CN117794537A - Solid dosage forms and dosing regimens comprising (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide - Google Patents

Solid dosage forms and dosing regimens comprising (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide Download PDF

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CN117794537A
CN117794537A CN202280052433.4A CN202280052433A CN117794537A CN 117794537 A CN117794537 A CN 117794537A CN 202280052433 A CN202280052433 A CN 202280052433A CN 117794537 A CN117794537 A CN 117794537A
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compound
pain
pharmaceutically acceptable
subject
acceptable salt
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Inventor
R·卡尔卡里
C·楚
B·西林乔奈
D·J·寇莱尔
P·K·H·戴尔夫
K·R·迪内哈特
P·贝尼托伽罗
T·L·哈瑞
江莉聪
J·B·琼斯
K·L·麦克卡迪
C·P·梅泽勒
J·M·米勒
M·C·皮特森
R·鲁普瓦尼
J·F·斯塔罗普尼
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Priority claimed from PCT/US2022/032253 external-priority patent/WO2022256708A1/en
Publication of CN117794537A publication Critical patent/CN117794537A/en
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Abstract

There is provided a solid dispersion of (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide (compound 1) or a pharmaceutically acceptable salt thereof as defined herein, and a tablet for the treatment of pain containing the solid dispersion. Also disclosed herein is compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating pain.

Description

Solid dosage forms and dosing regimens comprising (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide
Cross Reference to Related Applications
This application claims the benefit of U.S. provisional application No. 63/196,933 filed on 4 th 6 th 2021, U.S. provisional application No. 63/196,937 filed on 4 th 6 th 2021, U.S. provisional application No. 63/285,197 filed on 2 nd 12 th 2021, and U.S. provisional application No. 63/285,201 filed on 2 nd 12 th 2021, each of which is incorporated herein by reference in its entirety.
Background
Pain is a protective mechanism that allows healthy humans and animals to avoid tissue damage and to prevent further damage to injured tissue. In both acute and chronic clinical settings, managing pain in the clinical setting remains an unmet high need. In addition to acute pain, there are many situations where chronic pain continues to exceed its protective effect (neuropathic pain), in which case the patient would benefit from pain suppression. Neuropathic pain is a form of chronic pain caused by sensory nerve injury (Dieleman, j.p. et al, incidence rates and treatment of neuropathic pain conditions in the general delivery. Pain,2008.137 (3): pages 681-8). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to the nerve and pain caused by discrete nerve damage. Metabolic neuropathy includes post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injury indications include post-amputation pain, post-operative nerve injury pain, and nerve entrapment injuries, such as neuropathic back pain. Neuropathic pain is a major cause and disability worldwide, negatively affecting the sleep, mood and function of the patient. Clin. Ther.2018 (6): pages 828-49.
Current pain therapies have poor efficacy and high risk of Adverse Events (AEs). For example, lidocaine (a non-selective sodium channel blocker) is effective in alleviating pain, but has limited utility because it produces significant side effects when administered at the dosage levels required to alleviate pain. Opioid analgesics have a high abuse liability, leading to frequent death due to overdose. Furthermore, opioid-induced hyperalgesia also limits the long-term use of opioids. Opioid-induced hyperalgesia is often encountered in clinical practice and poses a significant challenge in pain management.
Antidepressants and anticonvulsants remain the first line treatment of neuropathic pain, although they are not designated for such purposes. Their use is often limited by a number of side effects or inadequate pain relief. Clinical development has shown that recent advances and innovations in new drugs for the treatment of acute and chronic pain are quite lacking. In the last decades, most analgesic drugs approved for the treatment of neuropathic pain act either on the serotonin-norepinephrine system, such as the serotonin-norepinephrine reuptake inhibitor duloxetine, or on voltage-gated calcium channels, such as gabapentin Ding Purui barren (gabapentionid pregabalin). Given the limited treatment options for pain, and the increasing awareness of the risks and relative ineffectiveness of current standards of care, the development of analgesics that target specific pathophysiological mechanisms with improved efficacy and safety profiles is critical for better pain management and patient health outcomes.
Voltage-gated sodium channel (Na) V ) Is involved in pain signaling. Na (Na) V Are biological mediators of electrical signal conduction in that they mediate rapid increases in action potential of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells). Claims supporting the key and central role of Nav in pain signaling stem from (1) assessing the role of Nav in normal physiology and (2) from pathological states caused by mutations in the Nav1.8 gene (SCN 10A). (3) Preclinical work in animal models, and (4) pharmacology of known nav1.8 modulators. Furthermore, because nav1.8 expression is limited to peripheral neurons, particularly those that feel pain (e.g., dorsal root ganglions), nav1.8 inhibitors are unlikely to be associated with the side effects commonly observed with other sodium channel modulators and abuse liabilities associated with opioid therapies. Thus, inhibition of the underlying biology of targeted pain by selective Nav1.8 represents a novel approach to analgesic drug development that potentially addresses the urgent unmet need for safe and effective acute and chronic pain therapies (Rush, A.M. and T.R. cummins, painful Research: identification of a Small-Molecule Inhibitor that Selectively Targets Na) V 1.8 Sodium channels.mol. Interv.,2007.7 (4): pages 192-5); england, S., voltage-gated sodium channels: the search for subtype-selective analysis, expert Opin. Invest. Drugs 17 (12), pages 1849-64 (2008); kraft, d.s. and Bannon, a.w., sodiumchannels and nociception: recent concepts and therapeutic optounities.curr.Opin.Pharmacol.8 (1), pages 50-56 (2008)). Due to Na V Acting in the initiation and propagation of neuronal signals to reduce Na V Antagonists of electric current can prevent or reduce nerve signaling, and Na V Channels may be considered Targets for pain reduction in the event of hyperexcitability observed (chafine, m., chatelier, a., babich, o., and Krupp, j.j., voltage-gated sodiumchannels in neurological displays, cns neurol. Several clinically useful analgesics have been identified as Na V Channel inhibitors. Local anesthetic drugs (such as lidocaine) are prepared by inhibiting Na V Channels to block pain, and other compounds such as carbamazepine (carbamazepine), lamotrigine (lamotrigine) and have been demonstratedTricyclic antidepressants effective in alleviating pain) have also been shown to act through sodium channel inhibition (sodeprpalm, b., anti-iconvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 journal a, pages 3-9 (2002); wang, g.k., mitchell, j. And Wang, s.y., block of persistent late Na + currents by antidepressant sertraline and paroxetine.J.Member.biol.222 (2), pages 79-90 (2008)).
Na V Subfamilies forming the voltage-gated ion channel superfamily and include 9 isoforms designated Na V 1.1–Na V 1.9. Tissue localization was different for the nine isoforms. Na (Na) V 1.4 is the main sodium channel of skeletal muscle, and Na V 1.5 is the main sodium channel of cardiomyocytes. Na (Na) V 1.7, nav 1.8 and Nav 1.9 are mainly localized to the peripheral nervous system, while Na V 1.1, nav 1.2, nav 1.3 and Nav 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms are similar, but differ in the details of their voltage dependence and kinetic behavior (calterall, w.a., goldin, a.l., and Waxman, s.g., international Union of pharmacology, xlv ii.nominal and structural-function relationships of voltage-gated sodium channels.pharmacol.rev.57 (4), page 397 (2005)).
Based on their findings, na V The 1.8 channel was identified as a possible target for analgesia (Akopian, A.N., L.Sivilotti and J.N.Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurones. Nature,1996.379 (6562): pages 257-62). Thereafter, na has been shown V 1.8 is a carrier of sodium current which maintains action potential discharge in small DRG neurons, supporting its potential as a target for multiple indications or multiple pain types (Blair, N.T. and B.P. beans, roles of tetrodotoxin (TTX) -active Na+ current, TTX-resistive Na + current,and Ca 2+ current in the action potentials of nociceptive sensory neurons.J. neurosci.,2002.22 (23): pages 10277-90). Na (Na) V 1.8 spontaneous firing of injured neurons involved in The driving of neuropathic pain like those neurons (Roza, C. Et al, the tetrodotoxin-resistance Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol. 2003.550 (section 3): pages 921-6; jarvis, M.F. et al, A-803467,a potent and selective Na V 1.8sodiumchannel blocker,attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.U S A,2007.104 (20) pages 8520-5; joshi, S.K. et al Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic, but not post-operational, pain states, pain,2006.123 (1-2): pages 75-82; lai, J. Et al Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, na V Pan, 2002.95 (1-2): pages 143-52; dong, X.W. et al Small interfering RNA-mediated selective knockdown of Na% V ) 1.8tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rates. Neuroscience 2007.146 (2): pages 812-21; huang, H.L. et al Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-exible new.mol.paint, 2008.4, page 33; black, J.A. et al Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol.,2008.64 (6): pages 644-53; coward, K.et al Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states, paint, 2000.85 (1-2): pages 41-50; YIangou, Y. Et al, SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett.,2000.467 (2-3): pages 249-52; ruangsri, S. et al Relationship of axonal voltage-gated sodium channel 1.8.1.8 (Na V 1.8 mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rates.J.biol.chem.286 (46): pages 39836-47). Expression of Na V 1.8 includes nociceptors involved in pain signaling. Na (Na) V 1.8 mediating large amplitude action potentials in small neurons of the dorsal root ganglion (Blair, N.T. and B.P.Bean, roles of tetrodotoxin (TTX) -active Na + current,TTX-resistant Na + current,and Ca 2+ current in the action potentials of nociceptive sensory neurons.J. neurosci.,2002.22 (23): pages 10277-90). Na (Na) V 1.8 are necessary for rapid repeated action potentials in nociceptors and spontaneous activity of injured neurons (Choi, j.s. And s.g. wankman, physiological interactions between Na) V 1.7 and Na V 1.8sodium channels acomputer simulation student.J.Neurohysiol.106 (6): pages 3173-84; renganathan, M., T.R.Cummins and S.G.Waxman, contribution of Na V ) 1.8sodiumchannels to action potential electrogenesis in DRG neurons.J.Neurophysiol, 2001.86 (2) pages 629-40; roza, C. Et al, tetrodotoxin-resistance Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol. 2003.550 (section 3): pages 921-6). In depolarized or damaged DRG neurons, na V 1.8 appears to be the driving factor for hyperexcitability (Rush, A.M. et al A single sodium channel mutation produces hyper-or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA 2006.103 (21): pages 8245-50). In some animal pain models, na in DRG has been shown V 1.8mRNA expression level increases (Sun, W.et al, reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rates. Brain,135 (part 2): pages 359-75; strickland, I.T. et al, changes in the expression of Na) V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain, eur.J. pain,2008.12 (5): pages 564-72; qia, F. Et al Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett.,512 (2): pages 61-6).
Disclosure of Invention
In one aspect, the present disclosure is directed to a method of treating pain or lessening the severity of pain in a subject, comprising administering to the subject a compound of the formula
Or a pharmaceutically acceptable salt thereof.
In another aspect, the present disclosure relates to a method of treating or lessening the severity of a variety of diseases, disorders or conditions in a subject, including but not limited to chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunyoctomy pain, hernial repair pain, or abdominal wall plastic pain), visceral pain, multiple sclerosis, xia Matu trise syndrome (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, and arrhythmia, by administering compound 1, a pharmaceutically acceptable salt, or a pharmaceutical composition to the subject.
In one aspect, the present disclosure relates to a solid dispersion comprising compound 1 or a pharmaceutically acceptable salt thereof, and at least one polymer.
In one aspect, compound 1 is substantially amorphous.
In one aspect, the present disclosure relates to a pharmaceutical composition comprising compound 1 and at least one polymer.
In another aspect, the pharmaceutical composition further comprises at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant.
Drawings
FIG. 1 depicts XRPD pattern characteristics for Compound 1 form A
Figure 2 depicts TGA thermogram characteristics of compound 1 form a.
Figure 3 depicts DSC thermogram characteristics of compound 1 form a.
Fig. 4 depicts XRPD pattern features of compound 1 form B.
FIG. 5 depicts compound 1 formB solid state 13 C NMR spectral features.
FIG. 6 depicts the solid state of Compound 1 form B 19 F NMR spectral features.
Figure 7 depicts TGA thermogram characteristics of compound 1 form B.
Figure 8 depicts DSC thermogram characteristics for compound 1 form B.
Figure 9 depicts the IR spectral features of compound 1 form B.
Figure 10 depicts the thermal ellipsometry signature of compound 1 form B.
Figure 11 depicts the XRPD pattern of a spray dried dispersion of compound 1 of example 3.
Fig. 12A depicts an XRPD pattern of the SDD tablet composition of example 3 in the range of about 3 ° to about 40 ° 2θ.
Fig. 12B depicts an XRPD pattern of the SDD tablet composition of example 3 in the range of about 14 ° to about 16 ° 2θ.
Fig. 13A depicts the solid state of the SDD tablet composition of example 3 19 F NMR spectral features.
Fig. 13B depicts the solid state of the SDD tablet composition powder of example 3 13 C NMR spectral features.
Detailed Description
Definition of the definition
Chemical elements were identified herein according to Periodic Table of the Elements, CAS version Handbook of Chemistry and Physics, 75 th edition. In addition, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, university Science Books, sausalato 1999 and "March's Advanced Organic Chemistry," 5 th edition, smith, m.b. and March, j. Editions, john Wiley & Sons, new york:2001, the entire contents of which are incorporated herein by reference.
As used herein, the term "amorphous" refers to a solid material that does not have long range order in its molecular positions. The molecules in amorphous solids are typically arranged in a random fashion without explicit alignment. Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have a defined melting point. For example, an amorphous material is a solid material that does not have sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern.
As used herein, the term "substantially amorphous" refers to a solid material that has little or no long range order in its molecular positions. For example, the substantially amorphous material has a crystallinity of less than about 15% (e.g., less than about 10% crystallinity or less than about 5% crystallinity). The term 'substantially amorphous' includes materials that do not have (0%) crystallinity.
As used herein, the term "dispersion" refers to a dispersion system in which one substance (i.e., the dispersed phase) is distributed throughout a second substance (the continuous phase or vehicle) in discrete units. The size of the dispersed phase may vary significantly (e.g., colloidal particles ranging in size from nanometer to several microns). In general, the dispersed phase may be a solid, a liquid, or a gas. In the case of solid dispersions, both the dispersed and continuous phases are solid. In pharmaceutical applications, the solid dispersion may comprise crystalline drug (dispersed phase) in amorphous polymer (continuous phase); or alternatively, amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, the solid dispersion includes a polymer that forms the dispersed phase and a drug that forms the continuous phase. In other embodiments, the solid dispersion includes a drug that forms the dispersed phase and a polymer that forms the continuous phase.
As used herein, the prefix "rac-" when used with a chiral compound refers to a racemic mixture of the compound. In compounds with a "rac-" prefix, the (R) -and (S) -indicators in the chemical name reflect the relative stereochemistry of the compound.
As used herein, the prefix "rel-" when used with chiral compounds refers to a single enantiomer of unknown absolute configuration. In compounds with a "rel-" prefix, the (R) -and (S) -indicators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound. Where the relative stereochemistry of a given stereocenter is unknown, no stereochemical indicator is provided. In some cases, the absolute configuration of some stereogenic centers is known, while only the relative configuration of other stereogenic centers is known. In these cases, stereochemical indicators associated with stereocenters of known absolute configuration are marked with asterisks, e.g., (R) -and (S) -, whereas stereochemical indicators associated with stereocenters of unknown absolute configuration are not so marked. Unlabeled stereochemical indicators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters relative to other stereocenters of unknown absolute configuration, but not necessarily relative to stereocenters of known absolute configuration.
As used herein, the term "compound 1" and the structure and chemical name corresponding to "compound 1" refer to a collection of molecules having the same chemical structure, i.e., a structure corresponding to "compound 1", but wherein there may be isotopic variations between the constituent atoms of the molecules. The term "compound 1" includes such a collection of molecules regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound 1" includes a collection of molecules in pure form or in a mixture (e.g., solution, suspension, or colloid) with one or more other substances.
In the description and claims, unless otherwise indicated, any atom not specifically designated as a particular isotope in compound 1 is meant to represent any stable isotope of the designated element. In instances where an atom is not specifically designated as a particular isotope, no effort has been made to enrich the atom with the particular isotope, and thus one of ordinary skill in the art will appreciate that such an atom may exist in approximately the natural abundance isotopic composition of the designated element.
As used herein, the term "compound 1a" refers to a compound having the chemical name: 2-carbamoyl-4- ((2 r,3s,4s,5 r) -3- (3, 4-difluoro-2-methoxyphenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamido) pyridine 1-oxide.
