 months.

[0032] The terms“formulation” or“composition” as used herein refers to the drug in combination with pharmaceutically acceptable excipients. These terms include orally administrable formulations as well as formulations administrable by other means.

[0033] The term“treating” refers to administering a therapy in an amount, manner, or mode effective (e.g., a therapeutic effect) to improve a condition, symptom, disorder, or parameter associated with a disorder, or a likelihood thereof.

[0034] The term“prophylaxis” refers to preventing or reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable to one skilled in the art.

[0035] The term“substantially” as used herein means to a great or significant extent, but not completely. [0036] As used herein, all percentages (%) refer to mass (weight) percent (w/w) unless noted otherwise.

[0037] The term“about” as used herein refers to any values, including both integers and fractional components that are within a variation of up to ±10% of the value modified by the term“about.”

[0038] As used herein,“a” or“an” means one or more unless otherwise specified.

[0039] Terms such as“include,”“including,”“contain,”“containing,”“having,” and the like mean “comprising.”

[0040] The term“or” can be conjunctive or disjunctive.

[0041] As used herein, the term“active pharmaceutical ingredient” or“API” refers to a biologically active compound. Exemplary APIs described herein include a voltage-gated sodium channel inhibitors, e.g., Compound 1 or 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide. In another embodiment, the active pharmaceutical ingredient may also be in the form of pharmaceutically acceptable uncharged or charged molecules, molecular complexes, solvates, or anhydrates thereof, and, if relevant, single isomers, enantiomers, racemic mixtures, or mixtures thereof. In another embodiment, the active pharmaceutical ingredient may be in any of its crystalline, semi-crystalline, amorphous, or polyamorphous forms, or mixtures thereof.

[0042] As used herein, the phrase“drug substance” refers to an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, and does not include intermediates used in the synthesis of such ingredient. The phrase“drug substance” can also be used to refer to a physical mixture of two or more drug substances used to produce a fixed-combination drug product. See FDA Guidance for Industry: Drug Substance Chemistry, Manufacturing, and Controls Information (August 2010), which is incorporated by reference herein for such teachings.

[0043] As used herein, the term“Compound 1” is used interchangeably with“2-(4-fluoro-2- methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide”, which has the following structure:

[0044] A synthesis of Compound 1 was described in Example 14 of U.S. Patent No.9,051,270, which is incorporated herein for such teachings by express reference thereto. A synthesis method is also described in Example 1 herein.

[0045] Provided herein are co-crystals of Compound 1, which include“Compound 1–tartaric acid co-crystals” or“tartaric acid co-crystals of Compound 1.” In one aspect, co-crystals of Compound 1 comprises “2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4- (trifluoromethyl)benzamide hemi(2,3-dihydroxysuccinate)”, which has the following structure:

[0046] As used herein the phrases“co-crystals” or“co-crystal” refer to crystalline materials composed of two or more different molecules, typically an active pharmaceutical ingredient (API) and co-crystal formers (“coformers”), in the same crystal lattice that are associated by nonionic and noncovalent bonds. See FDA Guidance: Regulatory Classification of Pharmaceutical Co- Crystals Guidance for Industry, Revision 1 (February 2018), which is incorporated by reference herein for such teachings. Co-crystals are distinguished from salts because unlike salts, the components that co-exist in the co-crystal lattice with a defined stoichiometry interact non- ionically.

[0047] Another embodiment described herein is a method for preparing co-crystals of Compound 1. In one aspect, the co-crystal comprises Compound 1 and co-crystal former. In another aspect, the co-crystal comprises Compound 1 and tartaric acid. In another aspect, the co-crystal is a Compound 1–tartaric acid co-crystal. In another aspect, the co-crystal comprises two molecules of Compound 1 and one molecule of tartaric acid. In another aspect, the Compound 1–tartaric acid co-crystals are produced by a process shown in Scheme 1.

[0048] In one aspect, Compound 1, tartaric acid, ethyl acetate, and ethanol were stirred until complete conversion to the co-crystal is achieved at 15–30 °C. The product was isolated by filtration and dried with heat under vacuum (35–45 °C). The process was also successful using only ethyl acetate as the solvent.

[0049] In another aspect, Compound 1 (1000 g) was slurried with tartaric acid (9.4 g, 0.063 moles, 0.025 equivalents) in ethyl acetate (26.62 L) and pure ethanol (2.03 L) at 20–30 °C. The slurry was seeded with Compound 1–tartaric acid co-crystal (50 g, 5.0% by mass) and aged for at least 30 minutes. A solution of tartaric acid (179 g, 1.192 moles, 0.485 equivalents) in ethanol (1.35 L) was charged to the stirring slurry over 24 h. The mixture was aged for an additional 2 h or until conversion to the co-crystal was confirmed to be complete (by XRPD). The crystalline white to off-white solid product was isolated by filtration. The solids were washed with 10% w/w ethanol in ethyl acetate (1 L) and then dried at 35–45 °C under vacuum to afford 1019 g Compound 1– tartaric acid co-crystals (86% yield).

[0050] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by high resolution mass spectrometry and has a spectrum as shown in FIG.1 having a [M+H]⁺ peak at m/z 407.1033. [0051] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more approximate peaks selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation. In one aspect, the Compound 1–tartaric acid co-crystal is characterized by the XRPD spectrum of FIG. 7. In another aspect, the XRPD data are presented in Table 8. In one aspect, the Compound 1–tartaric acid co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising 5 or more approximate peaks selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation. In one aspect, the Compound 1–tartaric acid co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising 7 or more approximate peaks selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation. In one aspect, the Compound 1–tartaric acid co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising 10 or more approximate peaks selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation. In another aspect, the Compound 1–tartaric acid co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 approximate peaks selected from 7.7, 17.6, 17.8, 19.2, 20.0, 25.6, 15.3, 26.5, 25.1, 21.2, 24.2, when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation.

[0052] Another embodiment described herein is a Compound 1–tartaric acid co-crystal has an an X-ray powder diffraction (XRPD) pattern substantially similar to the XRPD pattern of FIG.7. As used herein, an X-ray powder pattern is“substantially similar to that of FIG. [Figure number]” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two patterns overlap. In determining“substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms or patterns (in degrees two- theta (º2 ^) referred to herein) generally mean that value is identified as ±0.2 degrees 2 ^ of the reported value, an art-recognized variance. In some embodiments, the signal variance is identified as ±0.1 degrees 2 ^ of the reported value.

[0053] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by a ¹H-NMR spectrum substantially similar to the spectrum of FIG.2 or the ¹³C- NMR spectrum substantially similar to the spectrum of FIG. 3. In another aspect, both sets of NMR data are presented in Table 4.

[0054] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by the ¹⁹F-solid state NMR spectrum substantially similar to that of FIG. 4A; or having the peaks listed in Table 5; or the ¹³C-solid state NMR spectrum substantially similar to that of FIG.4B; or having the peaks listed in Table 6.

[0055] As used herein, a ¹H-NMR or ¹³C-NMR or a ¹³C or ¹⁹F solid state nuclear magnetic resonance (ssNMR) spectrum is“substantially similar to that of FIG. [Figure number]” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two spectra overlap. In determining“substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in NMR or ssNMR spectra even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the chemical shifts in NMR or ssNMR spectra (in parts per million (ppm) referred to herein) generally mean that value is identified as ± 0.2 ppm of the reported value, an art-recognized variance. In some embodiments, the signal variance is identified as ±0.1 ppm of the reported value.

[0056] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by the Infra-Red (IR) spectrum shown in FIG.5. In another aspect, the IR data are presented in Table 7.

[0057] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by the Ultra-violet (UV) spectrum shown in FIG. 6, comprising two maxima at approximately 204 nm and 260 nm, respectively.

[0058] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by the differential scanning calorimetry (DSC) thermogram shown in FIG. 8 comprising an endothermic peak having an onset temperature of 229 °C (±2.0 °C).

[0059] Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by the thermogravimetric analysis (TGA) thermogram shown if FIG.9 comprising a 1.07% mass loss from ambient temperature to 150 °C. [0060] In one embodiment, the pharmaceutical compositions described herein comprise solid particles of Compound 1–tartaric acid co-crystals that have been milled or micronized to a particular size or size distribution. The terms“micronized” or“milled” as used herein refers to preparations of Compound 1–tartaric acid co-crystals that have been subject to comminution to a defined particle size distribution through jet milling, ball milling, or other means known to those of skill in the art. Compound 1–tartaric acid co-crystal particles may be generated by any particle size reduction or particle growth methodology known to one having ordinary skill in the art. Exemplary and non-limiting methods may comprise a“top-down” reduction in particle size including mechanical micronization techniques, wherein a larger particle is crushed, bashed, or ground into a smaller particle through techniques, such as jet milling, ball milling, or high pressure homogenization; or particle engineering techniques such as cryogenic spraying or crystal engineering. In addition,“bottom-up” processing may be used to build a suitable size of particles as described herein using dual solvent/anti-solvent rapid precipitation techniques. See, Handbook of Pharmaceutical Granulation Technology, CRC Press, 3^rd edition, 2010, which is incorporated by reference herein for teachings related to generating pharmaceutical particles. In one aspect described herein, Compound 1–tartaric acid co-crystal particles of a specified size distribution are produce using a jet milling technique or ball milling.

[0061] In one embodiment, the Compound 1–tartaric acid co-crystals comprises a particle size distribution (d90) of about 0.5 mm to about 100 mm, including all integers and fractions within the specified range. In another embodiment, the Compound 1–tartaric acid co-crystal particles have median volume particle size distributions D(v,0.5) ranging from about 0.5 mm to about 100 mm, including all integers and fractions within the specified range. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals comprise median volume particle size distributions D(v,0.5) of about 1 mm to about 50 mm, including all integers and fractions within the specified range. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals comprise median volume particle size distributions D(v,0.5) of about 1 mm to about 20 mm, including all integers and fractions within the specified range. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals comprise median volume particle size distributions D(v,0.5) of about 1 mm to about 10 mm, including all integers and fractions within the specified range. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals comprise median volume particle size distributions D(v,0.5) of about 1 mm to about 5 mm, including all integers and fractions within the specified range. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals comprise median volume particle size distributions D(v,0.5) of about 2 mm to about 4 mm, including all integers and fractions within the specified range.

[0062] In another embodiment, the solid particles of Compound 1–tartaric acid co-crystals comprise median volume particle size distributions D(v,0.5) of about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6.0 mm, about 6.5 mm, about 7.0 mm, about 7.5 mm, about 8.0 mm, about 8.5 mm, about 9.0 mm, about 9.5 mm, or about 10 mm.

[0063] In another embodiment, the solid particles of Compound 1–tartaric acid co-crystals have a median volume particle size distribution D(v,0.5) of about 0.5 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of about 1 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of about 2 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of about 2.5 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of about 3.0 mm. In one aspect, the solid particles of Compound 1– tartaric acid co-crystals have a particle size D(v,0.5) of about 4.0 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of < 5.0 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of < 10.0 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of < 20 mm. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size D(v,0.5) of about 2–4 mm.

[0064] In another embodiment, Compound 1–tartaric acid co-crystals are micronized to a median volume particle size, D(v,0.5) of about 1–20 mm, 1–10 mm, 1–5 mm, 1–3 mm, 2–5 mm, 3–5 mm, or 2–4 mm.

[0065] In another embodiment, Compound 1–tartaric acid co-crystals are micronized to a median volume particle size, D(v,0.5) of £ 10 mm, £ 5 mm, £ 4 mm, £ 3 mm, £ 2.5 mm, or £ 2.0 mm. In one aspect, crystalline Compound 1–tartaric acid co-crystals are micronized to a median volume particle size, D(v,0.5) of about 2–4 mm.

