WO2020219867A1 - Compositions de co-cristaux d'amide de pyridone pour le traitement de la douleur - Google Patents

Compositions de co-cristaux d'amide de pyridone pour le traitement de la douleur Download PDF

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Publication number
WO2020219867A1
WO2020219867A1 PCT/US2020/029798 US2020029798W WO2020219867A1 WO 2020219867 A1 WO2020219867 A1 WO 2020219867A1 US 2020029798 W US2020029798 W US 2020029798W WO 2020219867 A1 WO2020219867 A1 WO 2020219867A1
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Prior art keywords
pain
composition
mass
compound
tartaric acid
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PCT/US2020/029798
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English (en)
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Mark Allen COSTELLO
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Vertex Pharmaceuticals Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • 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.
  • Na V s Voltage-gated sodium channels
  • a V s 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).
  • 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.
  • 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.
  • the local anesthetic drugs such as lidocaine block pain by inhibiting NaV channels
  • 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).
  • 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 V 1.4 is the primary sodium channel of skeletal muscle
  • Na V 1.5 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).
  • 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.
  • DRG 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 essential for spontaneous firing in damaged neurons, like those that drive neuropathic pain.
  • Roza et al. The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice, J. Physiol.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.
  • 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).
  • TTX tetrodotoxin
  • NaV1.8 is primarily restricted to the neurons that sense pain, selective Na V 1.8 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.
  • 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.
  • One embodiment described herein is a co-crystal comprising Compound 1 [0009] (1); and tartaric acid.
  • Compound 1 and tartaric acid are present in a molar ratio of 2:1.
  • 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.
  • XRPD X-ray powder diffraction
  • 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.
  • the co- crystal has an XRPD pattern substantially similar to the XRPD pattern of FIG.7.
  • 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.
  • the co-crystal has a 1.07% mass loss from ambient temperature to 150 °C in a thermogravimetric analysis.
  • 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 .
  • the co-crystal is characterized by a UV spectrum comprising two maxima at approximately 204 nm and 260 nm.
  • the co-crystal has a 1 H-NMR spectrum substantially similar to the NMR spectrum of FIG.2.
  • the co-crystal has a 13 C- NMR spectrum substantially similar to the NMR spectrum of FIG.3.
  • the co- crystal is characterized by 1 H- and 13 C-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 ( 1 H) and 125 MHz ( 13 C).
  • DMSO-d6 deuterated dimethyl sulfoxide
  • the co-crystal is characterized by the 19 F-solid state NMR spectrum substantially similar to that of FIG. 4A; or having the peaks listed in Table 5; or the 13 C-solid state NMR spectrum substantially similar to that of FIG.4B; or having the peaks listed in Table 6.
  • Another embodiment described herein is a drug substance comprising the Compound 1– tartaric acid co-crystal described herein.
  • compositions comprising the Compound 1–tartaric acid co-crystal described herein and one or more pharmaceutically acceptable excipients.
  • the composition comprises a tablet pharmaceutical composition.
  • the Compound 1–tartaric acid co-crystal is micronized.
  • 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.
  • 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.
  • the Compound 1–tartaric acid co-crystal has a median volume particle size, D(v,0.5) of about 2–4 mm.
  • the pharmaceutically acceptable excipients comprise: (a) one or more fillers or diluents; (b) one or more disintegrants; and (c) one or more lubricants.
  • 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.
  • 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.
  • 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.
  • 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.
  • the filler comprises microcrystalline cellulose.
  • the disintegrant comprises croscarmellose sodium.
  • the lubricant comprises magnesium stearate.
  • 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.
  • 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.
  • 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.
  • the composition further comprises an intragranular composition and an extragranular composition.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 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.
  • 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 stea
  • 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.
  • 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
  • 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.
  • the composition comprises about 50 mg to about 2000 mg of Compound 1–tartaric acid co-crystals.
  • 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.
  • the composition comprises about 350 mg of Compound 1–tartaric acid co-crystals.
  • the composition comprises about 300 mg of Compound 1 present in Compound 1–tartaric acid co-crystals.
  • 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%.
  • 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.
  • the composition is effective at inhibiting voltage gated sodium channel 1.8.
  • 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.
  • 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.
  • 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.
  • 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,
  • the pain comprises chronic and acute neuropathic pain.
  • the pain comprises herpetic neuralgia.
  • the pain comprises idiopathic small-fiber neuropathy.
  • the pain comprises osteoarthritis pain.
  • the pain comprises acute pain.
  • the pain comprises acute post-operative pain.
  • the pain comprises postsurgical pain.
  • the pain comprises bunionectomy pain.