As used herein, the term "stable" when referring to an isotope means that the isotope is known not to undergo spontaneous radioactive decay. Stable Isotopes include, but are not limited to, isotopes identified in the decay-free mode in v.s.shirley & c.m. lederer, isopes Project, nuclear Science Division, lawrence Berkeley Laboratory, table of Nuclides (month 1 of 1980).
As used herein, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e 1 H and D. In the example, where an atom is designated as "H," no effort has been made to enrich the atom for a particular hydrogen isotope, and thus one of ordinary skill in the art will appreciate that such a hydrogen atom may exist in an approximately natural abundance isotopic composition of hydrogen.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, comprises each constituent atom at the approximate natural abundance isotopic composition of the specified element.
In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof comprises one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the most abundant isotope of the specified element (the "isotopically labeled" compound or salt). Examples of stable isotopes that are commercially available and suitable for use in the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, such as, respectively 2 H、 13 C、 15 N、 18 O、 17 O and 31 P。
the terms "compound 1" and "pharmaceutically acceptable salts thereof" include compound 1 and any pharmaceutically acceptable salt of any form thereof, including any solid form thereof (including any amorphous or crystalline form thereof), any solvate, hydrate or co-crystal form thereof, and any solution or suspension thereof.
As used herein, the term "about" includes a specified amount or a range of values covering the specified amount, which is recognized by those of ordinary skill in the art as providing a pharmacological effect equivalent to that obtained from the specified amount. The term "about" may refer to an acceptable error for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In some embodiments, the term "about" means within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In some embodiments, the term "about" means within 20% of a given value or range. In some embodiments, the term "about" means within 15% of a given value or range. In some embodiments, the term "about" means within 10% of a given value or range. In some embodiments, the term "about" means within 5% of a given value or range. In some embodiments, the term "about" means within 1% of a given value or range. In some embodiments, the term "about" means within 0.5% of a given value or range.
As used herein, the term "subject" or "patient" means an animal, preferably a mammal, and most preferably a human.
As used herein, the term "amount" when referring to the amount of compound 1 or a pharmaceutically acceptable salt thereof administered to a subject, refers to an equimolar amount of the mass of (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide, irrespective of the actual mass of any salt, solvate, hydrate or co-crystal form that may be administered.
In certain embodiments, an "effective amount" of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is an amount effective to treat or reduce the severity of one or more of the conditions described herein.
As used herein and unless otherwise indicated, the terms "daily" and "total daily dose" when referring to the amount of compound 1 or a pharmaceutically acceptable salt thereof administered to a subject refer to the amount of compound 1 or a pharmaceutically acceptable salt thereof administered to a subject during at least one 24 hour period during the course of treatment. Unless otherwise indicated, it is understood that compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject in varying amounts on one or more other days in the course of treatment.
As used herein, the term "first day" refers to the first 24 hour period of administration of compound 1 or a pharmaceutically acceptable salt thereof during the course of treatment.
As used herein, the term "course of treatment" when referring to compound 1 or a pharmaceutically acceptable salt thereof, refers to the administration of one or more doses of the compound or salt over a period of time separate from any earlier or later administration of the compound or salt. Typically, compound 1 and any metabolites thereof are substantially eliminated from the subject's systemic circulation between treatment procedures.
As used herein, the term "dose" when referring to administration of compound 1 or a pharmaceutically acceptable salt thereof refers to the amount of compound or salt that is administered over a discrete period of time, separately from other amounts of compound or salt that may be administered on the same day or at other times during treatment. When a dose is administered orally, the dose may be administered in a single tablet, capsule, or other oral dosage form, or in a plurality of such dosage forms.
As used herein, the term "first dose" refers to a first dose of compound 1, or a pharmaceutically acceptable salt thereof, administered on a given day or during a given course of treatment, depending on the context.
As used herein, the term "subsequent dose" refers to any dose of compound 1 or a pharmaceutically acceptable salt thereof administered after the first dose on a given day or during a given course of treatment, depending on the context.
As used herein, the term "baseline pain score" refers to the pain score of a subject, such as the score of an 11-score pain rating scale or a speech classification rating scale, prior to the initiation of the course of treatment with compound 1 or a pharmaceutically acceptable salt thereof.
As used herein, the term "11-point digital pain rating scale" refers to a pain rating scale in which a subject rates his or her pain intensity according to a scale of 0 to 10, where a 0 point indicates no pain and a 10 point indicates the most severe pain intensity that is conceivable.
As used herein, the term "speech classification rating scale" refers to a pain rating scale that a subject rates his or her pain intensity as none, mild, moderate, or severe.
As used herein, the term "adverse event" is defined as any adverse medical event that occurs in a subject during a study; the event need not have a causal relationship with the treatment. This includes any newly occurring event or exacerbation of an original disease (e.g., an increase in its severity or frequency).
As used herein, an abnormal study assessment is considered "clinically significant" if the subject has one or more of the following: concomitant signs or symptoms associated with the aberrant study assessment, further diagnostic tests or medical/surgical interventions, dose changes of study drug or study discontinuation. The researcher will determine whether the research evaluation results are clinically significant.
Medical use of compound 1 or a pharmaceutically acceptable salt thereof
In one aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1 or a pharmaceutically acceptable salt thereof.
In another aspect, the present disclosure relates to the use of compound 1 or a pharmaceutically acceptable salt thereof in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject.
Dosing regimen
Compound 1 or a pharmaceutically acceptable salt thereof may be administered in any amount suitable to treat or reduce the severity of pain in a subject. In some embodiments of the present invention, in some embodiments, in the range of 20mg to 5000mg per day, or 20mg to 4500mg per day, or 20mg to 4000mg per day, or 20mg to 3500mg per day, or 20mg to 3000mg per day, or 20mg to 2500mg per day, or 20mg to 2000mg per day, or 20mg to 1500mg per day, or 20mg to 1000mg per day, or 20mg to 800mg per day, or 20mg to 700mg per day, or 20mg to 600mg per day, or 20mg to 500mg per day, or 20mg to 450mg per day, or 20mg to 400mg per day, or 20mg to 350mg per day, or 20mg to 300mg per day or 20 to 250 mg/day, or 20 to 200 mg/day, or 20 to 150 mg/day, or 20 to 30 mg/day, or 90 to 120 mg/day, or 100 to 5000 mg/day, or 100 to 4500 mg/day, or 100 to 4000 mg/day, or 100 to 3500 mg/day, or 100 to 3000 mg/day, or 100 to 2500 mg/day, or 100 to 2000 mg/day, or 100 to 1500 mg/day, or 100 to 1000 mg/day, or 100 to 800 mg/day, or 100 to 600 mg/day, or 100 to 500 mg/day, of the formula or 100 to 400mg, or 100 to 300mg, or 100 to 200mg, or 100 to 600mg, or 60 to 500mg, or 60 to 300mg, or 60 to 200mg, or 60 to 150mg, or 60 to 90mg, or about 10mg, or about 20mg, or about 23mg, or about 30mg, or about 46mg, or about 50mg, or about 60 to 1800mg, or 60 to 1700mg, or 60 to 1200mg, or 60 to 800mg, or about 60mg, or 60 to 700mg, or 60 to 600mg, or 60 to 500mg, or 60 to 300mg, or 60 to 200mg, or 60 to 150mg, or 60 to 90mg, or about 10mg, or about 20mg, or about 23mg, or about 46mg, or about 50mg, or about 69mg, or about 70, or about 60 to about 46mg, or about 150mg, or about 100mg of a pharmaceutically acceptable salt thereof may be administered daily.
When administered for multiple days, compound 1 or a pharmaceutically acceptable salt thereof can be administered in the same or different amounts per day.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in different amounts on the first day and after the first day. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 10mg to 3000mg, or 10mg to 2000mg, or 10mg to 1000mg, or 10mg to 500mg, or 10mg to 400mg, or 10mg to 350mg, or 10mg to 300mg, or 10mg to 250mg, or 10mg to 200mg, or about 100mg, or about 150mg, or about 120mg, or about 90mg, or about 30mg, in the first day, and in an amount of 10mg to 2000mg, or 10mg to 1500mg, or 10mg to 1000mg, or 10mg to 500mg, or 10mg to 400mg, or 10mg to 300mg, or 20mg to 100mg, or about 20mg, or about 60mg, or about 100mg, or about 30mg, or about 20mg, or about 50mg, per day after the first day.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 100mg, or 150mg, or 20mg, or about 30mg, or about 60mg, or about 90mg on the first day.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 100mg per day, or 150mg per day, or 50mg per day, or 30mg per day, or 60mg per day, or about 10mg per day, or about 20mg per day after the first day.
Compound 1 or a pharmaceutically acceptable salt thereof can be administered in any number of doses per day. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at one dose per day. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10mg to 500mg, or 10mg to 400mg, or 10mg to 300mg, or 10mg to 260mg, or 10mg to 200mg, or 10mg to 150mg, or 10mg to 100mg, or 10mg, or 20mg, or 30mg, or 60mg, or 90mg, or 100mg, or 120mg, or 150mg per day.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at two doses per day.
When administered for multiple days, compound 1 or a pharmaceutically acceptable salt thereof can be administered in the same or different number of doses per day. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at the same number of doses on and after the first day.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in two doses (i.e., a first dose and a subsequent dose) on the first day. The amounts of the first and subsequent doses may be the same or different.
In some embodiments, the first dose and subsequent doses are the same. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in two doses of 10mg to 1000mg, or 10mg to 500mg, or 10mg to 400mg, or 10mg to 300mg, or 10mg to 200mg, or about 100mg per day.
In some embodiments, the first dose is greater than the subsequent dose on the first day. In some embodiments, the first dose is 5mg to 2000mg, or 10mg to 1000mg, or 10mg to 200mg, or 10mg to 150mg, or 10mg to 100mg, or 20mg to 150mg, or 20mg to 100mg, or about 250mg, or about 200mg, or about 150mg, or about 100mg, or about 90mg, or about 60mg, or about 30mg, or about 20mg, or about 10mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at two doses (i.e., a first dose and a subsequent dose) daily after the first day. The amounts of the first and subsequent doses may be the same or different. In some embodiments, after the first day, the first dose and subsequent doses are the same.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at two doses of 10 to 100mg, or 10 to 200mg, or 10 to 250mg, or 10 to 300mg, or 10 to 350mg, or 10mg, or 30mg, or 50mg daily after the first day.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg every 12-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 23mg every 12-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30mg every 12-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 46mg every 12-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg every 12-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 69mg every 12-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70mg every 12-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 23mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 46mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 69mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in one or more doses totaling about 100mg every 24 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg once daily.
In some embodiments, about 50mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily (b.i.d.).
In some embodiments, about 50mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours (q 12 h).
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100mg every 18-30 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20mg to about 150mg every 21-27 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20mg to about 100mg every 21-27 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 23mg, 46mg, 50mg, 60mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, or 125mg every 21-27 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 75mg to 125mg every 21-27 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 80mg to 100mg every 21-27 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily at a dose of about 10mg (20 mg per day).
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg every 6-18 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg every 9-15 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, or about 75mg every 12 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, or 70mg every 12 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10mg every 12 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 20mg every 12 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30mg every 12 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 40mg every 12 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50mg every 12 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 60mg every 12 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 70mg every 12 hours.
In some embodiments, compound 1 is administered at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, or about 75mg every 12 hours.
In some embodiments, compound 1 is administered at a dose of 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, or 70mg every 12 hours. In some embodiments, compound 1 is administered at a dose of 10mg every 12 hours. In some embodiments, compound 1 is administered at a dose of 20mg every 12 hours. In some embodiments, compound 1 is administered at a dose of 30mg every 12 hours. In some embodiments, compound 1 is administered at a dose of 40mg every 12 hours. In some embodiments, compound 1 is administered at a dose of 50mg every 12 hours. In some embodiments, compound 1 is administered at a dose of 60mg every 12 hours. In some embodiments, compound 1 is administered at a dose of 70mg every 12 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg every 12 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily at a dose of about 30mg (60 mg per day).
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30mg every 6-18 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30mg every 9-15 hours.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg every 12 hours (q 12 h).
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 6-18 hours after a first dose of about 20mg and a subsequent dose of about 10 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 9-15 hours after a first dose of about 20mg and a subsequent dose of about 10 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours after a first dose of about 20mg and a subsequent dose of about 10 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg every 12 hours after a first dose of about 20mg and a subsequent dose of about 10 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10mg every 12 hours after the first dose of 20mg and the subsequent dose of 10 mg.
In some embodiments, compound 1 is administered at a dose of about 10mg every 12 hours after a first dose of about 20mg and a subsequent dose of about 10 mg.
In some embodiments, compound 1 is administered at a dose of 10mg every 12 hours after the first dose of 20mg and the subsequent dose of 10 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg every 12 hours after a first dose of about 20mg and a subsequent dose of about 10mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10mg every 12 hours after the first dose of 20mg and the subsequent dose of 10mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 10mg every 12 hours after a first dose of about 20mg and a subsequent dose of about 10mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 10mg every 12 hours after the first dose of 20mg and the subsequent dose of 10mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20mg every 12 hours after a first dose of about 40mg and a subsequent dose of about 20 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 20mg every 12 hours after the first dose of 40mg and the subsequent dose of 20 mg.
In some embodiments, compound 1 is administered at a dose of about 20mg every 12 hours after a first dose of about 40mg and a subsequent dose of about 20 mg.
In some embodiments, compound 1 is administered at a dose of 20mg every 12 hours after the first dose of 40mg and the subsequent dose of 20 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20mg every 12 hours after a first dose of about 40mg and a subsequent dose of about 20mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 20mg every 12 hours after the first dose of 40mg and the subsequent dose of 20mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of about 20mg every 12 hours after a first dose of about 40mg and a subsequent dose of about 20mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 20mg every 12 hours after the first dose of 40mg and the subsequent dose of 20mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 6-18 hours after a first dose of about 60mg and a subsequent dose of about 30 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 9-15 hours after a first dose of about 60mg and a subsequent dose of about 30 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours after a first dose of about 60mg and a subsequent dose of about 30 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30mg every 12 hours after a first dose of about 60mg and a subsequent dose of about 30 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30mg every 12 hours after the first dose of 60mg and the subsequent dose of 30 mg.
In some embodiments, compound 1 is administered at a dose of about 30mg every 12 hours after a first dose of about 60mg and a subsequent dose of about 30 mg.
In some embodiments, compound 1 is administered at a dose of 30mg every 12 hours after the first dose of 60mg and the subsequent dose of 30 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30mg every 12 hours after a first dose of about 60mg and a subsequent dose of about 30mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30mg every 12 hours after the first dose of 60mg and the subsequent dose of 30mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of about 30mg every 12 hours after a first dose of about 60mg and a subsequent dose of about 30mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 30mg every 12 hours after the first dose of 60mg and the subsequent dose of 30mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40mg every 12 hours after a first dose of about 80mg and a subsequent dose of about 40 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 40mg every 12 hours after the first dose of 80mg and the subsequent dose of 40 mg.
In some embodiments, compound 1 is administered at a dose of about 40mg every 12 hours after a first dose of about 80mg and a subsequent dose of about 40 mg.
In some embodiments, compound 1 is administered at a dose of 40mg every 12 hours after the first dose of 80mg and the subsequent dose of 40 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40mg every 12 hours after a first dose of about 80mg and a subsequent dose of about 40mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 40mg every 12 hours after the first dose of 80mg and the subsequent dose of 40mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of about 40mg every 12 hours after a first dose of about 80mg and a subsequent dose of about 40mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 40mg every 12 hours after the first dose of 80mg and the subsequent dose of 40mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 6-18 hours after a first dose of about 100mg and a subsequent dose of about 50 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 9-15 hours after a first dose of about 100mg and a subsequent dose of about 50 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered every 12 hours after a first dose of about 100mg and a subsequent dose of about 50 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg every 12 hours after a first dose of about 100mg and a subsequent dose of about 50 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50mg every 12 hours after the first dose of 100mg and the subsequent dose of 50 mg.
In some embodiments, compound 1 is administered at a dose of about 50mg every 12 hours after a first dose of about 100mg and a subsequent dose of about 50 mg.