[0066] In another embodiment, the solid particles of Compound 1–tartaric acid co-crystals have a D(v,0.5) of about 2 mm to about 4 mm, a surface area weighed particle size, SMD or D[3,2], of about 1.1 mm to about 3.5 mm, and a volume weighed particle size, VMD or D[4,3] of about 2.1 mm to about 16.5 mm.

[0067] In another embodiment, the solid Compound 1–tartaric acid co-crystal particles have a particle size distribution with a d90 of less than or equal to about 5 mm. In one aspect, the particle size distribution of solid particles of Compound 1–tartaric acid co-crystals have a d90 of less than or equal to about 10 mm, about 9 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm. In one aspect, the solid particles of Compound 1– tartaric acid co-crystals have a particle size distribution with a d90 of less than or equal to about 10 mm (d90 £10 mm). In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size distribution with a d90 of less than or equal to about 5 mm (d90 £5 mm). In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size distribution with a d90 of less than or equal to about 4 mm (d90 £ 4 mm). In one aspect, the solid particles of Compound 1–tartaric acid co-crystals have a particle size distribution with a d90 of less than or equal to about 3 mm (d90 £ 3 mm). In one aspect, the solid particles of Compound 1– tartaric acid co-crystals have a particle size distribution with a d90 of less than or equal to about 2 mm (d90 £ 2 mm).

[0068] In another embodiment, the solid particles of Compound 1–tartaric acid co-crystals comprise multiple distributions of particle sizes. In one aspect, the solid particles of Compound 1–tartaric acid co-crystals may comprise a plurality of independently combined mean particle size distributions, wherein each independent mean particle size distribution ranges from about 1 mm to about 200 mm, including all integers and fractions within the specified range. In another aspect, the plurality of mean particle size distributions can comprise a mean particle size distribution of about 1.0 mm to about 10 mm. In another aspect, the plurality of mean particle size distributions can comprise combinations of independent mean particle size distributions, wherein each independently combined mean particle size distribution is about 2 mm, about 5 mm, about 10 mm, about 15.0 mm, about 20.0 mm; about 50 mm, about 100 mm, or about 200 mm. In another aspect, the solid particles of Compound 1–tartaric acid co-crystals comprise a combination of independently combined mean particle size distributions of about 1.0 mm to about 100 mm in a single pharmaceutical composition. Any of the foregoing particle size distributions may be combined to provide the desired controlled release profile. [0069] The forgoing sizes of Compound 1–tartaric acid co-crystal particles may be determined using standard techniques known to one of ordinary skill in the art. The exemplary techniques that can be used for measuring the size of Compound 1–tartaric acid co-crystal particles may include laser diffraction analysis, light scattering (e.g., dynamic light scattering), microscopic particle image analysis, elutriation, or aerosol mass spectrometry. The sample of Compound 1–tartaric acid co-crystal particles may be measured as a dry sample or a wet sample. Any commercially available instrument for measuring particle sizes may be used, including instruments from Sympatec, Cilas; Brookhaven Instruments Corporation; Malvern Instruments; Horiba Scientific; or Wyatt following the recommended operating procedures according to the manufacturer’s instructions.

[0070] The measured particle sizes using the techniques described herein may be expressed as a derived diameter with a normal distribution or non-normal distribution with a mean, median (e.g., mass median diameter), and mode of particle diameter sizes. The particle size distribution may be expressed as a diameter number distribution, a surface area distribution, or a particle volume distribution. The mean of the particle size distribution may be calculated and expressed in various ways, such as the volume mean diameter (D[4,3] or d₄₃), mean surface area diameter (D[3,2] or d32) or the mean number particle diameter (D[1,0] or d10). Because the particle size distribution values vary depending on the measurement methodology and how the distribution is expressed, the comparison of different mean particle size distributions must be calculated by the same methodology in order to yield an accurate comparison. For example, a sample with a measured and calculated volume mean diameter must be compared with a second sample having a measured and calculated volume mean diameter, ideally measured using the same measuring instrument under the same conditions. Thus, the specific particle size distributions described herein are not intended to be limited to any one type of method for measuring or calculating a particle size distribution (e.g., a diameter number distribution, a surface area distribution, or a particle volume distribution), but rather indicate particle size values and distributions thereof for each method of measuring particle sizes described herein. As used herein, Dv50 or D(v,0.5) refers to the median (50%) particle size distribution for a volume distribution. For a particular sample, 50% of the particles are larger than the D(v,0.5) value and 50% are smaller.

[0071] Another embodiment described herein is a method for manufacturing particles of Compound 1–tartaric acid co-crystals of defined sizes using jet milling, ball milling, or other techniques for comminution. In one aspect, the particles are of a similar size distribution. In another aspect, the Compound 1–tartaric acid co-crystal particles comprise varied size distributions. In another aspect, the Compound 1–tartaric acid co-crystal particles comprise several size distributions. In another aspect, the Compound 1–tartaric acid co-crystal particles comprise a mixture of smaller and larger size distributions. Without being bound to any theory, smaller particles are generally solubilized and released more rapidly than larger particles. The release rate can be adjusted to achieve a specific therapeutic window over a defined period and produce controlled release, delayed release, or extended release compositions by combining multiple Compound 1–tartaric acid co-crystal particle sizes or size distributions.

[0072] Another embodiment described herein is a pharmaceutical composition comprising compound 1–tartaric acid co-crystals. One embodiment described herein is a pharmaceutical composition comprising a Compound 1–tartaric acid co-crystal. In another embodiment, the pharmaceutical composition comprises micronized or milled particles of Compound 1–tartaric acid co-crystals. In one aspect, the Compound 1–tartaric acid co-crystals are micronized to a median volume particle size, D(v,0.5) of about 1–10 mm, 1–5 mm, 1–3 mm, or 2–3 mm. In another aspect, the Compound 1–tartaric acid co-crystal is micronized to a median volume particle size, D(v,0.5) of £ 10 mm, £ 5 mm, £ 4 mm, £ 3 mm, £ 2.5 mm, or £ 2.0 mm. In another aspect, Compound 1–tartaric acid co-crystal is micronized to a median volume particle size, D(v,0.5) of about 2–3 mm.

[0073] In one aspect, the composition comprises about 20% to about 80% of Compound 1–tartaric acid co-crystals, and about 20% to about 80% of the one or more pharmaceutically acceptable excipients. In another aspect, the pharmaceutical composition comprises about 50 mg to about 1000 mg, including each integer within the specified range, of Compound 1–tartaric acid co- crystal. In one aspect, the pharmaceutical composition comprises one or more fillers or diluents, one or more fillers or diluents, one or more disintegrants, one or more lubricants, or one or more other pharmaceutical excipients. In one aspect, the pharmaceutical composition comprises an oral dosage form, including but not limited to a tablet or capsule.

[0074] As used herein, a“disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. Examples of disintegrants include crospovidone, croscarmellose sodium, alginic acid, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, or combinations thereof. In some aspects, the disintegrant is crospovidone (e.g., crosslinked homopolymers of N-vinyl-2-pyrrolidone) having a particular particle size such as Polyplasdone™ (Ashland), including Polyplasdone™ XL, XL-10, and INF- 10 which have average particle size distributions of 130 mm, 30 mm, and 11 mm, respectively. Other examples are Kollidon^® CL, CL-F, CL-SF, and CL-M (BASF), which have average particle size distributions of 166.8 mm, 45.7 mm, 28.7 mm, and 7.8 mm, respectively. In one aspect, the disintegrant is sodium croscarmellose.

[0075] As used herein, a“filler” or“diluent” is an excipient that adds bulkiness to a pharmaceutical composition. Examples of fillers or diluents include lactose, lactose monohydrate, glucose, fructose, sucrose, sorbitol, mannitol, dicalcium phosphate dihydrate, cellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, crospovidone, or a combination thereof.

[0076] In one embodiment, the filler or diluent is microcrystalline cellulose. In another aspect, the filler or diluent is microcrystalline cellulose such as Avicel^® PH-101 or PH-102 (FMC) that have particle sizes of 50 mm or 100 mm, respectively. Such grades of microcrystalline cellulose can be used as either intergranular or extragranular fillers. In one aspect, the microcrystalline cellulose is Avicel^® PH-101. In one aspect, the microcrystalline cellulose is Avicel^® PH-102. In one aspect, the microcrystalline cellulose is used as an intragranular filler. In another aspect, the microcrystalline cellulose is used as an extragranular filler. In another aspect, the microcrystalline cellulose is used as both an intragranular and extragranular filler.

[0077] As used herein, a“binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness). Examples of binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).

[0078] As used herein, a“lubricant” is an excipient that is added to pharmaceutical compositions that are pressed into tablets. The lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press. Examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, talc, glyceryl behenate, or a combination thereof. In one aspect, the lubricant is magnesium stearate.

[0079] As used herein, a“glidant” is an excipient that imparts a pharmaceutical composition with enhanced flow properties. Examples of glidants include colloidal silica, fumed silica, or talc. In one embodiment, the glidant is fumed silica. In one aspect, the glidant is CAB-O-SIL^® M-5P (pharmaceutical grade) fumed silica (CABOT). In one aspect, the fumed silica is used as an intragranular glidant. In another aspect, the fumed silica is used as an extragranular glidant. In another aspect, the fumed silica is used as both an intragranular and extragranular glidant. In some aspects, the fumed silica is added at a weight percentage of 0.1% to about 1% of the intragranular or extragranular mass. In one aspect the fumed silica is added at a weight percentage of 0.5 or 1% of the intragranular mass, extragranular mass, or both the intragranular and extragranular mass.

[0080] As used herein, a“surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability. Examples of surfactants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., Tween™), or a combination thereof.

[0081] As used herein, a“colorant” is an excipient that imparts a pharmaceutical composition with a desired color. Examples of colorants include commercially available pigments such as FD&C Blue # 1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.

[0082] As used herein, a“flavoring” is an excipient that imparts a flavor or taste masking property to a pharmaceutical composition. Examples of flavorings include anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orange flower oil, peppermint, peppermint oil, peppermint spirit, rose oil, stronger rose water, thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin, or combinations thereof.

[0083] As used herein a“coating agent” makes the dosage from smoother and easier to swallow, controls the release rate of the active ingredient, and makes the dosage from more resistant to the environment (extending its shelf life), or enhances the dosage form’s appearance. Examples of coating agents include sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein, or combinations thereof.

[0084] Another embodiment described herein is an oral pharmaceutical composition comprising (a) a solid dispersion of Compound 1–tartaric acid co-crystals; (b) one or more fillers or diluents; (c) one or more disintegrants; and (d) one or more lubricants. In one aspect, the filler comprises one or more of lactose, lactose monohydrate, glucose, fructose, sucrose, sorbitol, mannitol, dicalcium phosphate dihydrate, cellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, crospovidone, or a combination thereof. In one aspect, the disintegrant comprises one or more of crospovidone, croscarmellose sodium, alginic acid, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof. In one aspect, the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, talc, glyceryl behenate, or a combination thereof. In one aspect, the pharmaceutical composition comprises one or more colorants, flavorings, binders, glidants, coatings, or other pharmaceutically acceptable excipients. In one aspect, the filler comprises microcrystalline cellulose and lactose monohydrate; the disintegrant comprises crospovidone; and the lubricant comprises magnesium stearate. The composition can optionally contain one or more colorants, flavorings, additional fillers or diluents, additional disintegrants, additional lubricants, binders, glidants, coatings, or other pharmaceutically acceptable excipients.

[0085] Another embodiment described herein is an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition. In one aspect the composition comprises an intragranular composition comprising (a) a solid dispersion of Compound 1–tartaric acid co-crystals; (b) one or more diluents or fillers or diluents; (c) one or more disintegrants; and (d) one or more lubricants and an extragranular composition comprising (e) one or more diluents or fillers or diluents; (f) one or more disintegrants; and (g) one or more lubricants. The composition can optionally contain one or more colorants, flavorings, additional fillers or diluents, additional disintegrants, additional lubricants, binders, glidants, coatings, or other pharmaceutically acceptable excipients.