  • the pain comprises abdominoplasty pain.
  • the pain comprises visceral pain.
  • Another embodiment described herein is a method for manufacturing a pharmaceutical composition
  • 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.
  • the filler comprises microcrystalline cellulose
  • the first and second disintegrant comprises croscarmellose sodium
  • 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.
  • 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 ste
  • 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.
  • 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.
  • 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.
  • Another embodiment described herein is the Compound 1-tartaric acid co-crystal, or a pharmaceutical composition thereof, for use as a medicament.
  • 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).
  • FIG.2 shows a 1 H-NMR spectrum of Compound 1–tartaric acid co-crystals in deuterated dimethyl sulfoxide (DMSO-d6).
  • FIG.3 shows a 13 C-NMR spectrum of Compound 1–tartaric acid co-crystals in deuterated dimethyl sulfoxide (DMSO-d6).
  • FIG.4 shows solid state NMR spectra.
  • FIG.4A shows a 19 F magic angle spinning spectrum of Compound 1–tartaric acid co-crystals.
  • FIG. 4B shows a 13 C cross-polarization magic angle spinning spectrum of Compound 1–tartaric acid co-crystals.
  • FIG.5 shows an Infra-red (IR) spectrum of Compound 1–tartaric acid co-crystals.
  • FIG.6 shows a Ultra-violet (UV) spectrum of Compound 1–tartaric acid co-crystals.
  • FIG.7 shows an X-ray powder diffraction (XRPD) spectrum of Compound 1–tartaric acid co-crystals.
  • FIG. 8 shows a differential scanning calorimetry (DSC) thermogram of Compound 1– tartaric acid co-crystals.
  • FIG. 9 shows a thermogravimetric analysis (TGA) thermogram of Compound 1–tartaric acid co-crystals.
  • FIG.10 shows a flow chart for manufacturing tablets containing Compound 1–tartaric acid co-crystals.
  • pyridone amide compositions that inhibit voltage-gated sodium channels.
  • the pyridone amides inhibit voltage-gated sodium channel 1.8 (NaV1.8).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the active pharmaceutical ingredient may be in any of its crystalline, semi-crystalline, amorphous, or polyamorphous forms, or mixtures thereof.
  • 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 (March 2010), which is incorporated by reference herein for such teachings.
  • co-crystals of Compound 1 which include“Compound 1–tartaric acid co-crystals” or“tartaric acid co-crystals of Compound 1.”
  • 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:
  • 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.
  • API active pharmaceutical ingredient
  • coformers co-crystal formers
  • co-crystals of Compound 1.
  • the co-crystal comprises Compound 1 and co-crystal former.
  • the co-crystal comprises Compound 1 and tartaric acid.
  • the co-crystal is a Compound 1–tartaric acid co-crystal.
  • the co-crystal comprises two molecules of Compound 1 and one molecule of tartaric acid.
  • the Compound 1–tartaric acid co-crystals are produced by a process shown in Scheme 1.
  • 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.
  • 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.
  • 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.
  • XRPD X-ray powder diffraction
  • 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.
  • XRPD X-ray powder diffraction
  • 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.
  • XRPD X-ray powder diffraction
  • 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.
  • XRPD X-ray powder diffraction
  • 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.
  • XRPD X-ray powder diffraction
  • 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.
  • XRPD X-ray powder diffraction
  • 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.
  • 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.
  • 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.
  • Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by a 1 H-NMR spectrum substantially similar to the spectrum of FIG.2 or the 13 C- NMR spectrum substantially similar to the spectrum of FIG. 3.
  • both sets of NMR data are presented in Table 4.
  • Another embodiment described herein is a Compound 1–tartaric acid co-crystal that is characterized by the 19 F-solid state NMR spectrum substantially similar to that of FIG. 4A; or having the peaks listed in Table 5; or the 13 C-solid state NMR spectrum substantially similar to that of FIG.4B; or having the peaks listed in Table 6.
  • a 1 H-NMR or 13 C-NMR or a 13 C or 19 F 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.
  • ssNMR solid state nuclear magnetic resonance
  • 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.
  • IR Infra-Red
  • Table 7 the IR data are presented in Table 7.
  • 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.
  • UV Ultra-violet
  • 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).
  • DSC differential scanning calorimetry
  • 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.
  • “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.
  • Compound 1–tartaric acid co-crystal particles of a specified size distribution are produce using a jet milling technique or ball milling.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • crystalline Compound 1–tartaric acid co-crystals are micronized to a median volume particle size, D(v,0.5) of about 2–4 mm.
  • 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.
  • 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.
  • 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.
  • 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 Micro mm).
  • 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).