In some embodiments, compound 1 is administered at a dose of 50mg every 12 hours after the first dose of 100mg and the subsequent dose of 50 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg every 12 hours after a first dose of about 100mg and a subsequent dose of about 50mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50mg every 12 hours after the first dose of 100mg and the subsequent dose of 50mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of about 50mg every 12 hours after a first dose of about 100mg and a subsequent dose of about 50mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 50mg every 12 hours after the first dose of 100mg and the subsequent dose of 50mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60mg every 12 hours after a first dose of about 120mg and a subsequent dose of about 60 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 60mg every 12 hours after the first dose of 120mg and the subsequent dose of 60 mg.
In some embodiments, compound 1 is administered at a dose of about 60mg every 12 hours after a first dose of about 120mg and a subsequent dose of about 60 mg.
In some embodiments, compound 1 is administered at a dose of 60mg every 12 hours after the first dose of 120mg and the subsequent dose of 60 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60mg every 12 hours after a first dose of about 120mg and a subsequent dose of about 60mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 60mg every 12 hours after the first dose of 120mg and the subsequent dose of 60mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of about 60mg every 12 hours after a first dose of about 120mg and a subsequent dose of about 60mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 60mg every 12 hours after the first dose of 120mg and the subsequent dose of 60mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70mg every 12 hours after a first dose of about 140mg and a subsequent dose of about 70 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 70mg every 12 hours after the first dose of 140mg and the subsequent dose of 70 mg.
In some embodiments, compound 1 is administered at a dose of about 70mg every 12 hours after a first dose of about 140mg and a subsequent dose of about 70 mg.
In some embodiments, compound 1 is administered at a dose of 70mg every 12 hours after the first dose of 140mg and the subsequent dose of 70 mg.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70mg every 12 hours after a first dose of about 140mg and a subsequent dose of about 70mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 70mg every 12 hours after the first dose of 140mg and the subsequent dose of 70mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of about 70mg every 12 hours after a first dose of about 140mg and a subsequent dose of about 70mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1 is administered at a dose of 70mg every 12 hours after the first dose of 140mg and the subsequent dose of 70mg, wherein the subsequent dose is administered 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg to about 100mg once daily, or at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20mg every 18-30 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 23mg every 18-30 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 46mg every 18-30 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg every 18-30 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 69mg every 18-30 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70mg every 18-30 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100mg every 21-27 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100mg every 24 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg every 18-30 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50mg every 21-27 hours for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50mg twice daily after a first dose of 100mg and a subsequent dose of 50mg, wherein the subsequent dose is administered about 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30mg twice daily after the first dose of 60mg and the subsequent dose of 30mg, wherein the subsequent dose is administered about 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10mg twice daily after a first dose of 20mg and a subsequent dose of 10mg, wherein the subsequent dose is administered about 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30mg twice daily after the first dose of 90mg and the subsequent dose of 30mg, wherein the subsequent dose is administered about 12 hours after the first dose.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 43mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, or about 80mg every 24 hours (q 24 h). In some embodiments, the once daily (qd) dose is about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 43mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, or about 80mg of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 43mg, 45mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, or 80mg every 24 hours (q 24 h). In some embodiments, the once daily (qd) dose is 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 43mg, 45mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, or 80mg of compound 1, or a pharmaceutically acceptable salt thereof.
In some embodiments, compound 1 is administered at a dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 43mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, or about 80mg every 24 hours (q 24 h). In some embodiments, the once daily (qd) dose is about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 43mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, or about 80mg of compound 1. In some embodiments, compound 1 is administered at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 43mg, 45mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, or 80mg every 24 hours (q 24 h). In some embodiments, once daily (qd) administration is at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 43mg, 45mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, or 80mg of compound 1.
Compound 1 or a pharmaceutically acceptable salt thereof may be administered in any form, including any solid form (including any amorphous or crystalline form), any solvate, hydrate or co-crystalline form, or any solution or suspension of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 is administered in form B. In some embodiments, compound 1 is administered in the form of a pharmaceutical composition prepared by mixing form B with a pharmaceutically acceptable carrier, adjuvant or vehicle. In some embodiments, form B is characterized when Cu K is used α The X-ray powder diffraction pattern (XRPD) comprises at least three approximate peak locations (° 2θ±0.2) selected from the group consisting of: 4.4, 15.2, 16.4, 18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2, 24.8, 26.3, 29.6, 30.1, and 31.3, when XRPD is collected from about 4 to 40 ° 2θ (2θ). In some embodiments, form B is characterized when Cu K is used α The X-ray powder diffraction pattern (XRPD) comprises at least three approximate peak locations (° 2θ±0.2) selected from the group consisting of: 19.3, 22.2, 23.5, 26.3 and 30.1, when XRPD is collected from about 4 to 40 ° 2θ (2θ). In some embodiments, form B is characterized by the use of Cu K α The radiometric X-ray powder diffraction pattern (XRPD) is substantially similar to figure 1.
In some embodiments, the method comprises administering to the subject compound 1 in non-salt form (i.e., as the free acid (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide).
Compound 1 or a pharmaceutically acceptable salt thereof may be administered by any route known in the art. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.
Compound 1 or a pharmaceutically acceptable salt thereof may be administered for any number of days necessary or desired to continue to treat or reduce the severity of pain in a subject, depending on the type of pain experienced by the subject. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least two days. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 23mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 45mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 46mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 50mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 60mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 69mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 70mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 75mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 90mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 100mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 110mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 125mg once daily.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150mg once daily. In another aspect, the present disclosure relates to a method of treating or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 23mg once daily. In another aspect, the present disclosure relates to a method of treating or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 45mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 46mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 50mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 60mg once daily. In another aspect, the present disclosure relates to a method of treating or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 69mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 70mg once daily. In another aspect, the present disclosure relates to a method of treating or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 75mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 90mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 100mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 110mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 125mg once daily.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 23mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 45mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 46mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 50mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 60mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 69mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 70mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 75mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 90mg once daily. In another aspect, the invention relates to a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 100mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 110mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 125mg once daily.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150mg once daily. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 23mg once daily. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 45mg once daily. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 46mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 50mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 60mg once daily. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 69mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 70mg once daily. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 75mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 90mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 100mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 110mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 125mg once daily.
In another aspect, the present disclosure is directed to a method of treating pain or lessening the severity thereof in a subject, comprising administering to the subject compound 1, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 23 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 45 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 46 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 50 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 60 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 69 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 70 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 75 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 90 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 100 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 110 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of about 125 mg.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 23 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 45 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 46 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 50 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 60 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a total daily dose of 69 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 70 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 75 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 90 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 100 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 110 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a total daily dose of 125 mg.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 23 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 45 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 46 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 50 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 60 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 69 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 70 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 75 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 90 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 100 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 110 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of about 125 mg.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject in a total daily dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150 mg. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 23 mg. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 45 mg. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 46 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 50 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 60 mg. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 69 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 70 mg. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 75 mg. In another aspect, the disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 90 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 100 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 110 mg. In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a total daily dose of 125 mg.
Indication of disease
Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject for the treatment or lessening the severity of any type of pain known in the art.
In some embodiments, the disclosure features methods of treating or lessening the severity of the following diseases in a subject: acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain (nociceptive pain), arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychotic disorders, anxiety, depression, bipolar disorders, myotonic, arrhythmia, dyskinesia, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgical pain, herniation pain, bunyactomy pain or abdominal wall plastic pain), cancerous pain (including chronic cancerous pain and breakthrough cancerous pain), stroke (e.g., central nervous pain after stroke), whiplash-related conditions, brittle fracture, spinal fracture, ankylosing spondylitis, pemphigus, raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, lacrimal bone disease, polymyalgia rheumatica, pyoderma gangrenosum, chronic generalized pain, diffuse idiopathic hyperosteogeny, intervertebral disc degeneration/herniation, neuropathy, facet joint syndrome, back surgical failure syndrome, burn, carpal tunnel syndrome, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, cerolacrimiform bone disease, polymyalgia rheumatica, pyodermia gangrene, chronic generalized pain, paget's disease pain (Paget's disease pain), spinal stenosis, spinal disc inflammation, transverse myelitis, ewles-Danlover's disease pain, fabry's disease, mastocytosis, neurofibromatosis, neuropathic pain of the eye, sarcoidosis, vertebral discal, spondylolisthesis, chemotherapy-induced oral mucositis, charceicosis neuro-osteoarthropathy (Charcot neuropathic osteoarhropathy), temporomandibular joint disorders, painful joint replacement, non-cardiac chest pain, pudendum, renal colic, biliary tract disease, vascular leg ulcers, parkinson's disease (Parkinson's disease) pain, alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or gastrointestinal motility abnormalities, the method comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another embodiment, the disclosure features a method of treating or lessening the severity of a disease in a subject comprising: pain of femur cancer; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; lower back pain of neurogenic nature; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain and abdominal pain; pancreatic pain; IBS pain; chronic and acute headaches; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; shaco-marry-schmitt neuropathy (Charcot-Marie-Tooth nerve); hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy induced neuropathic pain; persistent/chronic postoperative pain (e.g., post amputation, post thoracotomy, post cardiac surgery), post mastectomy pain; central pain; spinal cord injury pain; pain after stroke; thalamic pain; phantom pain (e.g., after excision of lower, upper, breast); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; pain in the joints; mechanical lower back pain; neck pain; tendinitis; pain from injury; sport pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; ileus (intestinal obstruction); hernia; chest pain, cardiac pain; pelvic pain, renal colic, acute obstetrical pain, childbirth pain; pain in caesarean section; acute inflammatory pain, causalgia, and traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell anemia; acute pancreatitis; breakthrough pain; facial pain; sinusitis pain; toothache; multiple Sclerosis (MS) pain; depression pain; leprosy pain; behcet's disease pain (Behcet's disease pain); painful obesity; pain due to phlebitis; guillain-Barre pain; leg pain and active toe pain; ha Gelun De syndrome (Haglund syndrome); erythromelalgia pain; fabry's disease pain (Fabry's disease pain); bladder and genitourinary diseases; urinary incontinence and pathological cough; overactive bladder; painful bladder syndrome; interstitial Cystitis (IC); prostatitis (prostatitis); type I Complex Regional Pain Syndrome (CRPS), type II Complex Regional Pain Syndrome (CRPS); a method for treating pain induced by widespread pain, paroxysmal extreme pain, itch, tinnitus or angina pectoris, which comprises administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
In further embodiments, the disclosure features a method of treating or lessening the severity of acute pain in a subject comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the acute pain comprises acute post-operative pain.
In further embodiments, the disclosure features methods of treating or lessening the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgical pain, herniorrhaphy pain, bunyoctomy pain, or abdominal wall plastic pain) in a subject comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In further embodiments, the disclosure features a method of treating or lessening the severity of a bunaectomy pain in a subject comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In further embodiments, the disclosure features a method of treating or lessening the severity of herniorrhaphy pain in a subject comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In further embodiments, the disclosure features a method of treating or lessening the severity of an abdominal wall plastic pain in a subject comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In further embodiments, the disclosure features a method of treating visceral pain or lessening the severity thereof in a subject comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, visceral pain comprises visceral pain from abdominal wall angioplasty.
In further embodiments, the disclosure features a method of treating or lessening the severity of a neurodegenerative disease in a subject comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises peter-hopkins syndrome (Pitt Hopkins Syndrome) (PTHS).
In another embodiment, the disclosure features a method of treating or lessening the severity of a disease in a subject comprising: acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychotic disorders, anxiety, depression, bipolar disorders, myotonic, cardiac arrhythmias, dyskinesia, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., herniation pain, bunyactomy pain or abdominal wall plastic pain), cancerous pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or gastrointestinal dyskinesia, the method comprising administering an effective amount of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Patient population
Compound 1, or a pharmaceutically acceptable salt thereof, can be administered to a subject suffering from pain of any severity for treating pain or lessening the severity thereof.
In some embodiments, the subject has a baseline pain score of at least 4 according to the 11-point digital pain rating scale prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, the subject has a baseline pain level of moderate or severe intensity according to the speech classification rating scale prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
Compounds, pharmaceutically acceptable salts and compositions for use
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, or about 75mg twice daily.
In another aspect, the disclosure relates to compound 1 for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, or about 75mg twice daily.
In another aspect, the disclosure relates to compound 1 for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1 to the subject at a dose of 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, or 75mg twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a daily dose of about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, or about 150 mg.
In another aspect, the present disclosure relates to compound 1 for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a daily dose of about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, or about 150 mg.
In another aspect, the present disclosure relates to compound 1 for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a daily dose of 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, or 150 mg.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily. In another aspect, the invention relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of 10mg, 30mg, or 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a method of treating pain or lessening the severity of pain in a subject comprising administering to the subject compound 1 or a pharmaceutically acceptable salt thereof at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of an intestinal pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of an intestinal pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of an intestinal pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of an intestinal pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a method of treating or lessening the severity of compound 1, or a pharmaceutically acceptable salt thereof, in a subject, comprising administering to the subject a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of neuropathic pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of diabetic peripheral neuropathy in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of diabetic peripheral neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a dose of about 23mg, about 46mg, about 50mg, about 69mg, or about 70mg once daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of diabetic peripheral neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a dose of about 10mg, about 30mg, or about 50mg, or about 130mg twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of diabetic peripheral neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a dose of about 10mg, about 30mg, or about 50mg, or about 130mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of diabetic peripheral neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of diabetic peripheral neuropathy in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of musculoskeletal pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a method of treating or lessening the severity of musculoskeletal pain in a subject comprising administering to the subject a first dose of about 20mg, about 60mg or about 100mg and a subsequent dose of about 10mg, about 30mg or about 50mg on a first day, and two doses of about 10mg, about 30mg or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of osteoarthritis pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of acute pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of acute pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of acute pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of acute pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of acute pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of inflammatory pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a method of treating or lessening the severity of inflammatory pain in a subject comprising administering to the subject a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of cancer pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of cancer pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of cancer pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of cancer pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of cancer pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject twice daily at a dose of about 10mg, about 30mg, or about 50mg for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of post-operative pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of post-operative pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of post-operative pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of post-operative pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of post-operative pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating visceral pain or lessening the severity thereof in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of visceral pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily.
In another aspect, the present disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of visceral pain in a subject, the method comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 30mg, or about 50mg twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to compound 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating or lessening the severity of visceral pain in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50m g (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a method of treating visceral pain or lessening the severity thereof in a subject comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg or about 100mg and a subsequent dose of about 10mg, about 30mg or about 50mg on a first day, and at two doses of about 10mg, about 30mg or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 23mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 45mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 46mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 50mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 60mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 70mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 75mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 90mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 100mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 110mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 125mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 23mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 45mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 46mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 50mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 60mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 69mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 70mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 75mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 90mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 100mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 110mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 125mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 23mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 45mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 46mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 50mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 60mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 69mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 70mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 75mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 90mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 100mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 110mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of about 125mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 23mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 45mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of 46mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of 50mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of 60mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 69mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of 70mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 75mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 90mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 100mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 110mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a dose of 125mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 23 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 45 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 46 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 50 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 60 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 69 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 70 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 75 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 90 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 100 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 110 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of about 125 mg.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 23 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 45 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 46 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 50 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 60 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 69 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 70 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 75 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 90 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 100 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 110 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a total daily dose of 125 mg.
In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 23 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 45 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 46 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 50 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 60 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 69 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 70 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 75 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 90 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 100 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 110 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of about 125 mg.
In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 23 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 45 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 46 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 50 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 60 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 69 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 70 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 75 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 90 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 100 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 110 mg. In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 to a subject at a total daily dose of 125 mg.
In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of about 10mg, about 15mg, about 20mg, about 23mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 46mg, about 50mg, about 55mg, about 60mg, about 65mg, about 69mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 for use in a method of treating pain or lessening the severity thereof in a subject, wherein the composition is prepared for administering compound 1 to a subject at a dose of 10mg, 15mg, 20mg, 23mg, 25mg, 30mg, 35mg, 40mg, 45mg, 46mg, 50mg, 55mg, 60mg, 65mg, 69mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, or 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating chronic pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 140mg, or about 150mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 45mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 50mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 60mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 70mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 75mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 90mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 100mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 110mg once daily. In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of chronic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of 125mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of an intestinal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of an intestinal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of an intestinal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of an intestinal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of neuropathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of neuropathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of neuropathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of neuropathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once per day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once per day for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic small fiber neuropathy in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of osteoarthritis pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of acute pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of acute pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of acute pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of acute pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of cancer pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of cancer pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of cancer pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of cancer pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of post-operative pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of post-operative pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of post-operative pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating or lessening the severity of post-operative pain in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg, or about 100mg and a subsequent dose of about 10mg, about 30mg, or about 50mg on a first day, and at two doses of about 10mg, about 30mg, or about 50mg per day on each day after the first day.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating visceral pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating visceral pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg, about 20mg, about 30mg, about 50mg, about 60mg, about 90mg, about 100mg, or about 150mg once daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks, or one to six weeks.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating visceral pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a dose of about 10mg (20 mg per day), about 30mg (60 mg per day), or about 50mg (100 mg per day) twice daily.