[0086] Another embodiment described herein in an oral pharmaceutical composition comprising: (a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 30% to about 70% by mass of one or more fillers or diluents; (c) about 1% to about 10% by mass of one or more disintegrants; and (d) about 0.1% to about 5% by mass of one or more lubricants.

[0087] Another embodiment described herein in an oral pharmaceutical composition comprising: (a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 30% to about 70% by mass of microcrystalline cellulose; (c) about 1% to about 10% by mass of croscarmellose sodium; and (d) about 0.1% to about 5% by mass of magnesium stearate.

[0088] Another embodiment described herein in an oral pharmaceutical composition comprising: (a) about 30% to about 40% by mass of Compound 1–tartaric acid co-crystals; (b) about 50% to about 60% by mass of microcrystalline cellulose; (c) about 3% to about 7% by mass of croscarmellose sodium; and (d) about 1% to about 3% by mass of magnesium stearate.

[0089] Another embodiment described herein in an oral pharmaceutical composition comprising: (a) about 36% by mass of Compound 1–tartaric acid co-crystals; (b) about 58% by mass of microcrystalline cellulose; (c) about 5% by mass of croscarmellose sodium; and (d) about 2% by mass of magnesium stearate.

[0090] Another embodiment described herein in an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition. In one aspect, the intragranular composition comprises: (a) Compound 1–tartaric acid co-crystals; (b) a filler; (c) a disintegrant; (d) a lubricant; (e) optionally a brittle filler; and (f) optionally a glidant; and the extragranular composition comprises: (g) a filler; (h) a disintegrant; (i) a lubricant; and (j) optionally a glidant.

[0091] Another embodiment described herein in an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition. In one aspect, the intragranular composition comprises: (a) Compound 1–tartaric acid co-crystals; (b) microcrystalline cellulose; (c) croscarmellose sodium, and (d) magnesium stearate; and the extragranular composition comprises: (e) microcrystalline cellulose; (f) croscarmellose sodium; and (g) magnesium stearate. The composition can optionally contain one or more colorants, flavorings, additional fillers or diluents, additional disintegrants, additional lubricants, binders, glidants, coatings, or other pharmaceutically acceptable excipients.

[0092] Another embodiment described herein in an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition. In one aspect, the intragranular composition comprises: about 20–50% by mass of Compound 1–tartaric acid co-crystals; about 5– 10% by mass of one or more diluents or fillers or diluents; about 1–5% by mass of one or more disintegrants; and about 0.2–1.0% by mass of one or more lubricants; and the extragranular composition comprises about 30–60% by mass of one or more diluents or fillers or diluents; about 1.5–5% by mass of one or more disintegrants; and about 1–5% by mass of one or more lubricants. In one aspect, the total intragranular composition comprises about 40–55% of the mass of the pharmaceutical composition and the extragranular composition comprises about 45–60% of the mass of the pharmaceutical composition. The composition can optionally contain one or more colorants, flavorings, additional fillers or diluents, additional disintegrants, additional lubricants, binders, glidants, coatings, or other pharmaceutically acceptable excipients. [0093] Another embodiment described herein in an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition. In one aspect, the intragranular composition comprises about 20–50% by mass of Compound 1–tartaric acid co-crystals; about 5– 10% by mass of microcrystalline cellulose; about 1–5% by mass of croscarmellose sodium; and about 0.2–1.0% by mass of magnesium stearate; and the extragranular composition comprises about 30–60% by mass of microcrystalline cellulose; about 1.5–5% by mass of croscarmellose sodium; and about 1–5% by mass of magnesium stearate. In one aspect, the total intragranular composition comprises about 40–55% of the mass of the pharmaceutical composition and the extragranular composition comprises about 45–60% of the mass of the pharmaceutical composition.

[0094] Another embodiment described herein in an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition. In one aspect, the intragranular composition comprises about 30–40% by mass of Compound 1–tartaric acid co-crystals; about 5– 8% by mass of microcrystalline cellulose; about 1–2% by mass of croscarmellose sodium; and 0.4–1.0% by mass of magnesium stearate; and the extragranular composition comprises about 44– 55% by mass of microcrystalline cellulose; about 2–5% by mass of croscarmellose sodium; and about 1–4% by mass of magnesium stearate. In one aspect, the total intragranular composition comprises about 40–50% of the mass of the pharmaceutical composition and the extragranular composition comprises about 45–50% of the mass of the pharmaceutical composition.

[0095] Another embodiment described herein in an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition. In one aspect, the intragranular composition comprises about 35.5% by mass of Compound 1–tartaric acid co-crystals; about 6.75% by mass of microcrystalline cellulose; about 1.8% by mass of croscarmellose sodium; and about 0.6% by mass of magnesium stearate; and the extragranular composition comprises about 51% by mass of microcrystalline cellulose; about 3.2% by mass of croscarmellose sodium; and about 1.4% by mass of magnesium stearate. In one aspect, the total intragranular composition comprises about 45% of the mass of the pharmaceutical composition and the extragranular composition comprises about 55% of the mass of the pharmaceutical composition.

[0096] In one embodiment described herein, the oral pharmaceutical composition can comprise, but is not limited to, 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, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1200 mg, about 1250 mg, about 1500 mg, about 1750 mg, about 1800 mg, or about 2000 mg of Compound 1 present in the Compound 1–tartaric acid co-crystals.

[0097] In one embodiment, the pharmaceutical composition comprises about 355.4 mg of Compound 1–tartaric acid co-crystals or about 300 mg of Compound 1 present in the Compound 1–tartaric acid co-crystals. Compound 1 has a molecular weight of 407.1 g/mole. The Compound 1–tartaric acid co-crystals have a molecular weight of 964.3 g/mole and comprise two mole equivalents of Compound 1 and one mole equivalent of tartaric acid (150.09 g/mole). A 355.4 mg sample of Compound 1–tartaric acid co-crystals comprises 300 mg of Compound 1 and 55.4 mg of tartaric acid.

[0098] In another embodiment described herein, the pharmaceutical composition comprises, but is not limited to, about 50 mg to about 2000 mg of Compound 1 present in the Compound 1– tartaric acid co-crystals. In one aspect the pharmaceutical composition can comprise about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg of Compound 1 present in the Compound 1–tartaric acid co-crystals.

[0099] In one embodiment, the pharmaceutical composition described herein is administered as a unit dose at various times throughout a 24-hour period to achieve a total daily dosage. In some embodiments, the pharmaceutical composition is administered as a unit dose once per day (QD), twice per day (BID), three times per day (TID), four times per day (QID), a greater number of times per day, or as needed (PRN), to alleviate pain, for example.

[00100] In one embodiment, the pharmaceutical composition described herein provides co- crystals of Compound 1 (e.g., Compound 1–tartaric acid co-crystals) for administration to a subject. The pharmaceutical composition can be administered, for example, to a subject, or a subject in need thereof. As used herein,“a subject in need thereof” is a subject susceptible to or experiencing pain. In one aspect, the subject is a mammal, or a mammal in need thereof. In one aspect, the subject is a human, or human in need thereof. In one aspect, the human or human in need thereof is a medical patient. In one aspect, the human subject is a child (~0–9 years old) or an adolescent (~10–17 years old). In one aspect, the subject is from about 0 to about 9 years of age. In another aspect, the human subject is from about 10 years to about 17 years of age. In another aspect, the human subject is over 17 years of age. In another aspect, the human subject is an adult (³18 years of age).

[00101] Another embodiment described herein, is a method for treating or lessening the severity of any type of pain in a subject in need thereof comprising administering an effective amount of the pharmaceutical composition described herein to the subject in the fasted state or where the subject has not consumed food or non-clear liquids for about 4 to 6 hours.

[00102] Another embodiment described herein, is a method for treating or lessening the severity any type of pain in a subject in need thereof comprising administering an effective amount of the pharmaceutical composition described herein to the subject in the fed state or where the subject has consumed food or non-clear liquids within about 4 to 6 hours.

[00103] Another embodiment described herein, is a pharmaceutical composition that upon ingestion by a subject provides for one or more pharmacokinetic parameters described herein such as C_max, T_max, AUC_0®t, AUC_0®¥, t_½, or an elimination rate constant.

[00104] Another embodiment described herein, is a method for treating or lessening the severity any type of pain in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition described herein that upon ingestion by a subject provides for one or more pharmacokinetic parameters described herein such as C_max, T_max, AUC_0®t, AUC_0®¥, t_½, or an elimination rate constant.

[00105] Another embodiment described herein, is a pharmaceutical composition comprising any of the compositions or formulations described herein or shown in the Tables or Examples described herein. Any of the components described herein or shown in the Tables or Examples can be increased, decreased, combined, added to, recombined, switched, or removed to provide for a formulation comprising about 100% by mass.

[00106] Another embodiment described herein, the pharmaceutical composition is an oral pharmaceutical tablet comprising any of the compositions or formulations described herein or shown in the Tables or Examples described herein. Another embodiment described herein is an oral pharmaceutical tablet produced by the method described herein.

[00107] Another embodiment described herein is a method for manufacturing an oral pharmaceutical tablet comprising: (a) combining crystalline Compound 1–tartaric acid co-crystals with one or more fillers or diluents, one or more disintegrants, one or more lubricants, and optionally, one or more first glidants; (b) screening and blending; (c) dry granulating and milling the blend of (b); (d) combining the milled blend of (c) with a screened second filler, second disintegrant, and second lubricant; (e) blending the combination of (d); (f) compressing the blend of (e) into tablets; and (g) packaging the tablets. In one aspect described herein, the filler comprises microcrystalline cellulose; the first and second disintegrant comprises croscarmellose sodium; and the first and second lubricant comprises magnesium stearate.

[00108] Another embodiment described herein is a kit for dispensing the oral pharmaceutical composition form produced by any of the compositions or the methods described herein comprising: (a) at least one pharmaceutical composition comprising micronized Compound 1–tartaric acid co-crystals; (b) at least one moisture proof dispensing receptacle comprising blister or strip packs, an aluminum blister, a transparent or opaque polymer blister with pouch, polypropylene tubes, colored blister materials, tubes, bottles, and bottles optionally containing a child-resistant feature, optionally comprising a desiccant, such as a molecular sieve or silica gel; and optionally (c) an insert comprising instructions or prescribing information for Compound 1 comprised by the oral pharmaceutical composition; or (d) directions for administration or any contraindications. In one aspect described herein, the kit is useful for treating any type of pain or a medical condition according to any of the methods described herein.

[00109] As described herein, the pharmaceutical compositions can comprise pharmaceutically acceptable excipients, adjuvants, or vehicles, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various excipients used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional excipient is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of the embodiments described herein. Some examples of materials which can serve as pharmaceutically acceptable excipient include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [00110] Another embodiment described herein, is a Compound 1–tartaric acid co-crystal that is an inhibitor of voltage-gated sodium channels. Compound 1–tartaric acid co-crystals are useful for the treatment of diseases, disorders, and conditions including, chronic and acute neuropathic pain, herpetic neuralgia pain, idiopathic small-fiber neuropathy pain, osteoarthritis pain, acute pain, acute post-operative pain, postsurgical pain, bunionectomy pain, abdominoplasty pain, visceral pain, among others, or combinations thereof. One aspect described herein is a pharmaceutical composition comprising Compound 1–tartaric acid co-crystals and optionally a pharmaceutically acceptable excipient. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[00111] In another embodiment, the compounds and compositions of the present invention are useful for treating neurodegenerative diseases. In one embodiment, the neurodegenerative disease is multiple sclerosis. In another embodiment, the neurodegenerative disease is a genetic form of autism called Pitt Hopkins Syndrome (PTHS).