  • the solid particles of Compound 1–tartaric acid co-crystals comprise multiple distributions of particle sizes.
  • 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.
  • the plurality of mean particle size distributions can comprise a mean particle size distribution of about 1.0 mm to about 10 mm.
  • 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.
  • 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.
  • 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 d 43 ), 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the particles are of a similar size distribution.
  • the Compound 1–tartaric acid co-crystal particles comprise varied size distributions.
  • the Compound 1–tartaric acid co-crystal particles comprise several size distributions.
  • the Compound 1–tartaric acid co-crystal particles comprise a mixture of smaller and larger size distributions.
  • 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.
  • 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.
  • the pharmaceutical composition comprises micronized or milled particles of Compound 1–tartaric acid co-crystals.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition comprises an oral dosage form, including but not limited to a tablet or capsule.
  • a“disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion.
  • disintegrants include crospovidone, croscarmellose sodium, alginic acid, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, or combinations thereof.
  • the disintegrant is crospovidone (e.g., crosslinked homopolymers of N-vinyl-2-pyrrolidone) having a particular particle size such as PolyplasdoneTM (Ashland), including PolyplasdoneTM XL, XL-10, and INF- 10 which have average particle size distributions of 130 mm, 30 mm, and 11 mm, respectively.
  • PolyplasdoneTM AlplasdoneTM
  • XL PolyplasdoneTM XL
  • 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.
  • the disintegrant is sodium croscarmel
  • a“filler” or“diluent” is an excipient that adds bulkiness to a pharmaceutical composition.
  • 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.
  • the filler or diluent is microcrystalline cellulose.
  • 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.
  • the microcrystalline cellulose is Avicel ® PH-101.
  • the microcrystalline cellulose is Avicel ® PH-102.
  • the microcrystalline cellulose is used as an intragranular filler.
  • the microcrystalline cellulose is used as an extragranular filler.
  • the microcrystalline cellulose is used as both an intragranular and extragranular filler.
  • a“binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness).
  • binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).
  • 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.
  • the lubricant is magnesium stearate.
  • a“glidant” is an excipient that imparts a pharmaceutical composition with enhanced flow properties.
  • examples of glidants include colloidal silica, fumed silica, or talc.
  • the glidant is fumed silica.
  • the glidant is CAB-O-SIL ® M-5P (pharmaceutical grade) fumed silica (CABOT).
  • CABOT pharmaceutical grade fumed silica
  • the fumed silica is used as an intragranular glidant.
  • the fumed silica is used as an extragranular glidant.
  • the fumed silica is used as both an intragranular and extragranular glidant.
  • 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.
  • a“surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability.
  • surfactants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., TweenTM), or a combination thereof.
  • a“colorant” is an excipient that imparts a pharmaceutical composition with a desired color.
  • 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.
  • a“flavoring” is an excipient that imparts a flavor or taste masking property to a pharmaceutical composition.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition comprises one or more colorants, flavorings, binders, glidants, coatings, or other pharmaceutically acceptable excipients.
  • 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.
  • compositions comprising an intragranular composition and an extragranular composition.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition.
  • 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.
  • an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition.
  • 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.
  • 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.
  • 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.
  • 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.
  • an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition.
  • 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.
  • 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.
  • an oral pharmaceutical composition comprising an intragranular composition and an extragranular composition.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • a subject in need thereof is a subject susceptible to or experiencing pain.
  • the subject is a mammal, or a mammal in need thereof.
  • the subject is a human, or human in need thereof.
  • the human or human in need thereof is a medical patient.
  • the human subject is a child ( ⁇ 0–9 years old) or an adolescent ( ⁇ 10–17 years old).
  • 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).
  • 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.
  • 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.
  • 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 1 ⁇ 2 , or an elimination rate constant.
  • 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 1 ⁇ 2 , or an elimination rate constant.
  • compositions or formulations described herein or shown in the Tables or Examples described herein are pharmaceutical compositions 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.
  • 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.
  • 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.
  • the filler comprises microcrystalline cellulose; the first and second disintegrant comprises croscarmellose sodium; and the first and second lubricant comprises magnesium stearate.
  • kits 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.
  • the kit is useful for treating any type of pain or a medical condition according to any of the methods 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.
  • 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;
  • 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.
  • the compounds and compositions of the present invention are useful for treating neurodegenerative diseases.
  • the neurodegenerative disease is multiple sclerosis.
  • the neurodegenerative disease is a genetic form of autism called Pitt Hopkins Syndrome (PTHS).
  • 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,
  • abdominal pain e.g., 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
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pain comprises acute pain. In some embodiments, the acute pain comprises acute post-operative pain. In some embodiments, the pain comprises postsurgical pain.