In another aspect, the present disclosure relates to a composition comprising compound 1 or a pharmaceutically acceptable salt thereof for use in a method of treating visceral pain or lessening the severity thereof in a subject, wherein the composition is prepared for administration of compound 1 or a pharmaceutically acceptable salt thereof to a subject at a first dose of about 20mg, about 60mg or about 100mg and a subsequent dose of about 10mg, about 30mg or about 50mg on a first day, and at two doses of about 10mg, about 30mg or about 50mg per day on each day after the first day.
Pharmaceutical manufacturing
In another aspect, the present disclosure relates to the use of compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for treating or lessening the severity of pain in a subject according to the methods described herein (including any embodiments thereof).
In another aspect, the present disclosure provides the use of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating or lessening the severity of the following disease in a subject: chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancerous pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunyactomy pain, or abdominal wall plastic pain), visceral pain, multiple sclerosis, xia Matu three's syndrome, incontinence, pathological cough, or arrhythmia.
In another aspect, the present disclosure provides the use of compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating or lessening the severity of the following disease in a subject: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancerous pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunyactomy pain, multiple sclerosis, xia Matu three's syndrome, incontinence or arrhythmia.
In another aspect, the present disclosure provides the use of compound 1, a pharmaceutically acceptable salt or a pharmaceutical composition described herein for the manufacture of a medicament for treating or lessening the severity of an intestinal pain in a subject, wherein the intestinal pain comprises inflammatory bowel disease pain, crohn's disease pain, or interstitial cystitis pain.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of neuropathic pain in a subject. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small-fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, causalgia, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus nerve avulsion injury, complex regional pain syndrome, drug-therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, post-spinal cord injury pain, small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal neuropathy.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of musculoskeletal pain in a subject. In some aspects, musculoskeletal pain includes osteoarthritis pain.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of musculoskeletal pain in a subject, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burning pain, or dental pain.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises fibromyalgia.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of a pathological cough in a subject.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of acute pain in a subject. In some aspects, the acute pain comprises acute postoperative pain.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of post-operative pain (e.g., herniorrhaphy pain, bunyoctomy pain, or abdominal wall plastic pain) in a subject.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of herniorrhaphy pain in a subject.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of a bunaectomy pain in a subject.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of an abdominal wall plastic pain in a subject.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of visceral pain in a subject. In some aspects, visceral pain comprises visceral pain from abdominal wall angioplasty.
In another aspect, the disclosure features compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises peter-hopkins syndrome (Pitt Hopkins Syndrome) (PTHS).
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in combination with one or more additional therapeutic agents for the manufacture of a medicament, which are administered simultaneously, prior to, or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of: acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychotic disorders, anxiety, depression, bipolar disorders, myotonic, cardiac arrhythmias, dyskinesia, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., herniation pain, bunion resectioning pain or abdominal wall shaping pain), cancerous pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or gastrointestinal motility abnormalities.
In another aspect, the present disclosure provides compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or lessening the severity of: femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headaches, migraine, tension headaches, cluster headaches, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy; HIV-related neuropathy, trigeminal neuralgia, charpy-Mary-Saint neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamus pain, complex regional pain syndrome, phantom pain, intractable pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical lower back pain, neck pain, tendinitis, injury pain, motor pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute obstetric pain, childbirth pain caesarean section pain, acute inflammation, causalgia, trauma pain, acute intermittent pain, endometriosis, acute shingles pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, dental pain, multiple Sclerosis (MS) pain, depression pain, leprosy pain, behcet's disease pain, painful obesity, phlebitis pain, geobatwo's pain, leg pain and active toe pain, ha Gelun De syndrome, erythromelalgia pain, fabry's disease pain, bladder and genitourinary system diseases, urinary incontinence, pathological cough, overactive bladder, painful bladder syndrome, interstitial Cystitis (IC), prostatitis, type I Complex Regional Pain Syndrome (CRPS), type II Complex Regional Pain Syndrome (CRPS), CRPS, pain induced by widespread pain, paroxysmal extreme pain, itching, tinnitus or angina pectoris.
In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of the following disease in a subject: trigeminal neuralgia, migraine treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus neuropathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliofacial inguinal neuralgia, pudendum neuralgia, femoral neuropathy, paresthesia femoral pain, saphenous neuropathy, sciatic neuropathy, fibular neuropathy, tibial neuropathy, lumbosacral plexus neuropathy, traumatic neuroma residual pain, or post-amputation pain.
Pharmaceutically acceptable salts, pharmaceutical compositions, dosage forms and implementation pathways
Pharmaceutically acceptable salts
The methods described and claimed herein comprise administering compound 1 or a pharmaceutically acceptable salt thereof to a subject. As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. The "pharmaceutically acceptable salt" of compound 1 includes any non-toxic salt that, when administered to a recipient, is capable of providing compound 1 or an inhibited active metabolite or residue thereof (e.g., the parent compound of the prodrug), directly or indirectly. As used herein, the term "an active metabolite or residue thereof is inhibited" means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.
Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in J.pharmaceutical Sciences,1977,66,1-19 by S.M. Bere et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of compound 1 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonic acid salts, benzoic acid salts, bisulfate salts, boric acid salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionic acid salts, digluconate, dodecylsulfuric acid salts, ethanesulfonic acid salts, formic acid salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconic acid salts, hemisulfate, heptanoic acid salts, caproic acid salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonic acid salts, lactobionic aldehyde salts, lactic acid salts, lauric acid salts, lauryl sulfuric acid salts, malic acid salts, maleic acid salts, malonic acid salts, methanesulfonic acid salts, 2-naphthalenesulfonic acid salts, nicotinic acid salts, nitrate salts, oleic acid salts, oxalic acid salts, palmitic acid salts, pamoic acid salts, pectic acid salts, persulfates, 3-phenylpropionic acid salts, phosphates, picrate salts, pivalate salts, stearic acid salts, succinic acid salts, sulfuric acid salts, tartaric acid salts, thiocyanate salts, p-toluenesulfonic acid salts, undecanoate valerate salts, and the like. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate, as appropriate.
Pharmaceutical composition
In the methods described and claimed herein, compound 1 or a pharmaceutically acceptable salt thereof may be administered in the form of a pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
The term "pharmaceutically acceptable carrier, adjuvant or vehicle" includes any and all solvents, diluents or other liquid vehicles, dispersion or suspension adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, sixteenth edition, e.w. martin (Mack Publishing co., easton, pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with compound 1 or a pharmaceutically acceptable salt thereof, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any of the other components of the pharmaceutical composition, its use is contemplated as falling within the scope of the invention. Some examples of materials that may serve as pharmaceutically acceptable carriers 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), saturated vegetable fatty acid partial glyceride mixtures, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), celluloses and derivatives thereof (such as carboxymethylcellulose sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl ester), agar, such as magnesium hydroxide, and aluminum hydroxide, alginic acid, raw saline, ringer's solution, and the like; ethanol and phosphate buffers, as well as other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, mold release agents, coating agents, sweetening, flavoring and perfuming agents, preserving and antioxidant agents, depending on the formulation, may also be present in the composition.
Dosage forms and routes of administration
The methods described and claimed herein may involve administering compound 1 or a pharmaceutically acceptable salt thereof by any route of administration effective to treat or reduce the severity of one or more pain disorders described herein. Compound 1 or a pharmaceutically acceptable salt thereof may be formulated in dosage unit form to facilitate administration and uniformity of dosage. As used herein, the term "dosage unit form" refers to physically discrete units of medicament suitable for use in a subject to be treated.
Compound 1 or a pharmaceutically acceptable salt thereof may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), bucally, as an oral or nasal spray, etc., depending on the condition being treated.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to compound 1 or a pharmaceutically acceptable salt thereof, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable formulations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed are water, ringer's solution, u.s.p. And isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.
The injectable formulations may be sterilized, for example, by filtration through bacterial-retaining filters, or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the therapeutic effect of compound 1, it may be desirable to slow the absorption of the compound or a pharmaceutically acceptable salt thereof from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The rate of absorption of a compound then depends on its rate of dissolution, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microencapsulated matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound may be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by embedding the compounds in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing compound 1 or a pharmaceutically acceptable salt thereof with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, compound 1 or a pharmaceutically acceptable salt thereof is admixed with: at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate; and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) Binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) Humectants, such as glycerol; d) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) Solution retarders such as paraffin; f) Absorption enhancers such as quaternary ammonium compounds; g) Humectants such as cetyl alcohol and glycerol monostearate; h) Absorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation arts. The solid dosage form may optionally contain opacifying agents, and may also have a composition that releases the active ingredient only or in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
The active compound or salt may also be in microencapsulated form with one or more excipients as mentioned above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation arts. In such solid dosage forms, the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also conventionally contain other substances besides inert diluents, for example tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Dosage forms for topical or transdermal administration of compound 1 or a pharmaceutically acceptable salt thereof include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers, if required. Ophthalmic formulations, ear drops and eye drops are also considered to be within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches that have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of a compound across the skin. The rate may be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Spray-dried dispersion and tablet
Spray drying converts the liquid feed into a dry particulate form. Spray drying generally involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air to facilitate droplet drying. For example, a liquid solution containing compound 1 or a salt thereof and at least one polymer may be sprayed into a warm filtered gas stream that evaporates the solvent and delivers the dried product to a collector. The vaporized solvent and off-gas is removed from the collector and may be sent to a condenser to capture the solvent. For example, commercial spray dryers are manufactured by Buchi ltd. And Niro (e.g., PSD series of spray dryers manufactured by Niro) (see US2004/0105820, US 2003/0144257).
Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6 th edition, R.H.Perry, D.W.Green & j.o. maloney, mcGraw-Hill book co. (1984); in Marshall "Atomization and Spray-Drying"50,Chem.Eng.Prog.Monogr.Series 2 (1954). All three references are incorporated herein by reference in their entirety.
Additional drying steps may be required after spray drying to ensure removal of the solvent. Other drying techniques include, but are not limited to, tray drying, fluid bed drying (e.g., about room temperature to about 100 ℃), vacuum drying, microwave drying, drum drying, or biconic vacuum drying (e.g., about room temperature to about 200 ℃).
In some embodiments, the solvent used in spray drying is a volatile solvent. For example, the volatile solvent may have a boiling point below 100 ℃. Mixtures of volatile solvents or mixtures of volatile and non-volatile solvents may be used.
Exemplary solvents that can be tested include acetone, cyclohexane, methylene chloride, N-Dimethylacetamide (DMA), N-Dimethylformamide (DMF), 1, 3-dimethyl-2-imidazolidinone (DMI), dimethylsulfoxide (DMSO), dioxane, ethyl acetate, diethyl ether, glacial acetic acid (HOAc), methyl Ethyl Ketone (MEK), N-methyl-2-pyrrolidone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropanol, isopropyl acetate, DCM, and toluene. Exemplary cosolvents include acetone/DMSO, acetone/DMF, acetone/water, MEK/water, THF/water, dioxane/water. In a bi-solvent system, the solvent may be present from about 0.1% to about 99.9%. In some embodiments, water is a co-solvent with acetone, wherein water is present at about 0.1% to about 15%, such as about 9% to about 11%, such as about 10%. In some embodiments, water is a co-solvent with MEK, wherein water is present at about 0.1% to about 15%, such as about 9% to about 11%, such as about 10%. In some embodiments, the solvent system comprises three solvents. In some embodiments, where amorphous compound 1 is a component of a solid amorphous dispersion, one or more solvents dissolve compound 1 and at least one polymer. Suitable solvents include those described above, such as DCM, water, methanol, IPA and mixtures thereof. In some embodiments, the solvent comprises DCM and methanol.
In some embodiments, the at least one polymer is selected from: hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof.
In some embodiments, the at least one polymer is HPMCAS.
In some embodiments, at least one polymer is a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. Commercial examples of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers include
In some embodiments, at least one polymer is a compound of formula I, wherein n is about 13, m is about 30, and I is about 57. The weight average molecular weight as determined by gel permeation chromatography was about 118,000g/mol.
In some embodiments, the solid dispersions disclosed herein comprise at least one polymer and compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises from about 20% to about 50% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises from about 20 wt% to about 45 wt%, or from about 20 wt% to about 40 wt%, or from about 20 wt% to about 35 wt%, or from about 20 wt% to about 30 wt%, or from about 22 wt% to about 28 wt%, or about 23 wt%, or about 24 wt%, or about 25 wt%, or about 26 wt%, or about 27 wt%, or about 28 wt%, or about 29 wt%, or about 30 wt% of compound 1, or a pharmaceutically acceptable salt thereof.
In some embodiments, the solid dispersion comprises 5% to 35% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 5 to 30 weight percent of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 10% to 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 15 wt% to 30 wt% of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 20% to 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, the solid dispersion comprises 5 wt% to 35 wt% of compound 1. In some embodiments, the solid dispersion comprises 5 wt% to 30 wt% of compound 1. In some embodiments, the solid dispersion comprises 10 wt% to 30 wt% of compound 1. In some embodiments, the solid dispersion comprises 15 wt% to 30 wt% of compound 1. In some embodiments, the solid dispersion comprises 20 wt% to 30 wt% of compound 1.
In some embodiments, the solid dispersion comprises about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt% or about 35 wt% of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt% of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 20% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 25% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises about 35% by weight of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, the solid dispersion comprises about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt% or about 35 wt% of compound 1. In some embodiments the solid dispersion comprises about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt% of compound 1. In some embodiments, the solid dispersion comprises about 20 wt% of compound 1. In some embodiments, the solid dispersion comprises about 25 wt% of compound 1. In some embodiments, the solid dispersion comprises about 30 wt% of compound 1. In some embodiments, the solid dispersion comprises about 35 wt% of compound 1.
In some embodiments, the solid dispersion comprises 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt% or 35 wt% of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt% or 30 wt% of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 20% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 25% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 35% by weight of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, the solid dispersion comprises 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt% or 35 wt% of compound 1. In some embodiments the solid dispersion comprises 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt% or 30 wt% of compound 1. In some embodiments, the solid dispersion comprises 20 wt% of compound 1. In some embodiments, the solid dispersion comprises 25 wt% of compound 1. In some embodiments, the solid dispersion comprises 30 wt% of compound 1. In some embodiments, the solid dispersion comprises 35 wt% of compound 1.
In some embodiments, the solid dispersion comprises from about 50% to about 80% by weight of the polymer. In some embodiments, the solid dispersion comprises about 55 wt% to about 80 wt%, or about 60 wt% to about 80 wt%, or about 65 wt% to about 80 wt%, or about 70 wt% to about 80 wt%, or about 71 wt%, or about 72 wt%, or about 73 wt%, or about 74 wt%, or about 75 wt%, or about 76 wt%, or about 77 wt%, or about 78 wt%, or about 79 wt%, or about 80 wt% polymer.
In some embodiments, the solid dispersion comprises from about 65% to about 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises from about 70% to about 95% by weight of at least one polymer. In some embodiments, the solid dispersion comprises from about 70% to about 90% by weight of at least one polymer. In some embodiments, the solid dispersion comprises from about 70% to about 85% by weight of at least one polymer. In some embodiments, the solid dispersion comprises from about 70% to about 80% by weight of at least one polymer.
In some embodiments, the solid dispersion comprises 65 wt% to 95 wt% of at least one polymer. In some embodiments, the solid dispersion comprises 70 wt% to 95 wt% of at least one polymer. In some embodiments, the solid dispersion comprises 70 wt% to 90 wt% of at least one polymer. In some embodiments, the solid dispersion comprises 70 wt% to 85 wt% of at least one polymer. In some embodiments, the solid dispersion comprises 70 wt% to 80 wt% of at least one polymer.
In some embodiments, the solid dispersion comprises about 65 wt%, about 66 wt%, about 67 wt%, about 68 wt%, about 69 wt%, about 70 wt%, about 71 wt%, about 72 wt%, about 73 wt%, about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, about 83 wt%, about 84 wt%, about 85 wt%, about 86 wt%, about 87 wt%, about 88 wt%, about 89 wt%, about 90 wt%, about 91 wt%, about 92 wt%, about 93 wt%, about 94 wt%, or about 95 wt% of at least one polymer. In some embodiments the solid dispersion comprises about 70 wt%, about 71 wt%, about 72 wt%, about 73 wt%, about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, or about 80 wt% of at least one polymer. In some embodiments, the solid dispersion comprises about 65% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 70% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 80% by weight of at least one polymer.