[00112] Another embodiment described herein is a method for treating or lessening the severity of any type of pain known in the art in a subject in need thereof comprising administering an effective amount of the composition to a subject in need thereof. In one aspect, the pain comprises one or more of abdominal pain, abnormal gastrointestinal motility pain, acute herpes zoster pain, acute inflammatory pain, acute intermittent pain, acute musculoskeletal pain, acute obstetric pain, acute pain, acute post-operative pain (e.g., bunionectomy pain; abdominoplasty pain; knee pain from a total knee replacement; hip pain from a total hip replacement; pain from a laminectomy; pain from a hernia repair; or hemorrhoid removal pain), acute tendonitis pain, acute visceral pain, adiposis dolorosa pain, amyotrophic lateral sclerosis pain, angina-induced pain, anti- retroviral therapy induced neuralgia, anxiety pain, appendicitis pain, arrhythmia pain, arthritis pain, ataxia pain, back pain, Behçet’s disease pain, bipolar disorder pain, bladder and urogenital disease pain, bone pain, brachial plexus avulsion injury pain, breakthrough pain, burn pain, burning mouth syndrome pain, bursitis pain, cancer chemotherapy induced neuralgia, cancer pain, cardiac arrhythmia pain, cardiac pain, carpal tunnel syndrome pain, central pain, cerebral ischemia, Cesarean-section pain, Charcot-Marie Tooth neuropathic pain, chemotherapy induced neuropathic pain, chest pain, cholecystitis pain, chronic and acute headache pain, chronic and acute neuropathic pain, chronic arthritis, chronic pain, chronic visceral pain, cluster headache pain, cold pain, complex regional pain syndrome, Crohn’s disease pain, dental pain (e.g., third molar extraction), depression pain, diabetic neuralgia, diabetic neuropathic pain, diabetic peripheral neuropathic pain, drug therapy induced neuralgia, ectopic proximal and distal discharge pain, endometriosis pain, epilepsy pain, erythromelalgia pain, exercise induced angina pain, exercise induced pain, exercise pain, Fabry’s disease pain, femur cancer pain, fibromyalgia pain, general neuralgias, granuloma annulare pain, Guillain-Barre pain, gut pain, Haglund syndrome pain, head pain, headache pain, hereditary sensory neuropathic pain, hernia pain, herpetic neuralgia pain, HIV- associated neuropathic pain, HIV-associated sensory neuropathic pain, hyperactivity bladder pain, hypertension pain, idiopathic pain, idiopathic sensory neuropathic pain, idiopathic small-fiber neuropathic pain, incontinence pain, inflammatory bowel disease pain, inflammatory pain, injury pain, interstitial cystitis (IC) pain, intestinal obstruction pain, intractable pain, irritable bowel syndrome pain, joint pain, labor pain, leprosy pain, lipoidica pain, malignancy pain, mechanical low back pain, migraine pain, Morton’s neuroma pain, movement disorder pain, multiple sclerosis (MS) pain, musculoskeletal pain, myofascial pain syndrome pain, myotonia pain, neck pain, necrobiosis pain, nerve avulsion injury pain, nerve entrapment injury pain, neurodegenerative disorder pain, neuroendocrine disorder pain, neuropathic low back pain, neuropathic pain, nociceptive pain, non-malignant chronic bone pain, orofacial pain, osteoarthritis pain, painful bladder syndrome, painful legs, painful moving toes, painful neuromas, palpitations, pancreatic pain, paroxysmal extreme pain, pathological cough pain, pelvic pain, peripheral nerve injury pain, phantom pain, phlebitic pain, post spinal cord injury pain, post-amputation pain, post-herpetic neuralgia, post-mastectomy pain, post-stroke pain, postsurgical pain, premenstrual pain, prostatitis pain, pruritis pain, psychiatric disorder associated pain, pyelonephritis pain, radicular pain, radiculopathy, radiotherapy-induced neuropathic pain, renal colic pain, rheumatoid arthritis pain, sarcoidosis pain, sciatica pain, severe pain, shingles pain, sickle cell anemia pain, sinusitis pain, spinal cord injury pain, spinal stenosis pain, sports injury pain, stress-induced angina pain, stress- induced pain, stroke pain, temporomandibular joint pain, tendonitis pain, tension headache pain, thalamic pain, tinnitus pain, trauma pain, traumatic brain injury pain, traumatic neuroma, trigeminal autonomic cephalalgia, trigeminal neuralgia, urinary incontinence pain, visceral pain, widespread pain, or other types of pain.

[00113] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of acute pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. In one embodiment the pain comprises acute pain including bunionectomy pain, abdominoplasty pain, orthopedic procedure pain (e.g., total knee replacement, total hip replacement and laminectomy), hernia pain, hemorrhoid pain, or dental pain (e.g., third molar extractions).

[00114] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of chronic pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. In another embodiment the pain comprises chronic pain including diabetic peripheral neuropathy pain, trigeminal neuralgia, rheumatoid or osteoarthritis pain, chronic lower back pain, post-herpetic neuralgia, or radiculopathy pain.

[00115] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of acute pain, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00116] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of acute pain, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00117] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of gut pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. Another embodiment described herein comprises a method of treating or lessening the severity in a subject of gut pain, including inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00118] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. Another embodiment described herein comprises a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. In another embodiment, neuropathic pain comprises small-fiber neuropathy. In another embodiment, neuropathic pain comprises diabetic neuropathy.

[00119] Another embodiment described herein comprises a method of treating or lessening the severity of musculoskeletal pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. Another embodiment described herein comprises a method of treating or lessening the severity of musculoskeletal pain, such as osteoarthritis pain, back pain, cold pain, burn pain or dental pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00120] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of inflammatory pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. Another embodiment described herein comprises a method of treating or lessening the severity of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00121] Another embodiment described herein comprises a method of treating or lessening the severity of inflammatory pain, such as rheumatoid arthritis pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. [00122] Another embodiment described herein comprises a method of treating or lessening the severity in a subject of idiopathic pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof. Another embodiment described herein comprises a method of treating or lessening the severity of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00123] Another embodiment described herein comprises a method of treating or lessening the severity of pathological cough comprising administering an effective amount of Compound 1– tartaric acid co-crystals or a pharmaceutical composition thereof.

[00124] Another embodiment described herein comprises a method of treating or lessening the severity of trigeminal neuralgia or herpetic neuralgia comprising administering an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00125] In some embodiments, the pain comprises musculoskeletal pain. In some embodiments, the musculoskeletal pain comprises osteoarthritis pain. In some embodiments, the pain comprises neuropathic pain. In some embodiments, the neuropathic pain comprises idiopathic small-fiber neuropathy. As used herein, the phrase“idiopathic small-fiber neuropathy” includes any small fiber neuropathy.

[00126] In some embodiments, the pain comprises acute pain. In some embodiments, the acute pain comprises acute post-operative pain. In some embodiments, the pain comprises postsurgical pain.

[00127] Another embodiment described herein comprises a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00128] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of inflammatory pain. Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain. [00129] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of idiopathic pain. Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[00130] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of acute pain. In some embodiments, acute pain comprises acute post-operative pain.

[00131] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of chronic pain.

[00132] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain).

[00133] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity in a subject of pathological cough.

[00134] Another embodiment described herein comprises the use of a Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof.

[00135] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

[00136] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of abdominal pain, abnormal gastrointestinal motility pain, acute herpes zoster pain, acute inflammatory pain, acute intermittent pain, acute musculoskeletal pain, acute obstetric pain, acute pain, acute post-operative pain (e.g., bunionectomy pain; abdominoplasty pain; knee pain from a total knee replacement; hip pain from a total hip replacement; pain from a laminectomy; pain from a hernia repair; or hemorrhoid removal pain), acute tendonitis pain, acute visceral pain, adiposis dolorosa pain, amyotrophic lateral sclerosis pain, angina-induced pain, anti-retroviral therapy induced neuralgia, anxiety pain, appendicitis pain, arrhythmia pain, arthritis pain, ataxia pain, back pain, Behçet’s disease pain, bipolar disorder pain, bladder and urogenital disease pain, bone pain, brachial plexus avulsion injury pain, breakthrough pain, burn pain, burning mouth syndrome pain, bursitis pain, cancer chemotherapy induced neuralgia, cancer pain, cardiac arrhythmia pain, cardiac pain, carpal tunnel syndrome pain, central pain, cerebral ischemia, Cesarean-section pain, Charcot-Marie Tooth neuropathic pain, chemotherapy induced neuropathic pain, chest pain, cholecystitis pain, chronic and acute headache pain, chronic and acute neuropathic pain, chronic arthritis, chronic pain, chronic visceral pain, cluster headache pain, cold pain, complex regional pain syndrome, Crohn’s disease pain, dental pain (e.g., third molar extraction), depression pain, diabetic neuralgia, diabetic neuropathic pain, diabetic peripheral neuropathic pain, drug therapy induced neuralgia, ectopic proximal and distal discharge pain, endometriosis pain, epilepsy pain, erythromelalgia pain, exercise induced angina pain, exercise induced pain, exercise pain, Fabry’s disease pain, femur cancer pain, fibromyalgia pain, general neuralgias, granuloma annulare pain, Guillain-Barre pain, gut pain, Haglund syndrome pain, head pain, headache pain, hereditary sensory neuropathic pain, hernia pain, herpetic neuralgia pain, HIV-associated neuropathic pain, HIV-associated sensory neuropathic pain, hyperactivity bladder pain, hypertension pain, idiopathic pain, idiopathic sensory neuropathic pain, idiopathic small-fiber neuropathic pain, incontinence pain, inflammatory bowel disease pain, inflammatory pain, injury pain, interstitial cystitis (IC) pain, interstitial cystitis pain, intestinal obstruction pain, intractable pain, irritable bowel syndrome pain, joint pain, labor pain, leprosy pain, lipoidica pain, malignancy pain, mechanical low back pain, migraine pain, Morton’s neuroma pain, movement disorder pain, multiple sclerosis (MS) pain, musculoskeletal pain, myofascial pain syndrome pain, myotonia pain, neck pain, necrobiosis pain, nerve avulsion injury pain, nerve entrapment injury pain, neurodegenerative disorder pain, neuroendocrine disorder pain, neuropathic low back pain, neuropathic pain, nociceptive pain, non-malignant chronic bone pain, orofacial pain, osteoarthritis pain, painful bladder syndrome, painful legs, painful moving toes, painful neuromas, palpitations, pancreatic pain, paroxysmal extreme pain, pathological cough pain, pelvic pain, peripheral nerve injury pain, phantom pain, phlebitic pain, post spinal cord injury pain, post-amputation pain, post-herpetic neuralgia, post-mastectomy pain, post-stroke pain, postsurgical pain, premenstrual pain, prostatitis pain, pruritis pain, psychiatric disorder associated pain, pyelonephritis pain, radicular pain, radiculopathy, radiotherapy-induced neuropathic pain, renal colic pain, rheumatoid arthritis pain, sarcoidosis pain, sciatica pain, severe pain, shingles pain, sickle cell anemia pain, sinusitis pain, spinal cord injury pain, spinal stenosis pain, sports injury pain, stress-induced angina pain, stress-induced pain, stroke pain, temporomandibular joint pain, tendonitis pain, tension headache pain, thalamic pain, tinnitus pain, trauma pain, traumatic brain injury pain, traumatic neuroma, trigeminal autonomic cephalalgia, trigeminal neuralgia, urinary incontinence pain, visceral pain, widespread pain, or other types of pain. In one aspect, the pain comprises osteoarthritis or rheumatoid arthritis pain. In another aspect, the pain comprises trigeminal neuralgia or herpetic neuralgia.

[00137] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of neuropathic pain. In one aspect, the neuropathic pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia. In another embodiment, neuropathic pain comprises small-fiber neuropathy. In another embodiment, neuropathic pain comprises diabetic neuropathy.