  • 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.
  • 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.
  • 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.
  • 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.
  • acute pain comprises acute post-operative 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 chronic 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 postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain).
  • postsurgical pain e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty 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 pathological cough.
  • 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.
  • 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, amyotroph
  • 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, Behç
  • 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 autonom
  • Another embodiment described herein comprises the use of Compound 1–tartaric acid co-crystals or a pharmaceutical composition thereof for the treatment of pain.
  • 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.
  • the disclosure comprises a Compound 1-tartaric acid co- crystal, or a pharmaceutical composition thereof, for use as a medicament.
  • 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.
  • the pain comprises acute pain.
  • acute pain comprises acute post-operative pain.
  • the pain comprises chronic pain.
  • the pain comprises gut pain.
  • the pain comprises neuropathic pain.
  • neuropathic pain comprises small-fiber neuropathy.
  • neuropathic pain comprises idiopathic small-fiber neuropathy.
  • neuropathic pain comprises post-herpetic neuralgia.
  • neuropathic pain comprises trigeminal neuralgia.
  • neuropathic pain comprises diabetic neuropathy.
  • the pain comprises musculoskeletal pain.
  • musculoskeletal pain comprises osteoarthritis pain.
  • the pain comprises inflammatory pain.
  • the pain comprises cancer pain.
  • the pain comprises idiopathic pain.
  • the pain comprises postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain).
  • postsurgical pain e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain.
  • the pain comprises visceral pain.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.”
  • 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)
  • nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds described herein.
  • anesthesiologic intraspinal infusion, neural blockade
  • neurosurgical neurolysis of CNS pathways
  • neurostimulatory transcutaneous electrical nerve stimulation, dorsal column stimulation
  • physiatric physical therapy, orthotic devices, diathermy
  • psychologic psychologic
  • appropriate therapeutic agents are selected from the following:
  • 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;
  • 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,
  • NSAID nonsteroidal antiinflammatory drug
  • NSAID nonsteroidal antiinflammatory drug
  • 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
  • NSAID nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;
  • a benzodiazepine having a sedative action e.g., chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • a histamine (H1) antagonist having a sedative action e.g., diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
  • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadine;
  • 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;
  • NR2B antagonist
  • 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;
  • a tricyclic antidepressant e.g., desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g., carbamazepine (Tegretol ® ), lamotrigine, topiramate, lacosamide (Vimpat ® ) or valproate;
  • 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
  • a muscarinic antagonist e.g., oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • COX-2 selective inhibitor e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • 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;
  • a vanilloid receptor agonist e.g., resiniferatoxin or civamide
  • antagonist e.g., capsazepine, GRC-15300
  • a beta-adrenergic such as propranolol
  • a local anesthetic such as mexiletine
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT 1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
  • a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • 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;
  • Tramadol ® Tramadol ER (Ultram ER ® ), Tapentadol ER (Nucynta ® );
  • 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
  • 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)
  • mGluRl metabotropic glutamate subtype 1 receptor
  • 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;
  • 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;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta ® ), milnacipran and imipramine;
  • 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-thiazoly
  • an acetylcholinesterase inhibitor such as donepezil
  • 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;
  • 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;
  • 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);
  • a sodium channel blocker such as lidocaine, lidocaine plus tetracaine cream (ZRS- 201) or eslicarbazepine acetate;
  • a Na V 1.7 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;
  • 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
  • a Na V 1.8 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.
  • 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
  • a combined NaV1.7 and NaV1.8 blocker such as DSP-2230 or BL-1021;
  • a 5-HT3 antagonist such as ondansetron
  • TPRV 1 receptor agonist such as capsaicin (NeurogesX ® , Qutenza ® ); and the pharmaceutically acceptable salts and solvates thereof;
  • a nicotinic receptor antagonist such as varenicline
  • an N-type calcium channel antagonist such as Z-160
  • a nerve growth factor antagonist such as tanezumab
  • an endopeptidase stimulant such as senrebotase
  • an angiotensin II antagonist such as EMA-401.
  • 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.
  • 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.
  • additional appropriate therapeutic agents are selected from the following:
  • 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;
  • opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine
  • NSAID nonsteroidal antiinflammatory drug
  • ketorolac tromethamine e.g., Toradol®
  • meclofenamic acid mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • H 1 histamine (H 1 ) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
  • a sedative such as glutethimide, meprobamate, methaqualone or
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;
  • 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.