In some embodiments, the solid dispersion comprises 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, or 95 wt% of at least one polymer. In some embodiments the solid dispersion comprises 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt% or 80 wt% of at least one polymer. In some embodiments, the solid dispersion comprises 65% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 70% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 80% by weight of at least one polymer.
In some embodiments, the solid dispersion comprises from about 65% to about 95% by weight of at least one polymer and from about 5% to about 35% by weight of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises from about 70% to about 95% by weight of at least one polymer and from about 5% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises from about 70% to about 90% by weight of at least one polymer and from about 10% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises from about 70% to about 85% by weight of at least one polymer and from about 15% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises from about 70% to about 80% by weight of at least one polymer and from about 20% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments the solid dispersion comprises from about 65% to about 95% by weight of at least one polymer and from about 5% to about 35% by weight of compound 1. In some embodiments the solid dispersion comprises from about 70% to about 95% by weight of at least one polymer and from about 5% to about 30% by weight of compound 1. In some embodiments the solid dispersion comprises from about 70% to about 90% by weight of at least one polymer and from about 10% to about 30% by weight of compound 1. In some embodiments the solid dispersion comprises from about 70% to about 85% by weight of at least one polymer and from about 15% to about 30% by weight of compound 1. In some embodiments the solid dispersion comprises from about 70% to about 80% by weight of at least one polymer and from about 20% to about 30% by weight of compound 1.
In some embodiments, the solid dispersion comprises 65 to 95 weight percent of at least one polymer and 5 to 35 weight percent of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70 to 95 weight percent of at least one polymer and 5 to 30 weight percent of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70 to 90 wt% of at least one polymer and 10 to 30 wt% of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70 to 85 weight percent of at least one polymer and 15 to 30 weight percent of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises 70 to 80 weight percent of at least one polymer and 20 to 30 weight percent of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, the solid dispersion comprises 65 to 95 weight percent of at least one polymer and 5 to 35 weight percent of compound 1. In some embodiments, the solid dispersion comprises 70 to 95 weight percent of at least one polymer and 5 to 30 weight percent of compound 1. In some embodiments, the solid dispersion comprises 70 to 90 wt% of at least one polymer and 10 to 30 wt% of compound 1. In some embodiments, the solid dispersion comprises 70 to 85 weight percent of at least one polymer and 15 to 30 weight percent of compound 1. In some embodiments, the solid dispersion comprises 70 to 80 weight percent of at least one polymer and 20 to 30 weight percent of compound 1.
In some embodiments, the solid dispersion comprises from about 65% to about 95% by weight of at least one polymer and from about 5% to about 35% by weight of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 95% by weight of at least one polymer and from about 5% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 90% by weight of at least one polymer and from about 10% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 85% by weight of at least one polymer and from about 15% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 80% by weight of at least one polymer and from about 20% to about 30% by weight of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous.
In some embodiments, the solid dispersion comprises from about 65% to about 95% by weight of at least one polymer and from about 5% to about 35% by weight of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 95% by weight of at least one polymer and from about 5% to about 30% by weight of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 90% by weight of at least one polymer and from about 10% to about 30% by weight of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 85% by weight of at least one polymer and from about 15% to about 30% by weight of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises from about 70% to about 80% by weight of at least one polymer and from about 20% to about 30% by weight of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous.
In some embodiments, the solid dispersion comprises 65 to 95 weight percent of at least one polymer and 5 to 35 weight percent of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein the compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 95 weight percent of at least one polymer and 5 to 30 weight percent of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein the compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 90 wt% of at least one polymer and 10 to 30 wt% of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein the compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 85 weight percent of at least one polymer and 15 to 30 weight percent of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein the compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 80 weight percent of at least one polymer and 20 to 30 weight percent of compound 1 or a pharmaceutically acceptable salt thereof, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein the compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous.
In some embodiments, the solid dispersion comprises 65 to 95 weight percent of at least one polymer and 5 to 35 weight percent of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 95 weight percent of at least one polymer and 5 to 30 weight percent of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 90 wt% of at least one polymer and 10 to 30 wt% of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 85 weight percent of at least one polymer and 15 to 30 weight percent of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 70 to 80 weight percent of at least one polymer and 20 to 30 weight percent of compound 1, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous.
In some embodiments, the solid dispersion comprises about 25% by weight of compound 1 or a pharmaceutically acceptable thereof, and about 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises about 25% by weight of compound 1 and about 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 25% by weight of compound 1 or a pharmaceutically acceptable thereof, and 75% by weight of at least one polymer. In some embodiments, the solid dispersion comprises 25 wt% compound 1 and 75 wt% of at least one polymer.
In some embodiments, the solid dispersion comprises about 25 weight percent of compound 1 or a pharmaceutically acceptable salt thereof, and about 75 weight percent of at least one polymer, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises about 25 weight percent of compound 1 and about 75 weight percent of at least one polymer, wherein the at least one polymer is selected from the group consisting of HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 is substantially amorphous. In some embodiments, the solid dispersion comprises 25 weight percent of compound 1 or a pharmaceutically acceptable salt thereof, and 75 weight percent of at least one polymer, wherein the at least one polymer is selected from HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and wherein compound 1 or a pharmaceutically acceptable salt thereof is substantially amorphous. In some embodiments, the solid dispersion comprises about 25 weight percent of compound 1, and about 75 weight percent of at least one polymer, wherein the at least one polymer is selected from the group consisting of HPMCAS and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and wherein compound 1 is substantially amorphous.
In some embodiments, compound 1 in the solid dispersion is substantially amorphous. In some embodiments, compound 1 in the solid dispersion is amorphous.
A process for preparing a spray-dried dispersion comprising compound 1 or a pharmaceutically acceptable salt thereof is provided. The method comprises mixing compound 1 or a pharmaceutically acceptable salt thereof with at least one polymer in a solvent (or mixture of solvents).
The solvent may be any solvent as described above, for example, in some embodiments, the solvent comprises a mixture of DCM and methanol.
In one embodiment, the method further comprises filtering the mixture before the mixture is forced through the nozzle. In one embodiment, the method further comprises applying heat to the mixture as it enters the nozzle. In one embodiment, the nozzle includes an inlet and an outlet, and the inlet is heated to a temperature above the boiling point of the solvent. It should be appreciated that in certain embodiments, the temperature may be below the boiling point of the solvent, for example under high pressure conditions.
In one embodiment, the spray dryer is heated to a temperature of about 40 ℃ to about 150 ℃. In one embodiment, the spray dryer is heated to a temperature of about 40 ℃ to about 60 ℃, or about 45 ℃ to about 55 ℃, or about 48 ℃. In one embodiment, the mixture is forced through a nozzle by a pressurized gas. In one embodiment, the pressurized gas comprises molecular nitrogen. At the nozzle, the gas flow may be about 4 kg/hr to about 5 kg/hr.
In some embodiments, provided herein is a pharmaceutical composition comprising a solid dispersion disclosed herein. In some embodiments, the pharmaceutical composition may comprise one or more excipients. Examples of excipients include, but are not limited to, fillers, disintegrants, and lubricants.
Examples of fillers include, but are not limited to, microcrystalline cellulose, lactose monohydrate, mannitol, and mixtures thereof. In some embodiments, the filler comprises microcrystalline cellulose. In some embodiments, the filler comprises lactose monohydrate. In some embodiments, the bulking agent comprises mannitol. In some embodiments, the filler comprises a mixture of microcrystalline cellulose and lactose monohydrate. In some embodiments, the filler comprises microcrystalline cellulose, wherein the microcrystalline cellulose is Avicel PhH101. In some embodiments, the filler comprises microcrystalline cellulose, wherein the microcrystalline cellulose is Avicel PH102. In some embodiments, the filler comprises microcrystalline cellulose, wherein microcrystalline cellulose is a combination of Avicel PH101 and Avicel PH102.
Examples of suitable disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, and mixtures thereof. In some embodiments, the disintegrant comprises croscarmellose sodium. In some embodiments, the disintegrant comprises crospovidone.
Examples of suitable lubricants include, but are not limited to, sodium stearyl fumarate, magnesium stearate, and mixtures thereof. In some embodiments, the lubricant comprises sodium stearyl fumarate. In some embodiments, the lubricant comprises magnesium stearate.
In some embodiments, the pharmaceutical composition comprises compound 1 or a salt thereof, at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant. In some embodiments, the filler comprises microcrystalline cellulose and lactose monohydrate, the disintegrant comprises croscarmellose sodium, and the lubricant comprises sodium stearyl fumarate.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 72.5% by weight of at least one filler, about 4.5% by weight of at least one disintegrant, and about 3% by weight of at least one lubricant.
In some embodiments, the pharmaceutical composition comprises about 1 to about 50mg of compound 1. In some embodiments, the pharmaceutical composition comprises about 1 to about 45mg, or about 1 to about 40mg, or about 1 to about 35mg, or about 5 to about 40mg, or about 5 to about 35mg, or about 5 to about 30mg, or about 5mg, or about 10mg, or about 15mg, or about 20mg, or about 25mg, or about 30mg, or about 40mg, or about 50mg of compound 1. In some embodiments, the pharmaceutical composition comprises about 10mg of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent of at least one filler, about 1 to about 6 weight percent of at least one disintegrant, and about 0.5 to about 2 weight percent of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent of at least one filler, about 1 to about 6 weight percent of at least one disintegrant, and about 0.5 to about 2 weight percent of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 50 weight percent of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent of at least one filler, about 1 to about 6 weight percent of at least one disintegrant, about 0.5 to about 2 weight percent of at least one lubricant, and about 2 to about 4.5 weight percent of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent of at least one filler, about 1 to about 6 weight percent of at least one disintegrant, about 0.5 to about 2 weight percent of at least one lubricant, and about 2 to about 4.5 weight percent of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 50 weight percent of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 weight percent of a compound 1 spray-dried dispersion, 35 to 55 weight percent of at least one filler, 1 to 6 weight percent of at least one disintegrant, and 0.5 to 2 weight percent of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 weight percent of a compound 1 spray-dried dispersion, 35 to 55 weight percent of at least one filler, 1 to 6 weight percent of at least one disintegrant, and 0.5 to 2 weight percent of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 50 weight percent of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 weight percent of a compound 1 spray-dried dispersion, 35 to 55 weight percent of at least one filler, 1 to 6 weight percent of at least one disintegrant, 0.5 to 2 weight percent of at least one lubricant, and 2 to 4.5 weight percent of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 weight percent of a compound 1 spray-dried dispersion, 35 to 55 weight percent of at least one filler, 1 to 6 weight percent of at least one disintegrant, 0.5 to 2 weight percent of at least one lubricant, and 2 to 4.5 weight percent of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 50 weight percent of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent microcrystalline cellulose, about 1 to about 6 weight percent croscarmellose sodium, and about 0.5 to about 2 weight percent magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent microcrystalline cellulose, about 1 to about 6 weight percent croscarmellose sodium, and about 0.5 to about 2 weight percent magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50 weight percent compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent microcrystalline cellulose, about 1 to about 6 weight percent croscarmellose sodium, about 0.5 to about 2 weight percent magnesium stearate, and about 2 to about 4.5 weight percent Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 60 weight percent of a compound 1 spray-dried dispersion, about 35 to about 55 weight percent microcrystalline cellulose, about 1 to about 6 weight percent croscarmellose sodium, about 0.5 to about 2 weight percent magnesium stearate, and about 2 to about 4.5 weight percent Opadry blue, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50 weight percent compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 weight percent of a compound 1 spray dried dispersion, 35 to 55 weight percent microcrystalline cellulose, 1 to 6 weight percent croscarmellose sodium, and 0.5 to 2 weight percent magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 weight percent of a compound 1 spray-dried dispersion, 35 to 55 weight percent microcrystalline cellulose, 1 to 6 weight percent croscarmellose sodium, and 0.5 to 2 weight percent magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50 weight percent compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 wt% of a compound 1 spray-dried dispersion, 35 to 55 wt% microcrystalline cellulose, 1 to 6 wt% croscarmellose sodium, 0.5 to 2 wt% magnesium stearate, and 2 to 4.5 wt% Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising 40 to 60 weight percent of a compound 1 spray-dried dispersion, 35 to 55 weight percent microcrystalline cellulose, 1 to 6 weight percent croscarmellose sodium, 0.5 to 2 weight percent magnesium stearate, and 2 to 4.5 weight percent Opadry blue, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 50 weight percent compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent of at least one filler, about 1.5 to about 4 weight percent of at least one disintegrant, and about 0.75 to about 1.5 weight percent of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent of at least one filler, about 1.5 to about 4 weight percent of at least one disintegrant, and about 0.75 to about 1.5 weight percent of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 35 weight percent