[00138] Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the treatment of pain. In one aspect, the pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton’s neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

[00139] In another embodiment, the disclosure comprises a Compound 1-tartaric acid co- crystal, or a pharmaceutical composition thereof, for use as a medicament.

[00140] In another embodiment, the disclosure comprises a Compound 1-tartaric acid co- crystal, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of pain.

[00141] In some embodiments, the pain comprises acute pain. In some embodiments, acute pain comprises acute post-operative pain.

[00142] In some embodiments, the pain comprises chronic pain.

[00143] In some embodiments, the pain comprises gut pain.

[00144] In some embodiments, the pain comprises neuropathic pain. In some embodiments, neuropathic pain comprises small-fiber neuropathy. In some embodiments, neuropathic pain comprises idiopathic small-fiber neuropathy. In some embodiments, neuropathic pain comprises post-herpetic neuralgia. In some embodiments, neuropathic pain comprises trigeminal neuralgia. In another embodiment, neuropathic pain comprises diabetic neuropathy.

[00145] In some embodiments, the pain comprises musculoskeletal pain. In some embodiments, musculoskeletal pain comprises osteoarthritis pain.

[00146] In some embodiments, the pain comprises inflammatory pain.

[00147] In some embodiments, the pain comprises cancer pain. [00148] In some embodiments, the pain comprises idiopathic pain.

[00149] In some embodiments, the pain comprises postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain).

[00150] In some embodiments, the pain comprises visceral pain.

[00151] As used herein a“effective amount” of the Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[00152] Another embodiment described herein is the use of Compound 1–tartaric acid co- crystals or a pharmaceutical composition thereof described herein for the manufacture of a medicament for use in one or more of the foregoing methods.

[00153] Another embodiment described herein is the use of Compound 1–tartaric acid co- crystals or a pharmaceutical composition thereof described herein for the treatment of pain in one or more of the foregoing methods.

[00154] The Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof described herein can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (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 as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds described herein. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally 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 hereby incorporated by reference.

[00155] In one embodiment, appropriate therapeutic agents are selected from the following:

[00156] an opioid analgesic, e.g., morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

[00157] a nonsteroidal antiinflammatory drug (NSAID), e.g., aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[00158] a barbiturate sedative, e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

[00159] a benzodiazepine having a sedative action, e.g., chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[00160] a histamine (H1) antagonist having a sedative action, e.g., diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; [00161] a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

[00162] a skeletal muscle relaxant, e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadine;

[00163] an NMDA receptor antagonist, e.g., 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 formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g., ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l- piperidinyl]-l- hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[00164] an alpha-adrenergic, e.g., doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;

[00165] a tricyclic antidepressant, e.g., desipramine, imipramine, amitriptyline or nortriptyline;

[00166] an anticonvulsant, e.g., carbamazepine (Tegretol^®), lamotrigine, topiramate, lacosamide (Vimpat^®) or valproate;

[00167] a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g., (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H-[l,4]diazocino[2,l-g][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), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[00168] a muscarinic antagonist, e.g., oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[00169] a COX-2 selective inhibitor, e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[00170] a coal-tar analgesic, in particular paracetamol;

[00171] a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, belaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion^® or sarizotan;

[00172] a vanilloid receptor agonist (e.g., resiniferatoxin or civamide) or antagonist (e.g., capsazepine, GRC-15300);

[00173] a beta-adrenergic such as propranolol;

[00174] a local anesthetic such as mexiletine;

[00175] a corticosteroid such as dexamethasone;

[00176] a 5-HT receptor agonist or antagonist, particularly a 5-HT_1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[00177] a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[00178] a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl- 4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

[00179] Tramadol^®, Tramadol ER (Ultram ER^®), Tapentadol ER (Nucynta^®);

[00180] a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl- sulphonyl)phenyl]-l-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-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl- piperazin-l-yl-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3- azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pvrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l- ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3- d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin- l-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;

[00181] an alpha-2-delta ligand such as gabapentin (Neurontin^®), gabapentin GR (Gralise^®), gabapentin, enacarbil (Horizant^®), pregabalin (Lyrica^®), 3-methyl gabapentin, (l[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, [(lR,5R,6S)-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;

[00182] a cannabinoid such as KHK-6188;

[00183] a metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

[00184] a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, D,L- fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

[00185] a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan^®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

[00186] a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta^®), milnacipran and imipramine;

[00187] an inducible nitric oxide synthase (iNOS) inhibitor such as 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-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]- S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-4- chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5- thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(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 guanidinoethyldisulfide;

[00188] an acetylcholinesterase inhibitor such as donepezil;

[00189] a prostaglandin E2 subtype 4 (EP4) antagonist 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;

[00190] a leukotriene B4 antagonist; 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;

[00191] a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5- trimethyl-6-(3-pyridylmethyl)-l,4-benzoquinone (CV-6504);

[00192] a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS- 201) or eslicarbazepine acetate;

[00193] a Na_V1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, RG6029/GDC-0310, DSP-2230, and those such as disclosed in WO 2011/140425; WO 2012/106499; WO 2012/112743; WO 2012/125613, WO 2012/116440, WO 2011026240, WO 2013109521; US 8,883,840; or US 8,466,188, the entire contents of each application which are hereby incorporated by reference;

[00194] a NaV1.7 blocker such as (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¢-piperidine]-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¢-piperidine]-1¢-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-1¢-yl]-(5-isopropoxy-6-methyl-2- pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-1¢-yl]methanone, 5-[2- methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢- piperidine]-1¢-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6- (trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-1¢-yl]methanone, 2,2,2-trifluoro-1-[1¢-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1¢-(5- isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4¢-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1¢-(5-isopentyloxypyridine-2- carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-6-yl]ethanone, (4- isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4¢-piperidine]-1¢-yl]methanone, 2,2,2-trifluoro-1-[1¢-(5-isopentyloxypyridine-2- carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1¢-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4¢-piperidine]-6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6- (trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-1¢-yl]-[3-methoxy-4- [(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1¢-(5-isopropoxy-6-methyl- pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-6- yl]ethanone, 1-[1¢-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy- 3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢- piperidine]-1¢-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-1¢-yl]-[4-(3,3,3- trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4- piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4¢-piperidine]-1¢-yl]methanone;

[00195] a Na_V1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in International Patent Application Publication Nos. WO 2008/135826; WO 2006/011050; WO 2013/061205; WO 2013131018; WO 2013114250; WO 2014/1280808; WO 2014/120815; and WO 2014/120820; U.S. Patent Application Publication No. US 2013/0303535; and U.S. Patent No.8,466,188, the entire contents of each which are hereby incorporated by reference.

[00196] a NaV1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo- 1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo- 1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin- 4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N- (2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2- methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2- methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4- fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2- hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2- oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4- difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo- 1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4- fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, In one embodiment, the compound is 3-(4-fluoro-2-methoxyphenoxy)-N-(3- (methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3- carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3- sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3- sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2- methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 3-(4-fluoro-2- methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4- fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4- fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2- methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline- 2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2- carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2- (2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4- fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2- methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4- fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3- sulfamoylphenyl)benzamide or N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide;

[00197] a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230 or BL-1021;

[00198] a 5-HT3 antagonist, such as ondansetron;

[00199] a TPRV 1 receptor agonist, such as capsaicin (NeurogesX^®, Qutenza^®); and the pharmaceutically acceptable salts and solvates thereof;

[00200] a nicotinic receptor antagonist, such as varenicline;

[00201] an N-type calcium channel antagonist, such as Z-160;

[00202] a nerve growth factor antagonist, such as tanezumab;

[00203] an endopeptidase stimulant, such as senrebotase;

[00204] an angiotensin II antagonist, such as EMA-401.

[00205] In one embodiment, the additional appropriate therapeutic agents are selected from V-116517, Pregbalin, controlled release Pregbalin, Ezogabine (Potiga^®), Ketamine/amitriptyline topical cream (Amiket^®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur^®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558. [00206] In another embodiment, the additional appropriate therapeutic agents are selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4- (trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[00207] In another embodiment, additional appropriate therapeutic agents are selected from the following:

[00208] (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[00209] (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac

(including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[00210] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

[00211] (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[00212] (5) a histamine (H₁) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[00213] (6) a sedative such as glutethimide, meprobamate, methaqualone or

dichloralphenazone;

[00214] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[00215] (8) an NMDA receptor antagonist, e.g. 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 formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l- piperidinyl]-l- hydroxyethyl-3,4-dihydro-2(lH)-quinolinone;

[00216] (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;

[00217] (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

[00218] (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[00219] (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl- 5-(4- methylphenyl)-7H-[l,4]diazocino[2,l-g][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), aprepitant, lanepitant, dapitant or 3-[[2- methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[00220] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[00221] (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[00222] (15) a coal-tar analgesic, in particular paracetamol;

[00223] (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

[00224] (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

[00225] (18) a beta-adrenergic such as propranolol;

[00226] (19) a local anesthetic such as mexiletine;

[00227] (20) a corticosteroid such as dexamethasone; [00228] (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[00229] (22) a 5-HT_2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l- [2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[00230] (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N- methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2- chloropyridine (ABT-594) or nicotine;

[00231] (24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

[00232] (25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl- sulphonyl)phenyl]-l-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-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl- piperazin-l-yl-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-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-l- ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3- d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin- l-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;

[00233] (26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[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, [(lR,5R,6S)-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;

[00234] (27) a cannabinoid such as KHK-6188;

[00235] (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

[00236] (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l- fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

[00237] (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

[00238] (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[00239] (32) an inducible nitric oxide synthase (iNOS) inhibitor such as 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-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)- butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5- (trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(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

guanidinoethyldisulfide;

[00240] (33) an acetylcholinesterase inhibitor such as donepezil;

[00241] (34) a prostaglandin E2 subtype 4 (EP4) antagonist 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;

[00242] (35) a leukotriene B4 antagonist; 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;

[00243] (36) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy- 3,4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5- trimethyl-6-(3-pyridylmethyl)-l,4-benzoquinone (CV-6504);

[00244] (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate;

[00245] (38) a NaV1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074, BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP 1706, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in WO2011/140425 (US2011/306607); WO2012/106499 (US2012196869); WO2012/112743 (US2012245136); WO2012/125613 (US2012264749), WO2012/116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, or

WO2013/109521 (US2015005304), the entire contents of each application hereby incorporated by reference.

[00246] (38a) a Na_V1.7 blocker such as (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'-piperidine]-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'-piperidine]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2- pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2- methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6- (trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5- isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2- carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4- isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2- carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6- (trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[3-methoxy-4- [(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl- pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- yl]ethanone, 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy- 3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[4-(3,3,3- trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4- piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone.

[00247] (39) a Na_V1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008/135826 (US2009048306), WO2006/011050 (US2008312235),

WO2013/061205 (US2014296313), US20130303535, WO2013131018, US8466188,

WO2013114250 (US2013274243), WO2014/120808 (US2014213616), WO2014/120815 (US2014228371) WO2014/120820 (US2014221435), WO2015/010065 (US20160152561), WO2015/089361 (US20150166589), WO2019014352 (US20190016671), WO2020/014243 and WO2020/014246 the entire contents of each application hereby incorporated by reference.

[00248] (39a) a NaV1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N- (2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo- 1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin- 4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N- (2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2- methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2- methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4- fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2- hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2- oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4- difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo- 1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4- fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2- methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2- methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2- carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4- chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)- N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4- (trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin- 4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2- carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4- fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2- methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4- fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3- sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3- carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2- fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine- 2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine- 2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3- carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)- 2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4- pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4- carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6- [3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3- carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine- 2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2- [2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4- (difluoromethoxy)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro- phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4- cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4- (trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine- 2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3- (trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide.