  • 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;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;
  • 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-(trifluorin)-8,9,
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • a COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • 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;
  • a vanilloid receptor agonist e.g. resinferatoxin or civamide
  • antagonist e.g. capsazepine, GRC-15300
  • a beta-adrenergic such as propranolol
  • a corticosteroid such as dexamethasone
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • a 5-HT 2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l- [2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • 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;
  • 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
  • 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
  • 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;
  • 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;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;
  • 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-
  • 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;
  • 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;
  • 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);
  • a sodium channel blocker such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate;
  • 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
  • a NaV1.7 blocker such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-
  • a Na V 1.7 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-benzylspiro[3,4
  • a Na V 1.8 blocker such as PF-04531083, PF-06372865 and such as those disclosed in WO2008/135826 (US2009048306), WO2006/011050 (US2008312235),
  • 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.
  • 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-(trifluor
  • a combined Na V 1.7 and Na V 1.8 blocker such as DSP-2230, Lohocla201 or BL-1021;
  • a 5-HT3 antagonist such as ondansetron
  • TPRV 1 receptor agonist such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;
  • a nicotinic receptor antagonist such as varenicline
  • N-type calcium channel antagonist such as Z-160
  • nerve growth factor antagonist such as tanezumab
  • an endopeptidase stimulant such as senrebotase
  • an angiotensin II antagonist such as EMA-401
  • acetaminophen including without limitation intravenous acetaminophen (e.g., Ofirmev®));
  • bupivacaine including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and
  • bupivacaine and meloxicam combination e.g., HTX-011.
  • 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.
  • 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.
  • 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
  • a GlyT2/5HT2 inhibitor such as Operanserin (VZ149)
  • TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652
  • EGR1 inhibitor such as Brivoglide (AYX1)
  • an NGF inhibitor such as Tanezumab, Fas
  • a CB-1 agonist such as NEO1940 (AZN1940)
  • an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.
  • the additional therapeutic agent is oliceridine or ropivacaine (TLC590).
  • the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the Na V 1.7 and Na V 1.8 blockers identified above.
  • 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.
  • 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.
  • the voltage-gated sodium channel is Na V 1.8.
  • 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.
  • the voltage-gated sodium channel is Na V 1.8.
  • biological sample 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.
  • 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 V 1.8 is implicated in the disease, condition, or disorder.
  • Na V 1.8 When activation or hyperactivity of Na V 1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a“Na V 1.8 -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.
  • 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.
  • 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.
  • 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.
  • HRAM-LCMS High Resolution Accurate Mass Liquid Chromatography Mass Spectrometry
  • 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 ⁇ L.
  • 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.
  • 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 19 F spectrum is shown in FIG.4A and the peaks are listed in Table 5.
  • the 13 C spectrum is shown in FIG.4B and the peaks are listed in Table 6.
  • 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 ⁇ ).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 SeriesTM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE).
  • 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.
  • Tablets containing 355 mg of Compound 1–tartaric acid co-crystals were manufactured for oral administration.
  • the tablet composition, along with the quality reference and function of each component, are provided in Table 9.
  • 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.
  • Compound 1 is appropriately extracted from the content of the Compound 1– tartaric acid co-crystal tablets and analyzed by HPLC.
  • HPLC operating parameters and peak identification for content uniformity are described in Table 10.
  • 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.
  • 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 ⁇ m PVDF filters and were analyzed by HPLC. Dissolution results are shown in Table 13.
  • 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.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
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Abstract

L'invention concerne un inhibiteur du canal sodique d'amide de pyridone 2-(4-fluoro-2-méthylphénoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluorométhyl)benzamide, des co-cristaux de celui-ci, des compositions pharmaceutiques associées et des procédés de fabrication et d'administration des compositions pour le traitement de divers types de douleur.
PCT/US2020/029798 2019-04-25 2020-04-24 Compositions de co-cristaux d'amide de pyridone pour le traitement de la douleur WO2020219867A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022081742A1 (fr) * 2020-10-13 2022-04-21 New York Blood Center, Inc. Composés pour le traitement de maladies associées à l'hémolyse et à des inflammasomes
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
WO2023211990A1 (fr) 2022-04-25 2023-11-02 Siteone Therapeutics, Inc. Inhibiteurs d'amides hétérocycliques bicycliques de na v1.8 pour le traitement de la douleur

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Publication number Priority date Publication date Assignee Title
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
WO2022081742A1 (fr) * 2020-10-13 2022-04-21 New York Blood Center, Inc. Composés pour le traitement de maladies associées à l'hémolyse et à des inflammasomes
WO2023211990A1 (fr) 2022-04-25 2023-11-02 Siteone Therapeutics, Inc. Inhibiteurs d'amides hétérocycliques bicycliques de na v1.8 pour le traitement de la douleur

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