of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent of at least one filler, about 1.5 to about 4 weight percent of at least one disintegrant, about 0.75 to about 1.5 weight percent of at least one lubricant, and about 2.5 to about 3.5 weight percent of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 40 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent of at least one filler, about 1.5 to about 4 weight percent of at least one disintegrant, about 0.75 to about 1.5 weight percent of at least one lubricant, and about 2.5 to about 3.5 weight percent of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 35 weight percent of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 wt% of a spray-dried dispersion of compound 1, 40 to 50 wt% of at least one filler, 1.5 to 4 wt% of at least one disintegrant, and 0.75 to 1.5 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 weight percent of a compound 1 spray-dried dispersion, 40 to 50 weight percent of at least one filler, 1.5 to 4 weight percent of at least one disintegrant, and 0.75 to 1.5 weight percent of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 35 weight percent of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 wt% of a spray-dried dispersion of compound 1, 40 to 50 wt% of at least one filler, 1.5 to 4 wt% of at least one disintegrant, 0.75 to 1.5 wt% of at least one lubricant, and 2.5 to 3.5 wt% of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 weight percent of a compound 1 spray-dried dispersion, 40 to 50 weight percent of at least one filler, 1.5 to 4 weight percent of at least one disintegrant, 0.75 to 1.5 weight percent of at least one lubricant, and 2.5 to 3.5 weight percent of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 35 weight percent of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent microcrystalline cellulose, about 1.5 to about 4 weight percent croscarmellose sodium, and about 0.75 to about 1.5 weight percent magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent microcrystalline cellulose, about 1.5 to about 4 weight percent croscarmellose sodium, and about 0.75 to about 1.5 weight percent magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35 weight percent compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent microcrystalline cellulose, about 1.5 to about 4 weight percent croscarmellose sodium, about 0.75 to about 1.5 weight percent magnesium stearate, and about 2.5 to about 3.5 weight percent Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 45 to about 55 weight percent of a compound 1 spray-dried dispersion, about 40 to about 50 weight percent microcrystalline cellulose, about 1.5 to about 4 weight percent croscarmellose sodium, about 0.75 to about 1.5 weight percent magnesium stearate, and about 2.5 to about 3.5 weight percent Opadry blue, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35 weight percent compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 wt% of a spray-dried dispersion of compound 1, 40 to 50 wt% microcrystalline cellulose, 1.5 to 4 wt% croscarmellose sodium, and 0.75 to 1.5 wt% magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 weight percent of a compound 1 spray-dried dispersion, 40 to 50 weight percent microcrystalline cellulose, 1.5 to 4 weight percent croscarmellose sodium, and 0.75 to 1.5 weight percent magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35 weight percent compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 wt% of a spray-dried dispersion of compound 1, 40 to 50 wt% microcrystalline cellulose, 1.5 to 4 wt% croscarmellose sodium, 0.75 to 1.5 wt% magnesium stearate, and 2.5 to 3.5 wt% Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising 45 to 55 wt% of a compound 1 spray-dried dispersion, 40 to 50 wt% microcrystalline cellulose, 1.5 to 4 wt% croscarmellose sodium, 0.75 to 1.5 wt% magnesium stearate, and 2.5 to 3.5 wt% Opadry blue, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 35 wt% compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray-dried dispersion, about 42.5 to about 47.5 weight percent of at least one filler, about 2.5 to about 3.5 weight percent of at least one disintegrant, and about 0.75 to about 1.25 weight percent of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray-dried dispersion, about 42.5 to about 47.5 weight percent of at least one filler, about 2.5 to about 3.5 weight percent of at least one disintegrant, and about 0.75 to about 1.25 weight percent of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 30 weight percent of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray-dried dispersion, about 42.5 to about 47.5 weight percent of at least one filler, about 2.5 to about 3.5 weight percent of at least one disintegrant, about 0.75 to about 1.25 weight percent of at least one lubricant, and about 2.75 to about 3.25 weight percent of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray-dried dispersion, about 42.5 to about 47.5 weight percent of at least one filler, about 2.5 to about 3.5 weight percent of at least one disintegrant, about 0.75 to about 1.25 weight percent of at least one lubricant, and about 2.75 to about 3.25 weight percent of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 30 weight percent of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 wt% of a compound 1 spray-dried dispersion, 42.5 to 47.5 wt% of at least one filler, 2.5 to 3.5 wt% of at least one disintegrant, and 0.75 to 1.25 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 wt% of a compound 1 spray-dried dispersion, 42.5 to 47.5 wt% of at least one filler, 2.5 to 3.5 wt% of at least one disintegrant, and 0.75 to 1.25 wt% of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 30 wt% of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 wt% of a compound 1 spray-dried dispersion, 42.5 to 47.5 wt% of at least one filler, 2.5 to 3.5 wt% of at least one disintegrant, 0.75 to 1.25 wt% of at least one lubricant, and 2.75 to 3.25 wt% of at least one coating. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 wt% of a compound 1 spray-dried dispersion, 42.5 to 47.5 wt% of at least one filler, 2.5 to 3.5 wt% of at least one disintegrant, 0.75 to 1.25 wt% of at least one lubricant, and 2.75 to 3.25 wt% of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 20 to about 30 wt% of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray dried dispersion, about 42.5 to about 47.5 weight percent microcrystalline cellulose, about 2.5 to about 3.5 weight percent croscarmellose sodium, and about 0.75 to about 1.25 weight percent magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray-dried dispersion, about 42.5 to about 47.5 weight percent microcrystalline cellulose, about 2.5 to about 3.5 weight percent croscarmellose sodium, and about 0.75 to about 1.25 weight percent magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 weight percent compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray dried dispersion, about 42.5 to about 47.5 weight percent microcrystalline cellulose, about 2.5 to about 3.5 weight percent croscarmellose sodium, about 0.75 to about 1.25 weight percent magnesium stearate, and about 2.75 to about 3.25 weight percent Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 47.5 to about 52.5 weight percent of a compound 1 spray dried dispersion, about 42.5 to about 47.5 weight percent microcrystalline cellulose, about 2.5 to about 3.5 weight percent croscarmellose sodium, about 0.75 to about 1.25 weight percent magnesium stearate, and about 2.75 to about 3.25 weight percent Opadry blue, wherein the compound 1 spray dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 weight percent compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 wt% of a spray dried dispersion of compound 1, 42.5 to 47.5 wt% microcrystalline cellulose, 2.5 to 3.5 wt% croscarmellose sodium, and 0.75 to 1.25 wt% magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 weight percent of a compound 1 spray-dried dispersion, 42.5 to 47.5 weight percent microcrystalline cellulose, 2.5 to 3.5 weight percent croscarmellose sodium, and 0.75 to 1.25 weight percent magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 weight percent compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 wt% of a compound 1 spray dried dispersion, 42.5 to 52.5 wt% microcrystalline cellulose, 2.5 to 3.5 wt% croscarmellose sodium, 0.75 to 1.25 wt% magnesium stearate, and 2.75 to 3.25 wt% Opadry blue. In some embodiments, disclosed herein is a pharmaceutical composition comprising 47.5 to 52.5 wt% of a compound 1 spray-dried dispersion, 42.5 to 47.5 wt% microcrystalline cellulose, 2.5 to 3.5 wt% croscarmellose sodium, 0.75 to 1.25 wt% magnesium stearate, and 2.75 to 3.25 wt% Opadry blue, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 20 to about 30 wt% compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a compound 1 spray-dried dispersion, about 44.7% by weight of at least one filler, about 2.9% by weight of at least one disintegrant, and about 1% by weight of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a compound 1 spray-dried dispersion, about 44.7% by weight of at least one filler, about 2.9% by weight of at least one disintegrant, and about 1% by weight of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 25% by weight of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a compound 1 spray-dried dispersion, about 44.7% by weight of at least one filler, about 2.9% by weight of at least one disintegrant, about 1% by weight of at least one lubricant, and about 2.9% by weight of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and about 25% by weight of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% of a compound 1 spray-dried dispersion, 44.7 wt% of at least one filler, 2.9 wt% of at least one disintegrant, and 1 wt% of at least one lubricant. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% of a compound 1 spray-dried dispersion, 44.7 wt% of at least one filler, 2.9 wt% of at least one disintegrant, and 1 wt% of at least one lubricant, wherein the compound 1 spray-dried dispersion comprises at least one polymer and 25 wt% of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% of a compound 1 spray-dried dispersion, 44.7 wt% of at least one filler, 2.9 wt% of at least one disintegrant, 1 wt% of at least one lubricant, and 2.9 wt% of at least one coating, wherein the compound 1 spray-dried dispersion comprises at least one polymer and 25 wt% of compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a compound 1 spray-dried dispersion, about 44.7% by weight of microcrystalline cellulose, about 2.9% by weight of croscarmellose sodium, and about 1% by weight of magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5% by weight of a compound 1 spray-dried dispersion, about 44.7% by weight of microcrystalline cellulose, about 2.9% by weight of croscarmellose sodium, and about 1% by weight of magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 25% by weight of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising about 48.5 wt% of a compound 1 spray-dried dispersion, about 44.7 wt% microcrystalline cellulose, about 2.9 wt% croscarmellose sodium, about 1 wt% magnesium stearate, and about 2.9 wt% Opadry blue, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and about 25 wt% compound 1.
In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% of a spray-dried dispersion of compound 1, 44.7 wt% microcrystalline cellulose, 2.9 wt% croscarmellose sodium, and 1 wt% magnesium stearate. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt.% of a compound 1 spray-dried dispersion, 44.7 wt.% microcrystalline cellulose, 2.9 wt.% croscarmellose sodium, and 1 wt.% of at least one magnesium stearate, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and 25 wt.% of compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising 48.5 wt% of a compound 1 spray-dried dispersion, 44.7 wt% microcrystalline cellulose, 2.9 wt% croscarmellose sodium, 1 wt% magnesium stearate, and 2.9 wt% Opadry blue, wherein the compound 1 spray-dried dispersion comprises hydroxypropyl methylcellulose acetate succinate and 25 wt% compound 1.
In some embodiments, the pharmaceutical compositions described herein may be formulated as tablets. In some embodiments, the tablet comprises compound 1 or a pharmaceutically acceptable salt thereof, a polymer, a filler, a lubricant, and a disintegrant.
In some embodiments, the tablet comprises a polymer selected from the group consisting of: hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof.
In some embodiments, the tablet comprises HPMCAS.
In some embodiments, the tablet comprises about 72.5% by weight of at least one filler, about 4.5% by weight of at least one disintegrant, and about 3% by weight of at least one lubricant.
In some embodiments, the tablet comprises about 1 to about 50mg of compound 1. In some embodiments, the tablet comprises from about 1 to about 45mg, or from about 1 to about 40mg, or from about 1 to about 35mg, or from about 5 to about 40mg, or from about 5 to about 35mg, or from about 5 to about 30mg, or about 5mg, or about 10mg, or about 15mg, or about 20mg, or about 25mg, or about 30mg, or about 40mg, or about 50mg of compound 1. In some embodiments, the tablet comprises about 10mg of compound 1.
Additional therapeutic agents
It will also be appreciated that compound 1, a salt of compound 1, and a pharmaceutically acceptable composition may be used in combination therapy, i.e., the compound, salt, and pharmaceutically acceptable composition may be administered concurrently, before, or after one or more other desired therapies or medical procedures. The particular combination of therapies (therapeutic agents or procedures) used in the combination regimen will take into account the compatibility of the desired therapeutic agent and/or procedure and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect on the same condition (e.g., the compounds of the invention may be administered simultaneously with another agent for treating the same condition), or they may achieve a different effect (e.g., a control of any side effect). As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are referred to as "suitable for the disease or condition being treated. For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles) such as Etodolac, indomethacin, sulindac (superlink), tolmetin (Tolmetin), naphthanones such as Nabumetone (Nabumetone), oxicams (oxicams) such as Piroxicam (Piroxicam), p-aminophenol derivatives such as acetaminophen, propionic acids such as Fenoprofen (Fenoprofen), flurbiprofen (Flurbrofen), ibuprofen (Ibuprofen), ketoprofen (Ketoprofen), naproxen (Naproxen), naproxen sodium (Naproxen sodifen), oxaprozin (Oxaprozin), salicylic acid salts such as Aspirin (aspin), choline magnesium trisalicylate (Diflunisal), fenamic acid salts such as meclofenamic acid (meclofenamic acid), mefenamic acid (Mefenamic), buprofen (mefenone), ketoprofen (buprofen), buprofen (mevalonate), levorphine (Oxymorphone), buprofen (oxygenone), oxaprozin (Oxaprozin), salicylic acid (aspirinate), and other drugs such as buprofen (buprofen. Furthermore, non-pharmaceutical analgesic methods may be used in combination with the administration of one or more compounds of the invention. For example, anesthesia (intrathecal infusion, nerve block), neurosurgery (nerve lysis of CNS pathways), nerve stimulation (transcutaneous electrical nerve stimulation, spinal stimulation), physical (physiotherapy, correction devices, diathermy) or psychological (cognitive-hypnosis, biofeedback or behavioral) methods may also be utilized. Additional suitable therapeutic agents or methods are generally described in The Merck Manual, nineteenth edition, robert s.Porter and just l.kaplan, merck Sharp & Dohme corp., merck & co., inc. Sub.2011 and The Food and Drug Administration website www.fda.gov, the entire contents of which are hereby incorporated by reference.
In another embodiment, the additional suitable therapeutic agent is selected from the following:
(1) Opioid analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol (levvalorphan), methadone, pethidine, fentanyl, cocaine (cocaine), codeine, dihydrocodeine (dihydrocodeine), oxycodone, hydrocodone (hydrocodone), propoxyphene, nalmefene (nalmefene), nalorphine (nalorphine), naloxone (naloxone), naltrexone (naltrexone), buprenorphine, butorphanol, nalbuphine, pentazocine or dyclonine (difenofalin);
(2) Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac (diclofenac), diflunisal, etodolac, fenbufen (fenbufen), fenoprofen, flubensal (flufenisal), flurbiprofen, ibuprofen (including but not limited to intravenous ibuprofen (e.g.,) Indomethacin, ketoprofen, ketorolac (ketorolac) (including but not limited to ketorolac tromethamine (ketorolac tromethamine) (e.g.)>) Meclofenamic acid, mefenamic acid, meloxicam (meloxicam), meloxicam IV (e.g., +.>) Nabumetone, naproxen, nimesulide (nimesulide), niflumipine (nifroflumin), oxalazine (olsalazine), oxaprozin, phenylbutazone, piroxicam, sulfasalazine (sulfasalazine), sulindac (sulindac), tolmetin, or zomepirac (zomepirac);
(3) Barbital sedatives, such as amobarbital, aprobarbital, butabarbital, tolbarbital, methabarbital, methohexitabital, pentobarbital, phenobarbital, secobarbital, tabarbital, thiabarbital, or thiopentobarbital;
(4) Benzodiazepines with sedative action, such as chlorazepine (chlordiazepoxide), clorazepam (clorazepate), diazepam (diazepam), fluoxazepam (flurazepam), lorazepam (lorazepam), oxazepam (oxazepam), temazepam (temazepam) or triazolam (triazolam);