[00249] (40) a combined Na_V1.7 and Na_V1.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;

[00250] (41) a 5-HT3 antagonist, such as ondansetron;

[00251] (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

[00252] (43) a nicotinic receptor antagonist, such as varenicline;

[00253] (44) an N-type calcium channel antagonist, such as Z-160; [00254] (45) a nerve growth factor antagonist, such as tanezumab;

[00255] (46) an endopeptidase stimulant, such as senrebotase;

[00256] (47) an angiotensin II antagonist, such as EMA-401;

[00257] (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®));

[00258] (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

[00259] (50) bupivacaine and meloxicam combination (e.g., HTX-011).

[00260] In one embodiment, the additional appropriate therapeutic agents are selected from XEN907, NW3509, GTX analogs, ASP 1807, OLP 1002, ST-2427, V-116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.

[00261] In another embodiment, the additional appropriate therapeutic agents are selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4- (trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[00262] In another embodiment, the additional therapeutic agent is selected from a GlyT2/5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGR1 inhibitor such as Brivoglide (AYX1), an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, Apadaz, NKTR181

(oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.

[00263] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[00264] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the Na_V1.7 and Na_V1.8 blockers identified above. [00265] The amount of additional therapeutic agent present in the compositions described herein will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions will range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[00266] Another embodiment described herein comprises a method of inhibiting a voltage- gated sodium channel in a subject comprising administering to the subject Compound 1–tartaric acid co-crystals or a composition thereof. In one aspect, the voltage-gated sodium channel is Na_V1.8.

[00267] Another embodiment described herein comprises a method of inhibiting a voltage- gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of Compound 1–tartaric acid co-crystals or a composition thereof. In one aspect, the voltage-gated sodium channel is Na_V1.8. The term“biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[00268] Inhibition of NaV1.8 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative evaluation of new sodium channel inhibitors. Without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Na_V1.8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of Na_V1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a“Na_V1.8 -mediated disease, condition, or disorder.” Another embodiment described herein comprises a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of NaV1.8 is implicated in the disease state.

[00269] The activity of a compound described herein as an inhibitor of NaV1.8 may be assayed according to methods described in U.S. Patent No.9,163,042 which is incorporated herein by reference for the teachings thereof, or according to methods available to one of ordinary skill in the art. [00270] It will be readily apparent to one of ordinary skill in the relevant arts that suitable modifications and adaptations to the compositions, formulations, methods, and applications described herein can be made without departing from the scope of any embodiments or aspects thereof. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein can be combined in any variations or iterations. The scope of the compositions, formulations, processes, and methods described herein include all actual or potential combinations of embodiments, aspects, options, examples, and preferences herein described. Compositions and formulations described herein may omit any component on include any component disclosed elsewhere herein. The ratios of the mass of any component of any of the formulations disclosed herein to the mass of any other component in the formulation or to the total mass of the other components in the formulation are hereby disclosed as if they were expressly disclosed. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes exemplary embodiments. All patents and publications cited herein are incorporated by reference herein for the relevant specific teachings thereof.

EXAMPLES

Example 1

[00271] Synthesis Methods

[00272] A synthesis method for 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4- yl)-4-(trifluoromethyl)benzamide (Compound 1) is described in Example 14 (col. 178, line 43– col.179, line 16) of U.S. Patent No.9,051,270, which is incorporated herein by reference for the teachings thereof.

[00273] A modification of this method was used herein. Briefly, a mixture of 2-fluoro-N- (2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)-benzamide, 4-fluoro-2-methyl-phenol, K₂CO₃, and N,N-dimethylformamide (DMF) was heated at 100 °C for 1.5 hours. Once complete, the reaction was cooled and diluted with water, the layers separated and then crude Compound 1 was isolated from the organic layer by crystallization. The solids were slurried in water and then slurried with heat in isopropyl acetate to produce purified Compound 1. See Scheme 2, Steps 1–2.

[00274] Compound 1 was isolated as Compound 1–tartaric acid co-crystal. The polymorphism of Compound 1–tartaric acid co-crystal was investigated under several conditions which included solvent mediated transformation (slurry) experiments in organic solvents and water. A single crystalline form of the co-crystal was observed.

[00275] The Compound 1–tartaric acid co-crystal drug substance was characterized and proof of structure was determined. All data presented are in agreement with the assigned chemical structure of the drug substance.

[00276] Compound 1, tartaric acid, ethyl acetate, and ethanol were stirred until complete conversion to the co-crystal was achieved, at least 12 h at 15–30 °C. The product was isolated by filtration and dried with heat under vacuum (35–45 °C). See Scheme 2, Step 3. The process was also successful using only ethyl acetate as the solvent.

Scheme 2: Synthesis of Compound 1 and Tartaric Acid Co-Crystals

[00277] In another process, Compound 1 (1000 g) was slurried with tartaric acid (9.4 g, 0.063 moles, 0.025 equivalents) in ethyl acetate (26.62 L) and pure ethanol (2.03 L) at 20–30 °C. The slurry was seeded with Compound 1–tartaric acid co-crystals (50 g, 5.0% by mass) and aged for at least 30 minutes. A solution of tartaric acid (179 g, 1.192 moles, 0.485 equivalents) in ethanol (1.35 L) was charged to the stirring slurry over 24 h. The mixture was aged for an additional 2 h or until conversion to the co-crystal was confirmed to be complete (by XRPD). The crystalline white to off-white solid product was isolated by filtration. The solids were washed with 10% w/w ethanol in ethyl acetate (1 L) and then dried at 35–45 °C under vacuum to afford 1019 g of Compound 1–tartaric acid co-crystal (86% yield). See Scheme 2, Step 3. This produced 2-(4- fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide hemi(2,3-dihydroxysuccinate) as shown below:

[00278] The solid Compound 1–tartaric acid co-crystals were jet-milled and had a target d50 of approximately 2–4 mm (e.g., d50 not more than 5 mm). The larger batches were put through a co-mill prior to jet-milling because the neat crystalline material was quite granular.

[00279] About 3.74 kg of Compound 1–tartaric acid co-crystals were milled and this yielded 3.16 kg of micronized product (plus 0.36 kg of samples that were taken).

Example 2

[00280] Physicochemical Characteristics

[00281] The physical and chemical characteristics of the Compound 1–tartaric acid co- crystals are listed in Table 1.

Example 3

[00282] HPLC Method

[00283] The operating conditions for the HPLC method for assaying the Compound 1– tartaric acid co-crystal drug substance and the retention times are provided in Table 2.

Example 4

[00284] Elemental Analysis

[00285] The elemental analysis of Compound 1–tartaric acid co-crystal drug substance is presented in Table 3. The measured elemental composition is consistent with the theoretical composition as determined from the molecular formula C44H34F8N4O12.

Example 5

[00286] High-Resolution Mass Spectrum Analysis

[00287] Compound 1 was analyzed by High Resolution Accurate Mass Liquid Chromatography Mass Spectrometry (HRAM-LCMS) to provide confirmation of the molecular weight and molecular formula of Compound 1 present in the Compound 1–tartaric acid co-crystals. The high-resolution accurate mass (HRAM) analysis was performed using an LTQ-Orbitrap FTMS. The instrument was calibrated with a standard calibration solution consisting of caffeine, MRFA and Ultramark 1621 in an acetonitrile:methanol:water solution containing 1% acetic acid (Thermo-Fisher). A sample of Compound 1–tartaric acid co-crystal was dissolved in methanol. The injection volume was 1 µL. The Agilent HPLC 1290 Infinity II system had a Waters Acquity UPLC BEH C181.7 mm, 2.1 × 100 mm HPLC column. The mass spectrometer was operated in a positive ionization mode with an ESI source. Mobile phase A: 0.1% formic acid in water. Mobile phase B was acetonitrile. The gradient was 20% B to 80% B in 6 minutes with a flow rate of 0.5 mL/min.

[00288] The molecular formula of Compound 1, free form, present in the tartaric acid co- crystals was confirmed as C₂₀H₁₄O₃N₂F₄ by accurate mass measurement. The mass spectrum in FIG.1 shows a [M+H]⁺ peak at m/z 407.1033 that is consistent with a calculated mass of 407.1013 for the assigned structure of Compound 1. The error in the observed mass is 4.7650 ppm. Compound 1 was analyzed as free form since tartaric acid dissolved in methanol during sample preparation. The calculated molecular weight for the (Compound 1)₂-tartaric acid co-crystal is 964.3 g/mole. Example 6

[00289] NMR Spectroscopy

[00290] The NMR spectra (1D and 2D) of Compound 1–tartaric acid co-crystal drug substance were acquired at 500 MHz (¹H) and 125 MHz (¹³C) on a Bruker 500 MHz spectrometer equipped with a 1.7 mm probe as shown in FIG.2 and 3 respectively. The sample was prepared for NMR analysis by diluting it in 99.9% deuterated dimethyl sulfoxide (DMSO-d6). DMSO-d6 displays a residual proton resonance at 2.49 ppm, a HOH/HOD resonance at ~3.3, and a carbon (¹³C) resonance of 39.5. These proton and carbon resonances were used as internal references for determining the unknown resonances in the 1D spectrum of the compound. The ¹H- and ¹³C-NMR assignments (Table 4) were confirmed by 2D NMR spectral analysis.

[00291] The molar ratio of 2:1 for Compound 1–tartaric acid co-crystal is confirmed by the integration of protons peaks from tartaric acid (atom 2¢ at 4.34 ppm) to the proton in the amide group of Compound 1 (Compound 1 atom 7 at 10.69 ppm). The results below show that the ratio of Compound 1 to tartaric acid is 2:1. Spectroscopic data of the compound are consistent with the assigned structure shown below.

Compound 1–Tartaric Acid Co-crystal Structure and Numbering Scheme

Example 7

[00292] Solid State NMR

[00293] Compound 1–tartaric acid co-crystals were analyzed using solid state NMR using a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe. Samples were packed into 4 mm ZrO2 rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using ¹H MAS T1 saturation recovery relaxation experiment in order to set up proper recycle delay of the ¹³C cross-polarization (CP) MAS experiment. The fluorine relaxation time was measured using ¹⁹F MAS T₁ saturation recovery relaxation experiment in order to set up proper recycle delay of the ¹⁹F MAS experiment. The CP contact time of carbon CPMAS experiment was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) was employed. The carbon Hartmann- Hahn match was optimized on external reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz. The ¹⁹F spectrum is shown in FIG.4A and the peaks are listed in Table 5. The ¹³C spectrum is shown in FIG.4B and the peaks are listed in Table 6.

Example 8

[00294] Infra-Red Spectroscopy

[00295] The IR spectrum of Compound 1-tartaric acid co-crystal was obtained on a NicoletTM 6700 FT-IR spectrometer with a diamond ATR.

[00296] The IR spectrum for Compound 1–tartaric acid co-crystal is shown in FIG.5 and vibrational assignments are summarized in Table 7. The IR spectrum is consistent with the assigned structure of Compound 1–tartaric acid co-crystal drug substance.

Example 9

[00297] UV Spectroscopy

[00298] The UV-visible spectrum of the Compound 1–tartaric acid co-crystal was obtained in methanol using an Agilent UV-Vis Cary SD008296.

[00299] The UV spectrum for Compound 1–tartaric acid co-crystal is shown in FIG. 6. Using a concentration of approximately 0.01 mg/mL drug substance in methanol, a representative spectrum was acquired. Two maxima are observed at approximately 204 nm and 260 nm, respectively. Example 10

[00300] X-Ray Powder Diffraction Spectroscopy

[00301] X-ray powder diffraction (XRPD) patterns were recorded at room temperature in reflection mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-2 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X- Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Å). The powder sample was placed in a back filled sample holder and loaded into the instrument. The sample was scanned over the range of about 3° to about 40° 2q with a step size of 0.0131303° and 49.725s per step.