(5) Histamine (H) with sedative effect 1 ) Antagonists such as diphenhydramine (diphenhydramine), pyrilamine (pyrilamine), promethazine (promethazine), chlorpheniramine (chlorohen amine) or chlorocyclizine (chloromycelizine);
(6) Sedatives, such as hypnotic (gladiate), methamphetamine, methaqualone, or ketazine (dichloralphenozone);
(7) Skeletal muscle relaxants such as baclofen (baclofen), carisoprodol (carisoprodol), chlorzoxazone (chlorzoxazone), cyclobenzaprine (cyclobenzaprine), methocarbamol (methocarbamol), or oxyphendrarine (oxyphenadine);
(8) NMDA receptor antagonists, for example dextromethorphan (dextromethorphan) or its metabolite dextrorphan (dextrorphan) ((+) -3-hydroxy-N-methyl morphinan), ketamine (ketamine), memantine, pyrroloquinoline quinone (pyrroloquinoline quinine), cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, bupirine, EN-3231Combined formulations of morphine and dextromethorphan, topiramate, nemethyl or pezifotel, including NR2B antagonists, such as ifenprodil, traxotropel or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3, 4-dihydro-2 (lH) -quinolinone;
(9) Alpha-adrenergic agents such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil or 4-amino-6, 7-dimethoxy-2- (5-methane-sulfonylamino-l, 2,3, 4-tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline;
(10) Tricyclic antidepressants such as desipramine, imipramine, amitriptyline or nortriptyline;
(11) Anticonvulsants, e.g. carbamazepine (carbamazepine)Lamotrigine, topiramate, lacosamide>Or valproate;
(12) Tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (αr, 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, 3 s) -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 (aprepitant), lanetant (laneptant), dapitant (dapitant) or 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] -2-phenylpiperidine (3 s);
(13) Muscarinic antagonists such as oxybutynin (oxybutynin), tolterodine (tolterodine), propiverine (propiverine), trospium chloride (tropsium chloride), darifenacin (darifenacin), solifenacin (solifenacin), temivalin (temirine), and ipratropium;
(14) COX-2 selective inhibitors such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib;
(15) Coal tar analgesics, in particular paracetamol (paracetamol);
(16) Neuroleptic agentSuch as haloperidol (droperidol), chlorpromazine (chlororomazine), haloperidol (haloperidol), oxypiperazine (perphenazine), thioridazine (thioridazine), mesoridazine (mesoridazine), trifluoperazine (trifluoperazine), flufenazine (fluhenazine), clozapine (clozapine), olanzapine (olanzapine), risperidone (risperidone), ziprasidone (ziprasidone), quetiapine, sertindole (sertindole), aripiprazole (aripiprazole), flufenazine (aripiprazole) Suonepiprazole, blonanserin, iloperidone, pimentone Luo Luotong, lansopirane, lansopirine, asenapine, diphenoxylane, asenapine, lurasidone, amisulpride, balapidone, pamidone, palinode, irinotecan, oxalinant, rimonabant, meclo Lin Tan, meclozinert,Or Sha Lizuo tan (sarizotan);
(17) Vanilloid receptor agonists (e.g., resiniferatoxin (resiniferatoxin) or cevaline (civamide)) or antagonists (e.g., capsazepine (GRC-15300);
(18) Beta-adrenergic agents such as propranolol (propranolol);
(19) Local anesthetics such as mexiletine (mexiletine);
(20) Corticosteroids such as dexamethasone (dexamethasone);
(21) 5-HT receptor agonists or antagonists, in particular 5-HT 1B/1D Agonists such as eletriptan (eletriptan), sumatriptan (sumatriptan), naratriptan (naratriptan), zolmitriptan (zolmitriptan) or rizatriptan (rizatriptan);
(22)5-HT 2A receptor antagonists such as R (+) -alpha- (2, 3-dimethoxy-phenyl) -l- [2- (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
(23) Cholinergic (nicotinic) analgesics such as isopropylgram (isproniline) (TC-1734), (E) -N-methyl-4- (3-pyridyl) -3-buten-l-amine (RJR-2403), (R) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine;
(24)Tramadol ER(Ultram/>)、IV Tramadol、Tapentadol ER
(25) PDE5 inhibitors such as 5- [ 2-ethoxy-5- (4-methyl-l-piperazinyl-sulfonyl) phenyl ] -l-methyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (sildenafil)), (6R, 12 aR) -2,3,6,7,12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2', l':6,l ] -pyrido [3,4-b ] indole-l, 4-dione (IC-351 or tadalafil), 2- [ 2-ethoxy-5- (4-ethyl-piperazin-l-yl-l-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5,l-f ] [ l,2,4] triazin-4-one (vardenafil), 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (l-ethyl-3-azetidine) -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (l-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 5- [ 2-ethoxy-5- (4-ethylpiperazin-l-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 4- [ (3-chloro-4-methoxybenzyl) amino ] -2- [ (2S) -2- (hydroxymethyl) pyrrolidin-l-yl ] -N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide, 3- (l-methyl-7-oxo-3-propyl-6, 7-dihydro-lH-pyrazolo [4,3-d ] pyrimidin-5-yl) -N- [2- (l-methylpyrrolidin-2-yl) ethyl ] -4-propoxybenzenesulfonamide;
(26) Alpha-2-delta ligands such as gabapentin (Neurostatin), gabapentin GRGabapentin enroaca (gabapentin enaca)rbil)/>Pregabalin (pregabalin)/(pregabalin)>3-methylgabapentin, (lα)],3[α],5[α]) (3-amino-methyl-bicyclo [ 3.2.0)]Hept-3-yl) -acetic acid, (3 s,5 r) -3-aminomethyl-5-methyl-heptanoic acid, (3 s,5 r) -3-amino-5-methyl-octanoic acid, (2 s,4 s) -4- (3-chlorophenoxy) proline, (2 s,4 s) -4- (3-fluorobenzyl) -proline, [ (lR, 5r,6 s) -6- (aminomethyl) bicyclo [3.2.0]Hept-6-yl]Acetic acid, 3- (l-aminomethyl-cyclohexylmethyl) -4H- [1,2,4]Oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl]-methylamine, (3 s,4 s) - (l-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (3 s,5 r) -3-aminomethyl-5-methyl-octanoic acid, (3 s,5 r) -3-amino-5-methyl-nonanoic acid, (3 s,5 r) -3-amino-5-methyl-octanoic acid, (3 r,4r,5 r) -3-amino-4, 5-dimethyl-heptanoic acid and (3 r,4r,5 r) -3-amino-4, 5-dimethyl-octanoic acid;
(27) Cannabinoids such as KHK-6188;
(28) Metabotropic glutamate subtype 1 receptor (mGluRl) antagonists;
(29) Serotonin reuptake inhibitors such as sertraline (sertraline), sertraline metabolite norsertraline, fluoxetine (fluoxetine), norfluoxetine (fluoxetine norfluoxetine), fluvoxamine (fluvoxamine), paroxetine (paroxetine), citalopram (citalopram), citalopram metabolite norcitalopram, escitalopram (escitalopram), d, l-fenfluramine (d, l-fenfluramine), femoxetine (femoxetine), ifecetin (ifoxetine), cyanothioether flat (cyclic ketotifaine), rituxidine (linezolid), dapoxetine (dapoxetine), nefazodone (nezodone), western chloramine (triclosamide), and trazodone (zodone);
(30) Norepinephrine reuptake inhibitors such as maprotiline (maprotiline), rofepramine (rofepramine), mirtazapine (mirtazepine), oxaprotiline (oxaprotiline), non-adjunctive amine (fezolamine), tolteroneMoxidectin (tomoxetine), mianserin (mianserin), bupropion (buprofion), bupropion metabolite hydroxy bupropion, nomifensine (nomifensine), and viloxazine (viloxazine)In particular selective norepinephrine reuptake inhibitors such as reboxetine, in particular (S, S) -reboxetine;
(31) Dual serotonin-norepinephrine reuptake inhibitors such as venlafaxine, the metabolite of venlafaxine O-desmethylvenlafaxine, clomipramine, the metabolite of clomipramine, desmethylchloromipramine, duloxetineMilnacipran (milnacipran) and imipramine; />
(32) Inducible Nitric Oxide Synthase (iNOS) inhibitors 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, 5 z) -2-amino-2-methyl-7- [ (L-iminoethyl) amino ] -5-heptenoic acid, 2- [ [ (lR, 3S) -3-amino-4-hydroxy-L- (5-thiazolyl) -butyl ] thio ] -S-chloro-S-pyridinecarbonitrile; 2- [ [ (lR, 3S) -3-amino-4-hydroxy-l- (5-thiazolyl) butyl ] thio ] -4-chlorobenzonitrile, (2S, 4 r) -2-amino-4- [ [ 2-chloro-5- (trifluoromethyl) phenyl ] thio ] -5-thiazolbutanol, 2- [ [ (lR, 3S) -3-amino-4-hydroxy-l- (5-thiazolyl) butyl ] thio ] -6- (trifluoromethyl) -3-pyridinecarbonitrile, 2- [ (lR, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -5-chlorobenzonitrile, N- [4- [2- (3-chlorobenzylamino) ethyl ] phenyl ] thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide;
(33) Acetylcholinesterase inhibitors such as donepezil (donepezil);
(34) Prostaglandin E2 subtype 4 (EP 4) antagonists such as N- [ ({ 2- [4- (2-ethyl-4, 6-dimethyl-lH-imidazo [4,5-c ] pyridin-l-yl) phenyl ] ethyl } amino) -carbonyl ] -4-methylbenzenesulfonamide or 4- [ (15) -l- ({ [ 5-chloro-2- (3-fluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid
(35) Leukotriene B4 antagonists; such as l- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) -5E-hexenyl ] oxyphenoxy ] -pentanoic acid (ONO-4057) or DPC-11870;
(36) 5-lipoxygenase inhibitors such as zileuton (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);
(37) Sodium channel blockers such as lidocaine, lidocaine plus tetracaine (tetracaine) cream (ZRS-201), or eslicarbazepine acetate (eslicarbazepine acetate);
(38)Na V 1.7 blockers such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrizine)), 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 WO2011/140425 (US 2011/306327); WO2012/106499 (US 2012/196869); WO2012/112743 (US 2012245136); WO2012/125613 (US 2012/264749), WO2012/116440 (US 2014/187533), WO2011/026240 (US 2012/220605), US8883840, US8466188, WO2013/109521 (US 2015005304), WO2020/092667 (US 2020/140411) or CN111217776, the entire contents of each of which are hereby incorporated by reference.
(38a)Na V 1.7 blockers, such as (2-benzylspiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1 '-yl) - (4-isopropoxy-3-methyl-phenyl) methanone, 2-trifluoro-1- [1' - [ 3-methoxy-4- [2- (trifluoromethoxy) ethoxy ]]Benzoyl group]-2, 4-dimethyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, [ 8-fluoro-2-p-ro-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]- (4-isobutoxy-3-methoxy-phenyl) methanone, 1- (4-benzhydryl piperazin-1-yl) -3- [2- (3, 4-dimethylphenoxy) ethoxy]Propan-2-ol, (4-butoxy-3-methoxy-phenyl) - [ 2-methyl1, 2-alpha-spiro [3, 4-dihydropyrrolo- (trifluoromethyl) yl-6- (trifluoromethyl) spiro [3, 4-dihydro-pyrrolo]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, [ 8-fluoro-2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]- (5-isopropoxy-6-methyl-2-pyridinyl) methanone, (4-isopropoxy-3-methyl-phenyl) - [ 2-methyl-6- (1, 2-pentafluoroethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, 5- [ 2-methyl-4- [ 2-methyl-6- (2, 2-trifluoroacetyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -carbonyl group]Phenyl group]Pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl) - [6- (trifluoromethyl) spiro [3, 4-dihydro-2H-pyrrolo [1,2-a ] ]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, 2-trifluoro-1- [1' - [ 3-methoxy-4- [2- (trifluoromethoxy) ethoxy ]]Benzoyl group]-2-methyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, 2-trifluoro-1- [1' - (5-isopropoxy-6-methyl-pyridine-2-carbonyl) -3, 3-dimethyl-spiro [2, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, 2-trifluoro-1- [1' - (5-isopentyloxy pyridine-2-carbonyl) -2-methyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, (4-isopropoxy-3-methoxy-phenyl) - [ 2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, 2-trifluoro-1- [1' - (5-isopentyloxy pyridine-2-carbonyl) -2, 4-dimethyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, 1- [ (3S) -2, 3-dimethyl-1' - [4- (3, 3-trifluoropropoxymethyl) benzoyl ]]Spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]-2, 2-trifluoro-ethanone, [ 8-fluoro-2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]- [ 3-methoxy-4- [ (1R) -1-methylpropyloxy ]]Phenyl group]Methanone, 2-trifluoro-1- [1' - (5-isopropoxy-6-methyl-pyridine-2-carbonyl) -2, 4-dimethyl-spiro [3, 4-dihydropyrrolo [1,2-a ] ]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, 1- [1' - [ 4-methoxy-3- (trifluoromethyl) benzoyl ]]-2-methyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]-2, 2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl) - [ 2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, [ 2-methyl-6- (1-methylcyclopropane carbonyl) spiro [3, 4-dihydropyrrolo [1 ],2-a]Pyrazine-1, 4' -piperidines]-1' -yl]- [4- (3, 3-trifluoropropoxymethyl) phenyl ]]Methanone, 4-bromo-N- (4-bromophenyl) -3- [ (1-methyl-2-oxo-4-piperidinyl) sulfamoyl]Benzamide or (3-chloro-4-isopropoxy-phenyl) - [ 2-methyl-6- (1, 2-pentafluoroethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]A ketone.
(39)Na V 1.8 blockers such as PF-04531083, PF-06372865 and CN applications such as those in WO2008/135826 (US 2009048306), WO 2006/01050 (US 2008312235), WO2013/061205 (US 2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US 2013274243), WO2014/120808 (US 2014213616), WO2014/120815 (US 2014228371) WO2014/120820 (US 2014221435), WO2015/010065 (US 20160152561), WO2015/089361 (US 20150166589), WO2019/014352 (US 20190016671), WO2018/213426, WO2020/146682, WO2020/014243, WO2020/014246, WO2020/092187, WO2020/092667 (US 2020140411), WO2020/140959, WO2020/151728, WO 2020/032974, CN112390745, CN 2023575, CN112225695, CN112300051, CN 4882, CN 63, CN 37, CN 37, and the like are all cited herein;
(39a)Na V 1.8 blocking agents such as 4, 5-dichloro-2- (4-fluoro-2-methoxyphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide, 2- (4-fluoro-2-methoxyphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (perfluoroethyl) benzamide, 4, 5-dichloro-2- (4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide, 4, 5-dichloro-2- (3-fluoro-4-methoxyphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide, 2- (4-fluoro-2-methoxyphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide, N- (2-oxo-1, 2-dihydropyridin-4-yl) -2- (trifluoromethoxy) -4- (trifluoromethyl) benzamide, 2- (4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (perfluoroethyl) benzamide, 5-chloro-2- (4-fluoro-2-methoxyphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide, N- (2-oxo-1, 2-dihydropyridin-4-yl) -2- (4- (trifluoromethoxy) phenoxy) -5- (trifluoromethyl) benzamide, 2- (4- -Fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide, 2- (2-chloro-4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide, 5-chloro-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide, 4-chloro-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide, 5-chloro-2- (2-chloro-4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide, 2- ((5-fluoro-2-hydroxybenzyl) oxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide, N- (2-oxo-1, 2-dihydropyridin-4-yl) -2- (o-tolyloxy) -5- (trifluoromethyl) benzamide, 2- (2, 4-difluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide, N- (2-oxo-1, 2-dihydropyridin-4-yl) -2- (2- (trifluoromethoxy) phenoxy) -5- (trifluoromethyl) benzamide, 2- (4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide, 2- (4-fluoro-2-methyl-phenoxy) -N- (2-oxo-1H-pyridin-4-yl) -4- (trifluoromethyl) benzamide, [4- [ [2- (4-fluoro-2-methyl-phenoxy) -4- (trifluoromethyl) benzoyl [ ]Amino group]-2-oxo-1-pyridinyl]Methyl dihydrogen phosphate, 2- (4-fluoro-2- (methyl-d) 3 ) Phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide, (4- (2- (4-fluoro-2- (methyl-d) 3 ) Phenoxy) -4- (trifluoromethyl) benzoylamino) -2-oxopyridin-1 (2H) -yl) methyldihydro-phosphate, 3- (4-fluoro-2-methoxyphenoxy) -N- (3- (methylsulfonyl) phenyl) quinoxaline-2-carboxamide, 3- (2-chloro-4-fluorophenoxy) -N- (3-sulfamoylphenyl) quinoxaline-2-carboxamide, 3- (2-chloro-4-methoxyphenoxy) -N- (3-sulfamoylphenyl) quinoxaline-2-carboxamide, 3- (4-chloro-2-methoxyphenoxy) -N- (3-sulfamoylphenyl) quinoxaline-2-carboxamide, 4- (3- (4- (trifluoromethoxy) phenoxy) quinoxaline-2-carboxamide) picolinic acid, 2- (2, 4-difluorophenoxy) -N- (3-sulfamoylphenyl) quinoline-3-carboxamide, 2- (4-fluoro-2-methoxyphenoxy) -N- (3-sulfamoylphenyl) quinoline-3-carboxamide, 3- (2, 4-difluorophenoxy) -N- (3-sulfamoylphenyl) quinoxaline-2-carboxamide, N- (3-sulfamoylphenyl) -2- (4- (trifluoromethoxy) phenoxy) quinoline-3-carboxamide, N- (3-sulfamoylphenyl) fluvium3- (4- (trifluoromethoxy) phenoxy) quinoxaline-2-carboxamide, 3- (4-chloro-2-methylphenoxy) -N- (3-sulfamoylphenyl) quinoxaline-2-carboxamide, 5- (3- (4- (trifluoromethoxy) phenoxy) quinoxaline-2-carboxamide) picolinic acid, 3- (4-fluoro-2-methoxyphenoxy) -N- (2-oxo-2, 3-dihydro-1H-benzo [ d ] ]Imidazole-5-yl) quinoxaline-2-carboxamide, 3- (4-fluoro-2-methoxyphenoxy) -N- (pyridin-4-yl) quinoxaline-2-carboxamide, 3- (4-fluorophenoxy) -N- (3-sulfamoylphenyl) quinoxaline-2-carboxamide, N- (3-cyanophenyl) -3- (4-fluoro-2-methoxyphenoxy) quinoxaline-2-carboxamide, N- (4-carbamoylphenyl) -3- (4-fluoro-2-methoxyphenoxy) quinoxaline-2-carboxamide, 4- (3- (4- (trifluoromethoxy) phenoxy) quinoxaline-2-carboxamide) benzoic acid, N- (4-cyanophenyl) -3- (4-fluoro-2-methoxyphenoxy) quinoxaline-2-carboxamide, 5- (4, 5-dichloro-2- (4-fluoro-2-methoxyphenoxy) benzoylamino) picolinic acid, 5- (2, 4-dimethoxyphenoxy) -4, 6-bis (trifluoromethyl) benzoylamino) picolinic acid, 4- (4, 5-dichloro-2- (4-fluoro-2-methoxyphenoxy) benzoylamino) benzoic acid, 5- (2- (4-fluoro-2-methoxyphenoxy) -4, 6-bis (trifluoromethyl) benzoylamino) picolinic acid, 4- (2- (4-fluoro-2-methoxyphenoxy) -4- (perfluoroethyl) benzoylamino) benzoic acid, 5- (2- (4-fluoro-2-methoxyphenoxy) -4- (perfluoroethyl) benzoylamino) picolinic acid, 4- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoylamino) benzoic acid, 5- (4, 5-dichloro-2- (4-fluoro-2-methoxyphenoxy) benzoylamino) picolinic acid, 4- (2- (2-chloro-4-fluorophenoxy) -4- (perfluoroethyl) benzoylamino) benzoic acid, 4- (2- (4-fluoro-2-methylphenoxy) -4- (perfluoroethyl) benzoylamino) benzoic