[00302] The XRPD pattern for Compound 1–tartaric acid co-crystal is shown in FIG. 7. The salient peaks are listed in Table 8.

Example 11

[00303] Differential Scanning Calorimetry (DSC)

[00304] DSC data were acquired using a TA Instruments Q2000 or equivalent instrumentation. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10 °C/min to a temperature of 300 °C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The observed endo- and exo- therms were integrated between baseline temperature points that were above and below the temperature range over which the endotherm was observed. The data reported were the onset temperature, peak temperature and enthalpy of dehydration and melting.

[00305] The DSC thermogram of Compound 1–tartaric acid co-crystal drug substance is shown in FIG.8. An endothermic peak indicative of the melting point is observed at 230 °C with an onset temperature at 229 °C. An additional peak is observed at 146 °C with an onset temperature at 122 °C, indicating dehydration.

Example 12

[00306] Thermogravimetric Analysis

[00307] TGA data were collected on a TA Discovery Thermogravimetric Analyzer or equivalent instrumentation. A sample with weight of approximately 1–5 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min. Data were collected by Thermal Advantage Q Series™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE).

[00308] The TGA thermogram of Compound 1–tartaric acid co-crystal drug substance is shown in FIG. 9. The thermogram shows a loss of 1.07% by mass during the transition from ambient temperature to 150 °C. Example 13

[00309] Compound 1–Tartaric Acid Co-crystal Tablet Manufacturing

[00310] Tablets containing 355 mg of Compound 1–tartaric acid co-crystals (equivalent to 300 mg of Compound 1) were manufactured for oral administration. The tablet composition, along with the quality reference and function of each component, are provided in Table 9.

[00311] The flow diagram for the manufacturing of Compound 1–tartaric acid co-crystal tablets is shown in Figure 10. [00312] Process Description

[00313] Compound 1–tartaric acid co-crystal, microcrystalline cellulose, croscarmellose sodium and magnesium stearate are individually screened, dispensed and blended to form the intragranular blend. The intragranular blend is then dry granulated with a roller compactor and milled into granules. The granules are further blended with screened microcrystalline cellulose, croscarmellose sodium and magnesium stearate to form the extragranular blend. The extragranular blend is then compressed to form Compound 1–tartaric acid co-crystal tablets. Following compression, tablets are packaged, tested, and released. Example 14

[00314] Uniformity of Dosage Units

[00315] Compound 1 is appropriately extracted from the content of the Compound 1– tartaric acid co-crystal tablets and analyzed by HPLC. The HPLC operating parameters and peak identification for content uniformity are described in Table 10.

[00316] Batch Analyses (Compound 1–tartaric acid co-crystal, Tablet)

[00317] Compound 1–tartaric acid co-crystal tablets were manufactured using the process described herein. A batch analyses summary for representative Compound 1–tartaric acid co- crystal tablets is provided in Table 11.

[00318] Data reported is from the t0 time point in the 12-month stability study. Example 15

[00319] Dissolution

[00320] The HPLC parameters for the dissolution method for Compound 1–tartaric acid co- crystal tablets are the same as the method use to analyze the uniformity of dosage units shown in Table 10.

[00321] The operating conditions for dissolution testing of the Compound 1–tartaric acid co-crystal tablets are provided in Table 12. The method for determining the release of Compound 1 from the 300 mg tablet formulation uses U.S.P. Apparatus 2, paddle speed of 75 rpm, and a medium of 1% sodium dodecyl sulfate in 0.1 N HCl at 37 °C. General dissolution methods are described in the United States Pharmacopeia Convention〈711〉 Dissolution (2011), which is incorporated by reference herein for such teachings. Samples were removed during dissolution at 5, 10, 15, 20, 30, 45, and 60, minute time points while the paddle speed was increased to ³250 rpm to homogenize the solution. The samples were filtered through 10 µm PVDF filters and were analyzed by HPLC. Dissolution results are shown in Table 13.

Example 16

[00322] Stability

[00323] No significant change in chemical or physical stability was observed for Compound 1–tartaric acid co-crystal tablets after 1 month of storage at 25 °C/60% relative humidity (RH) and 40 °C/75% RH in open containers. [00324] Stability Protocol

[00325] The lead-in stability protocol for development, 355 mg Compound 1–tartaric acid co-crystal tablets (equivalent to 300 mg of Compound 1), in open containers is provided in Table 14. The stability protocol for the clinical lot of 355 mg Compound 1–tartaric acid co-crystal tablets packaged in HDPE bottles is provided in Table 15.

Example 17

[00326] Degradation Products

[00327] Compound 1 is appropriately extracted from the content of the tablet and analyzed by HPLC. The HPLC operating parameters and peak identification for the HPLC method is provided in Table 16.

[00328] Stability and dissolution results are shown in Tables 17–20.

Table 20. Stability Data for Compound 1–Tartaric Acid Co-crystal Tablets, 40 °C/75% RH

Claims

What is claimed is: 1. A co-crystal comprising Compound 1

tartaric acid.

2. The co-crystal of claim 1, wherein the Compound 1 and tartaric acid are present in a molar ratio of 2:1. 3. The co-crystal of claim 1 or 2, wherein the co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one peak selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.

3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 degrees 2 theta (2 q) ± 0.2, when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation.

4. The co-crystal of any one of claims 1–3, wherein the co-crystal is characterized by an X- ray powder diffraction (XRPD) pattern comprising at least three peak positions selected from 7.7, 9.1, 14.6, 15.3, 16.5, 17.6, 17.8, 18.3, 19.2, 20.0, 21.2, 22.6, 24.2, 25.1, 25.6, or 26.5 degrees 2 theta (2 q) ± 0.2, when the XRPD is collected from about 5 to about 40 degrees 2 q using Cu Ka radiation.

5. The co-crystal of any one of claims 1–4, wherein the co-crystal has an XRPD pattern substantially similar to the XRPD pattern of FIG.7.

6. The co-crystal of any one of claims 1–5, wherein the co-crystal is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 146 °C (±2.0 °C) indicative of dehydration and an endothermic peak at 230 °C (±2.0 °C) indicative of the melting point.

7. The co-crystal of any one of claims 1–6, wherein the co-crystal have a 1.07% mass loss from ambient temperature to 150 °C in a thermogravimetric analysis.

8. The co-crystal of any one of claims 1–7, wherein the co-crystal is characterized by an infra- red (IR) spectrum comprising at least three peak positions selected from wavenumbers 1121, 1183, 1336, 1492, 1566, 1651, 1693, 1722, 1740, 3372, or 3338 cm^-1.

9. The co-crystal of any one of claims 1–8, wherein the co-crystal is characterized by a UV spectrum comprising two maxima at approximately 204 nm and 260 nm.

10. The co-crystal of any one of claims 1–9, wherein the co-crystal is characterized by: a ¹H- and ¹³C-NMR chemical shifts shown in Table 4 and substantially similar to the NMR spectra of FIG. 2 or 3, respectively when acquired in deuterated dimethyl sulfoxide (DMSO-d6) at 500 MHz (¹H) and 125 MHz (¹³C).

11. The co-crystal of any one of claims 1–10, wherein the co-crystal is characterized by: a ¹⁹F- solid state NMR spectrum substantially similar to that of FIG. 4A, or having the peaks listed in Table 5; or a ¹³C-solid state NMR spectrum substantially similar to that of FIG. 4B, or having the peaks listed in Table 6.

12. A drug substance comprising the co-crystal of any one of claims 1–11.

13. A pharmaceutical composition comprising the co-crystal of any one of claims 1–11 and one or more pharmaceutically acceptable excipients.

14. The composition of claim 12, wherein the composition comprises a tablet.

15. The composition of claim 13 or 14, wherein the Compound 1–tartaric acid co-crystal is micronized.

16. The composition of any one of claims 13–15, wherein the Compound 1–tartaric acid co- crystal has a median volume particle size, D(v,0.5) of about 1–10 mm, 1–5 mm, 1–4 mm, or 2–4 mm.

17. The composition of any one of claims 13–15, wherein the Compound 1–tartaric acid co- crystal has a median volume particle size, D(v,0.5) of about £ 10 mm, £ 5 mm, £ 4 mm, £ 3 mm, £ 2.5 mm, or £ 2.0 mm.

18. The composition of any one of claims 13–17, wherein the Compound 1–tartaric acid co- crystal has a median volume particle size, D(v,0.5) of about 2–4 mm.

19. The composition of any one of claims 13–18, wherein the pharmaceutically acceptable excipients comprise:

(a) one or more fillers or diluents;

(b) one or more disintegrants; and

(c) one or more lubricants.

20. The composition of claim 19, wherein the filler comprises one or more of lactose, lactose monohydrate, glucose, fructose, sucrose, sorbitol, mannitol, dicalcium phosphate dihydrate, cellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, crospovidone, or a combination thereof.

21. The composition of claim 19, wherein the disintegrant comprises one or more of crospovidone, croscarmellose sodium, alginic acid, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof.

22. The composition of claim 19, wherein the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, talc, glyceryl behenate, or a combination thereof.

23. The composition of any one of claims 13–22, further comprising one or more colorants, flavorings, additional fillers or diluents, additional disintegrants, additional lubricants, binders, glidants, coatings, or other pharmaceutically acceptable excipients.

24. The composition of any one of claims 19–23, wherein the filler comprises microcrystalline cellulose.

25. The composition of any one of claims 19–24 wherein the disintegrant comprises croscarmellose sodium.

26. The composition of any one of claims 19–25, wherein the lubricant comprises magnesium stearate.

27. The composition of any one of claims 19–26, wherein the composition comprises:

(a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals;

(b) about 30% to about 70% by mass of one or more fillers or diluents;

(c) about 1% to about 10% by mass of one or more disintegrants; and

(d) about 0.1% to about 5% by mass of one or more lubricants.

28. The composition of any one of claims 19–27, wherein the composition comprises:

(a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals;

(b) about 30% to about 70% by mass of microcrystalline cellulose;

(c) about 1% to about 10% by mass of croscarmellose sodium; and

(d) about 0.1% to about 5% by mass of magnesium stearate.

29. The composition of any one of claims 19–28, wherein the composition comprises:

(a) about 30% to about 40% by mass of Compound 1–tartaric acid co-crystals; (b) about 50% to about 60% by mass of microcrystalline cellulose;

(c) about 3% to about 7% by mass of croscarmellose sodium; and

(d) about 1% to about 3% by mass of magnesium stearate.

30. The composition of any one of claims 19–29, wherein the composition further comprises an intragranular composition and an extragranular composition.

31. The composition of claim 30, wherein:

the intragranular composition comprises:

(a) Compound 1–tartaric acid co-crystals;

(b) a filler;

(c) a disintegrant;

(d) a lubricant;

(e) optionally a ductile or brittle filler; and

(f) optionally a glidant; and

the extragranular composition comprises:

(g) a filler;

(h) a disintegrant;

(i) a lubricant; and

(j) optionally a glidant.

32. The composition of claim 30 or 31, wherein the composition comprises:

an intragranular composition comprising:

(a) Compound 1–tartaric acid co-crystals;

(b) a filler;

(c) a disintegrant; and

(d) a lubricant; and

an extragranular composition comprising:

(e) a filler;

(f) a disintegrant; and

(g) a lubricant.

33. The composition of any one of claims 30–32, wherein the composition comprises:

an intragranular composition comprising:

(a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 5% to about 10% of a filler;

(c) about 1% to about 5% by mass of a disintegrant; and

(d) about 0.2% to about 1% by mass of a lubricant; and

an extragranular composition comprising:

(e) about 30% to about 60% by mass of a filler;

(f) about 1.5% to about 5% by mass of a disintegrant; and

(g) about 1% to about 5% by mass of a lubricant.

34. The composition of claim 30–33, wherein

the intragranular composition comprises:

(a) Compound 1–tartaric acid co-crystals;

(b) microcrystalline cellulose;

(c) croscarmellose sodium, and

(d) magnesium stearate; and

the extragranular composition comprises:

(e) microcrystalline cellulose;

(f) croscarmellose sodium; and

(g) magnesium stearate.

35. The composition of any one of claims 30–34, wherein the composition comprises:

an intragranular composition comprising:

(a) about 20% to about 50% by mass of Compound 1–tartaric acid co-crystals; (b) about 5% to about 10% by mass of microcrystalline cellulose; (c) about 1% to about 5% by mass of croscarmellose sodium; and (d) about 0.2% to about 1% by mass of magnesium stearate; and an extragranular composition comprising:

(e) about 30% to about 60% by mass of microcrystalline cellulose; (f) about 1.5% to about 5% by mass of croscarmellose sodium; and

(g) about 1% to about 5% by mass of magnesium stearate.

36. The composition of any one of claims 30–35, wherein the composition comprises:

an intragranular composition comprising:

(a) about 30% to about 40% by mass of Compound 1–tartaric acid co-crystals; (b) about 6% to about 8% by mass of microcrystalline cellulose; (c) about 1% to about 2% by mass of croscarmellose sodium; and (d) about 0.2% to about 0.8% by mass of magnesium stearate; and an extragranular composition comprising:

(e) about 45% to about 55% by mass of microcrystalline cellulose;

(f) about 2% to about 4% by mass of croscarmellose sodium; and (g) about 1% to about 3% by mass of magnesium stearate.

37. The composition of any one of claims 30–36, wherein the composition comprises:

an intragranular composition comprising:

(a) about 35% by mass of Compound 1–tartaric acid co-crystals; (b) about 7% by mass of microcrystalline cellulose;

(c) about 2% by mass of croscarmellose sodium; and

(d) about 0.6% by mass of magnesium stearate; and

an extragranular composition comprising:

(e) about 50% by mass of microcrystalline cellulose;

(f) about 3% by mass of croscarmellose sodium; and

(g) about 1.5% by mass of magnesium stearate.

38. The composition of any one of claims 13–37, wherein the composition comprises about 50 mg to about 2000 mg of Compound 1–tartaric acid co-crystals.

39. The composition of any one of claims 13–38, wherein the composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 750 mg, or about 1000 mg of Compound 1–tartaric acid co-crystal.

40. The composition of any one of claims 13–39, wherein the composition comprises about 350 mg of Compound 1–tartaric acid co-crystals.

41. The composition of any one of claims 13–40, wherein the composition comprises about 300 mg of Compound 1 present in Compound 1–tartaric acid co-crystals.

42. The composition of any one of claims 13–41, wherein the composition is stable for at least 3 months when stored at a temperature up to 30 °C and a relative humidity up to 65%.

43. The composition of any one of claims 13–42, wherein about 50% of the composition dissolves within about 10 minutes at 37 °C and 75 rpm in a medium of 0.1 N hydrochloric acid and 1.0% w/v sodium dodecyl sulfate (SDS), pH 4.5, using a U.S.P. Apparatus 2.

44. The composition of any one of claims 13–43, wherein the composition is effective at inhibiting voltage gated sodium channel 1.8.

45. The composition of any one of claims 13–44, wherein the composition is effective at treating or lessening the severity of pain in a subject in need thereof.

46. Use of the composition of one of claims 13–45, wherein the composition is effective at treating or lessening the severity of any type of pain in a subject in need thereof.

47. A method for treating or lessening the severity of any type of pain in a subject in need thereof comprising administering an effective amount of the Compound 1–tartaric acid co- crystal of any one of claims 1–11 or the drug substance of claim 12.

48. A method for treating or lessening the severity of any type of pain in a subject in need thereof comprising administering an effective amount of the composition of any one of claims 13–46.

49. The method of claim 47 or 48, wherein the pain comprises one or more of abdominal pain, abnormal gastrointestinal motility pain, acute herpes zoster pain, acute inflammatory pain, acute intermittent pain, acute musculoskeletal pain, acute obstetric pain, acute pain, acute post-operative pain (e.g., bunionectomy pain; abdominoplasty pain; knee pain from a total knee replacement; hip pain from a total hip replacement; pain from a laminectomy; pain from a hernia repair; or hemorrhoid removal pain), acute tendonitis pain, acute visceral pain, adiposis dolorosa pain, amyotrophic lateral sclerosis pain, angina-induced pain, anti- retroviral therapy induced neuralgia, anxiety pain, appendicitis pain, arrhythmia pain, arthritis pain, ataxia pain, back pain, Behçet’s disease pain, bipolar disorder pain, bladder and urogenital disease pain, bone pain, brachial plexus avulsion injury pain, breakthrough pain, burn pain, burning mouth syndrome pain, bursitis pain, cancer chemotherapy induced neuralgia, cancer pain, cardiac arrhythmia pain, cardiac pain, carpal tunnel syndrome pain, central pain, cerebral ischemia, Cesarean-section pain, Charcot-Marie Tooth neuropathic pain, chemotherapy induced neuropathic pain, chest pain, cholecystitis pain, chronic and acute headache pain, chronic and acute neuropathic pain, chronic arthritis, chronic pain, chronic visceral pain, cluster headache pain, cold pain, complex regional pain syndrome, Crohn’s disease pain, dental pain (e.g., third molar extraction), depression pain, diabetic neuralgia, diabetic neuropathic pain, diabetic peripheral neuropathic pain, drug therapy induced neuralgia, ectopic proximal and distal discharge pain, endometriosis pain, epilepsy pain, erythromelalgia pain, exercise induced angina pain, exercise induced pain, exercise pain, Fabry’s disease pain, femur cancer pain, fibromyalgia pain, general neuralgias, granuloma annulare pain, Guillain-Barre pain, gut pain, Haglund syndrome pain, head pain, headache pain, hereditary sensory neuropathic pain, hernia pain, herpetic neuralgia pain, HIV-associated neuropathic pain, HIV-associated sensory neuropathic pain, hyperactivity bladder pain, hypertension pain, idiopathic pain, idiopathic sensory neuropathic pain, idiopathic small-fiber neuropathic pain, incontinence pain, inflammatory bowel disease pain, inflammatory pain, injury pain, interstitial cystitis (IC) pain, intestinal obstruction pain, intractable pain, irritable bowel syndrome pain, joint pain, labor pain, leprosy pain, lipoidica pain, malignancy pain, mechanical low back pain, migraine pain, Morton’s neuroma pain, movement disorder pain, multiple sclerosis (MS) pain, musculoskeletal pain, myofascial pain syndrome pain, myotonia pain, neck pain, necrobiosis pain, nerve avulsion injury pain, nerve entrapment injury pain, neurodegenerative disorder pain, neuroendocrine disorder pain, neuropathic low back pain, neuropathic pain, nociceptive pain, non-malignant chronic bone pain, orofacial pain, osteoarthritis pain, painful bladder syndrome, painful legs, painful moving toes, painful neuromas, palpitations, pancreatic pain, paroxysmal extreme pain, pathological cough pain, pelvic pain, peripheral nerve injury pain, phantom pain, phlebitic pain, post spinal cord injury pain, post-amputation pain, post-herpetic neuralgia, post-mastectomy pain, post-stroke pain, postsurgical pain, premenstrual pain, prostatitis pain, pruritis pain, psychiatric disorder associated pain, pyelonephritis pain, radicular pain, radiculopathy, radiotherapy-induced neuropathic pain, renal colic pain, rheumatoid arthritis pain, sarcoidosis pain, sciatica pain, severe pain, shingles pain, sickle cell anemia pain, sinusitis pain, spinal cord injury pain, spinal stenosis pain, sports injury pain, stress-induced angina pain, stress-induced pain, stroke pain, temporomandibular joint pain, tendonitis pain, tension headache pain, thalamic pain, tinnitus pain, trauma pain, traumatic brain injury pain, traumatic neuroma, trigeminal autonomic cephalalgia, trigeminal neuralgia, urinary incontinence pain, visceral pain, widespread pain, or other types of pain.

50. The method of any one of claims 47-49, wherein the pain comprises chronic and acute neuropathic pain.

51. The method of any one of claims 47-49, wherein the pain comprises herpetic neuralgia.

52. The method of any one of claims 47-49, wherein the pain comprises idiopathic small-fiber neuropathy.

53. The method of any one of claims 47-49, wherein the pain comprises osteoarthritis pain.

54. The method of any one of claims 47-49, wherein the pain comprises acute pain.

55. The method of any one of claims 47-49, wherein the pain comprises acute post-operative pain.

56. The method of any one of claims 47-49, wherein the pain comprises postsurgical pain.

57. The method of any one of claims 47-49, wherein the pain comprises bunionectomy pain.

58. The method of claim any one of claims 47-49, wherein the pain comprises abdominoplasty pain.

59. The method of any one of claims 47-49, wherein the pain comprises visceral pain.

60. The method of any one of claims 47-49, wherein the pain comprises herniorrhaphy pain.

61. The method of any one of claims 47-49, wherein the pain comprises chronic pain.

62. The method of any one of claims 47-49, where in the pain comprises neuropathic pain.

63. The method of any one of claims 47-49, wherein the pain comprises small-fiber neuropathy.

64. The method of any one of claims 47-49, wherein the pain comprises diabetic neuropathy.

65. A method for manufacturing a pharmaceutical composition comprising:

(a) combining Compound 1–tartaric acid crystals with one or more fillers or diluents, one or more disintegrants, one or more lubricants, and optionally, one or more first glidants;

(b) screening and blending;

(c) dry granulating and milling the blend of (b); (d) combining the milled blend of (c) with a screened second filler, second disintegrant, and second lubricant;

(e) blending the combination of (d);

(f) compressing the blend of (e) into tablets; and

(g) packaging the tablets.

66. The method of claim 65, wherein the filler comprises microcrystalline cellulose; the first and second disintegrant comprises croscarmellose sodium; the first and second lubricant comprises magnesium stearate.

67. A pharmaceutical composition produced by the method of claim 65 or 66.

68. The pharmaceutical composition of claim 67, wherein the pharmaceutical composition comprises:

an intragranular composition comprising:

(e) about 30% to about 60% by mass of microcrystalline cellulose;

(f) about 1.5% to about 5% by mass of croscarmellose sodium; and

(g) about 1% to about 5% by mass of magnesium stearate.

69. The pharmaceutical composition of claim 67 or 68, wherein the pharmaceutical composition comprises about 350 mg of Compound 1–tartaric acid co-crystals.

70. The pharmaceutical composition of claim 67 or 68, wherein the pharmaceutical composition comprises 300 mg of Compound 1 present in the Compound 1-tartaric acid co-crystal.

71. The pharmaceutical composition of any one of claims 67–70, wherein the pharmaceutical composition is effective at treating, amelioration of, reducing the symptoms of, prophylaxis of, or lessening the severity of pain in a subject in need thereof.

72. A kit for dispensing the pharmaceutical composition of any one of claims 67–71, wherein the kit comprises:

(a) at least one comprising micronized Compound 1–tartaric acid co-crystals;

(b) at least one moisture proof dispensing receptacle comprising blister or strip packs, an aluminum blister, a transparent or opaque polymer blister with pouch, polypropylene tubes, colored blister materials, tubes, bottles, and bottles optionally containing a child-resistant feature, optionally comprising a desiccant, such as a molecular sieve or silica gel; and

(c) optionally, an insert comprising instructions or prescribing information; or (d) optionally, directions for administration or any contraindications.

73. A method for treating or lessening the severity of pain comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of claims 67–71.

74. Use of the pharmaceutical composition of any one of claims 67–71 for treating or lessening the severity of any type of pain in a subject in need thereof.