acid, 4- (4, 5-dichloro-2- (trifluoromethoxy) phenoxy) benzoic acid, 4- (4, 5-dichloro-2- (4-chloro-2-methylphenoxy) benzoylamino) benzoic acid, 5- (4- (tert-butyl) -2- (4-fluoro-2-methoxyphenoxy) benzoylamino) picolinic acid, 5- (4, 5-dichloro-2- (4- (trifluoromethoxy) phenoxy) benzoylamino) picolinic acid, 4- (4, 5-dichloro-2- (4-fluoro-2-methylphenoxy) benzoylamino) benzoic acid, 5- (4, 5-dichloro-2- (2, 4-dimethoxyphenoxy) benzoylamino) picolinic acid, 5- (4, 5-dichloro-2- (2-chloro-4-fluorophenoxy) benzoylamino) picolinic acid, 5- (4, 5-dichloro-2-) (4-fluoro-2-methylphenoxy) benzoylamino) picolinic acid, 4- (4, 5-dichloro-2- (4-chloro-2-methoxyphenoxy) benzoylamino) benzoic acid, 5- (4, 5-dichloro-2- (2, 4-difluorophenoxy) benzoylamino) picolinic acid, 2- (4-fluorophenoxy) -N- (3-sulfamoylphenyl) -5- (trifluoromethyl) benzamide, 2- (4-fluorophenoxy) -N- (3-sulfamoylphenyl) -4- (trifluoromethyl) benzamide, 2- (2-chloro-4-fluorophenoxy) -N- (3-sulfamoylphenyl) -6- (trifluoromethyl) benzamide, 2- (2-chloro-4-fluorophenoxy) -N- (3-sulfamoylphenyl) -5- (3-sulfamoylphenyl) benzamide, 2- (4-fluorophenoxy) -4- (3-sulfamylphenyl) benzamide, 2- (4-chloro-2-methoxyphenoxy) -4- (perfluoroethyl) -N- (3-sulfamylphenyl) benzamide, 2- (4-fluoro-2-methoxyphenoxy) -N- (3-sulfamylphenyl) -5- (trifluoromethyl) benzamide, 5-chloro-2- (4-fluoro-2-methylphenoxy) -N- (3-sulfamylphenyl) benzamide, 4, 5-dichloro-2- (4-fluoro-2-methoxyphenoxy) -N- (3-sulfamylphenyl) benzamide, 2, 4-dichloro-6- (4-chloro-2-methoxyphenoxy) -N- (3-sulfamylphenyl) benzamide, 2, 4-dichloro-6- (4-fluoro-2-methylphenoxy) -N- (3-sulfamylphenyl) benzamide, 2- (4-fluoro-2-methoxyphenoxy) -N- (3-sulfamylphenyl) -4, 6-bis (trifluoromethyl) benzamide, 2- (4-fluoro-2-methylphenoxy) -N- (3-sulfamoylphenyl) -4, 6-bis (trifluoromethyl) benzamide, 5-chloro-2- (2-chloro-4-fluorophenoxy) -N- (3-sulfamoylphenyl) benzamide, 2- (4-fluoro-2-methoxyphenoxy) -N- (3-sulfamoylphenyl) -4- (trifluoromethoxy) benzamide, 2- (4-fluoro-2-methoxyphenoxy) -N- (3-sulfamoylphenyl) -4- (trifluoromethyl) benzamide, 4, 5-dichloro-2- (4-fluorophenoxy) -N- (3-sulfamoylphenyl) benzamide, 2- (4-fluoro-2-methoxyphenoxy) -4- (perfluoroethyl) -N- (3-sulfamoylphenyl) benzamide, 5-fluoro-2- (4-fluoro-2-methylphenoxy) -N- (3-sulfamoylphenyl) benzamide, 2- (2-chloro-4-fluorophenoxy) -4-cyano-N- (3-sulfamoylphenyl) benzamide, N- (3-sulfamoylphenyl) -2- (4- (trifluoromethoxy) phenoxy) -4- (trifluoromethyl) benzamide, N- 3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- [2- (tridecylmethoxy) -4- (trifluoromethoxy) phenoxy]-3- (trifluoromethyl) benzamide, N- (3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy } -]-3- (trifluoromethyl) benzamide, N- (3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- [2- (tridecylmethoxy) -4- (trifluoromethoxy) phenoxy } -]-3- (trifluoromethoxy) benzamide, 4- [ [ 2-fluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy ]]-3- (trifluoromethyl) benzoyl]Amino group]Pyridine-2-carboxamide, 4- [ [ 3-chloro-2-fluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy ]]Benzoyl group]Amino group]Pyridine-2-carboxamide, 4- [ [ 2-fluoro-6- [2- (tridecylemethoxy) -4- (trifluoromethoxy) phenoxy ]]-3- (trifluoromethyl) benzoyl]Amino group]Pyridine-2-carboxamide, N- (3-carbamoyl-4-fluoro-phenyl) -3- (difluoromethyl) -2-fluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy]Benzamide, 4- [ [ 2-fluoro-6- [2- (tridecylmethoxy) -4- (trifluoromethoxy) phenoxy ]]-3- (trifluoromethoxy) benzoyl]Amino group]Pyridine-2-carboxamide, N- (3-carbamoyl-4-fluoro-phenyl) -6- [ 2-chloro-4- (trifluoromethoxy) phenoxy]-2-fluoro-3- (trifluoromethyl) benzamide, N- (3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- [ 2-methyl-4- (trifluoromethoxy) phenoxy ]-3- (trifluoromethyl) benzamide, N- (3-carbamoyl-4-fluoro-phenyl) -2,3, 4-trifluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy } -]Benzamide, N- (2-carbamoyl-4-pyridinyl) -3-fluoro-5- [ 2-methoxy-4- (trifluoromethoxy) phenoxy ]]-2- (trifluoromethyl) pyridine-4-carboxamide, 4- [ [6- [2- (difluoromethoxy) -4- (trifluoromethoxy) phenoxy ]]-2-fluoro-3- (trifluoromethyl) benzoyl]Amino group]Pyridine-2-carboxamide, N- (3-carbamoyl-4-fluoro-phenyl) -6- [ 3-chloro-4- (trifluoromethoxy) phenoxy]-2-fluoro-3- (trifluoromethyl) benzamide, N- (3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- [4- (trifluoromethoxy) phenoxy } -]-3- (trifluoromethyl) benzamide, N- (4-carbamoyl-3-fluoro-phenyl) -2-fluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy } -]-3- (trifluoromethyl) benzamide, 4- [ [ 2-fluoro-6- [2- (tridecylemethoxy) -4- (trifluoromethoxy) phenoxy ]]-4- (trifluoromethyl) benzoyl]Amino group]Pyridine-2-carboxamide, N- (3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- [ 3-fluoro-4- (trifluoromethoxy) phenoxy]-3- (trifluoromethyl) benzamide, N- (3-carbamoyl-4-fluoro-phenyl) -2- [ 2-methoxy-4- (trifluoromethoxy) phenoxy]-5- (1, 2-pentafluoroethyl) benzamide, 4- [ [4- (difluoromethoxy) -2-fluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy ] ]Benzoyl group]Amino group]Pyridine-2-carboxamide, N- (3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- [ 2-fluoro-4- (trifluoromethoxy) phenoxy]-3- (trifluoromethyl) benzamide, 4- [ [ 4-cyclopropyl-2-fluoro-6- [ 2-methoxy-4- (trifluoromethoxy) phenoxy ]]Benzoyl group]Amino group]Pyridine-2-carboxamide, N- (3-carbamoyl-4-fluoro-phenyl) -5-fluoro-2- [ 2-methoxy-4- (trifluoromethoxy) phenoxy]-4- (trifluoromethyl) benzamide, 5- [ [ 2-fluoro-6- [2- (tridecylemethoxy) -4- (trifluoromethoxy) phenoxy ]]-3- (trifluoromethyl) benzoyl]Amino group]Pyridine-2-carboxamide, N- (3-carbamoyl-4-fluoro-phenyl) -2-fluoro-6- (4-fluorophenoxy) -3- (trifluoromethyl) benzamide, 4- (2-fluoro-6- (2-methoxy-4- (trifluoromethoxy) phenoxy) -3- (trifluoromethyl) benzoylamino) pyridine carboxamide, or 4- [ [ 2-fluoro-6- [ 3-fluoro-2-methoxy-4- (trifluoromethoxy) phenoxy ]]-3- (trifluoromethyl) benzoyl]Amino group]Pyridine-2-carboxamide;
(40) Combined Na V 1.7 and Na V 1.8 blockers such as DSP-2230, lohocla201 or BL-1021;
(41) 5-HT3 antagonists, such as ondansetron (ondansetron);
(42) TPRV 1 receptor agonists such as capsaicin And pharmaceutically acceptable salts and solvates thereof;
(43) Nicotinic receptor antagonists such as varenicline;
(44) N-type calcium channel antagonists such as Z-160;
(45) Nerve growth factor antagonists such as tanizumab;
(46) Endopeptidase agonists such as senpozzolanase (senrebotase);
(47) Angiotensin II antagonists such as EMA-401;
(48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g.)))；
(49) Bupivacaine (including but not limited to bupivacaine liposome injectable suspensions (e.g.,) Bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and bupivacaine Pi Bubi) The method comprises the steps of carrying out a first treatment on the surface of the And
(50) Bupivacaine and meloxicam combinations (e.g., HTX-011/ZynrelefTM).
In one embodiment, the additional suitable therapeutic agent is selected from the group consisting of V-116517, pregabalin, controlled release pregabalin, ezogabineKetamine/amitriptyline topical cream +.>AVP-923, perampanel (E-2007), ralfinamide (Ralfinamide), via Pi Bubi-Calin>CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.
In another embodiment, the additional suitable therapeutic agent is 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.
In another embodiment, the additional therapeutic agent is selected from GlyT2/5HT2 inhibitors, such as opiperidin (VVZ 149); TRPV modulators such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523 or MDR652; EGR1 inhibitors such as brivolide (AYX); NGF inhibitors such as tanizumab, fasnuumab (Fasinumab), ASP6294, MEDI7352; mu opioid agonists such as sibrofadol (Cebranopadol), NKTR181 (oxycodone); CB-1 agonists such as NEO1940 (AZN 1940); imidazoline 12 agonists such as CR4056; or a p75NTR-Fc modulator, such as LEVI-04.
In another embodiment, the additional therapeutic agent is oseltamidine (oleridine) or ropivacaine (TLC 590).
In another embodiment, the additional therapeutic agent is Na V 1.7 blockers, such as ST-2427 or ST-2578 and those disclosed in WO2010129864, WO2015157559, WO2017059385, WO2018183781, WO2018183782, WO2020072835 and WO2002036297, the entire contents of each of which are hereby incorporated by reference. In some embodiments, the additional therapeutic agent is Na disclosed in WO2020072835 V 1.7 blocking agent. In some embodiments, the additional therapeutic agent is Na disclosed in WO2022036297 V 1.7 blocking agent.
In another embodiment, the additional therapeutic agent is ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, opimarin (Opiranserin) (Unafra) TM ) Brivolitide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, or XT-150.
iN another embodiment, the additional therapeutic agent is O Lin Weike (Olinvyk), zynrelef (Zynrelef), serratiferin (Seglentis), nemapheresis (Neumentum), navack (Nevakar), HTX-034, CPL-01, ACP-044, HRS-4800, tarlige, BAY2395840, LY3526318, E Lin Pisheng (Eliapixant), TRV045, RTA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin (tetrodotoxin), otenaphroxeul (Otenaphroxeul), CFTX-1554, funapided (Funapide), iN1011-N17, JMKX000623, ETX-801, or ACD440.
In another embodiment, the additional therapeutic agent is a compound disclosed in WO2021257490, WO2021257420, WO2021257418, WO2020014246, WO2020092187, WO2020092667, WO2020261114, CN112457294, CN112225695, CN111808019, WO2021032074, WO2020151728, WO2020140959, WO2022037641, WO2022037647, CN112300051, CN112300069, WO2014120808, WO2015089361, WO2019014352, WO2021113627, WO2013086229, WO2013134518, WO2014211173, WO2014201206, WO2016141035, WO2021252818, WO2021252822 and WO 2021252820.
In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2013086229. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2013134518. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2014211173. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2014201206. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2016141035. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2021252818. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2021252822. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2021252820. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2020072835. In some embodiments, the additional therapeutic agent is a compound disclosed in WO 2022036297.
In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also referred to as a sodium channel blocker), such as Na identified above V 1.7 and Na V 1.8 blocking agents.
The amount of additional therapeutic agent present in the compositions of the present invention may not exceed the amount normally administered in compositions comprising the therapeutic agent as the sole active agent. The amount of additional therapeutic agent in the compositions disclosed herein may be about 10% to 100% of the amount typically present in compositions comprising the agent as the sole therapeutically active agent.
Compound 1 or a pharmaceutically acceptable composition thereof may also be incorporated into compositions for coating implantable medical devices such as prostheses, prosthetic valves, vascular grafts, stents and catheters. Thus, another aspect includes a composition for coating an implantable device comprising compound 1 or a salt thereof, and within the classes and subclasses herein, and a carrier suitable for coating said implantable device. In a further aspect, the implantable device may be coated with a composition comprising compound 1 or a salt thereof, and a carrier suitable for coating the implantable device. General preparation of suitable coatings and coated implantable devices is described in U.S. patent 6,099,562;5,886,026; and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered with a suitable top coat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or a combination thereof to impart controlled release characteristics to the composition.
Detailed description of the illustrated embodiments
Other embodiments of the present disclosure are set forth in the following numbered clauses:
1. A method of treating pain or lessening the severity of pain in a subject, said method comprising administering to said subject compound 1 in an amount of from about 10mg to about 300mg per day,
or a pharmaceutically acceptable salt thereof.
2. The method of clause 1, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20mg to 200mg per day.
3. The method of clause 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10mg to about 300mg on the first day and about 5mg to about 200mg per day after the first day.
4. The method of clause 3, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20mg to about 200mg on the first day.
5. The method of clause 3, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20mg to about 30mg on the first day.
6. The method of clause 3, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 60mg to about 90mg on the first day.
7. The method of clause 3, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 150mg on the first day.
8. The method of any one of clauses 1 to 7, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered at two doses per day.
9. The method of clause 8, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at a first dose and a subsequent dose on the first day, wherein the first dose is greater than the subsequent dose.
10. The method of clause 9, wherein the subsequent dose is administered 12 hours after the first dose.
11. The method of any one of clauses 9 to 10, wherein the first dose is about 20mg to about 100mg.
12. The method of any one of clauses 9 to 11, wherein the first dose is about 20mg.
13. The method of any one of clauses 9 to 11, wherein the first dose is about 60mg.
14. The method of any one of clauses 9 to 11, wherein the first dose is about 100mg.
15. The method of any one of clauses 9 to 14, wherein the subsequent dose is about 10mg to about 100mg.
16. The method of any one of clauses 9 to 14, wherein the subsequent dose is about 10mg to about 50mg.
17. The method of any one of clauses 9 to 16, wherein the subsequent dose is about 10mg.
18. The method of any one of clauses 9 to 16, wherein the subsequent dose is about 30mg.
19. The method of any one of clauses 9 to 16, wherein the subsequent dose is about 50mg.
20. The method of any one of clauses 3 to 19, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at two doses per day after the first day.
21. The method of clause 20, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in two doses of about 10mg to 50mg per day after the first day.
22. The method of clause 20, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at two doses of about 10mg per day after the first day.
23. The method of clause 20, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at two doses of about 30mg per day after the first day.
24. The method of clause 20, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at two doses of about 50mg per day after the first day.
25. The method of any one of clauses 20 to 24, wherein a period of 12 hours elapses between administration of each of the two doses.
26. The method of clause 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at one dose per day.
27. The method of any one of clauses 1 to 26, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 1 week.
28. The method of any one of clauses 1 to 26, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least 6 weeks.
29. The method of any one of clauses 1 to 26, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least two days.
30. The method of any one of clauses 1 to 29, wherein the compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
31. The method of any one of clauses 1 to 29, wherein the compound 1, or a pharmaceutically acceptable salt thereof, is administered intravenously.
32. The method of any one of clauses 1 to 30, wherein the pain comprises chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancerous pain, idiopathic pain, post-operative pain, or visceral pain.
33. The method of any one of clauses 1 to 30, wherein the pain is associated with multiple sclerosis, xia Matu trise syndrome, incontinence, pathological cough, or arrhythmia.
34. The method of clause 32, wherein the pain comprises neuropathic pain.
35. The method of clause 34, wherein the neuropathic pain comprises post-herpetic neuralgia.
36. The method of clause 34, wherein the neuropathic pain comprises a small fiber neuropathy.
37. The method of clause 34, wherein the neuropathic pain comprises idiopathic small fiber neuropathy.
38. The method of clause 34, wherein the neuropathic pain comprises diabetic neuropathy.
39. The method of clause 38, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy.
40. The method of clause 32, wherein the pain comprises musculoskeletal pain.
41. The method of clause 40, wherein the musculoskeletal pain comprises osteoarthritis pain.
42. The method of clause 32, wherein the pain comprises acute pain.
43. The method of clause 42, wherein the acute pain comprises acute postoperative pain.
44. The method of clause 32, wherein the pain comprises post-operative pain.
45. The method of clause 44, wherein the post-operative pain comprises a bunion excision pain.
46. The method of clause 44, wherein the post-operative pain comprises an abdominal wall plastic pain.
47. The method of clause 44, wherein the post-operative pain comprises hernia repair pain.
48. The method of clause 32, wherein the pain comprises visceral pain.
49. The method of any one of clauses 1 to 48, wherein the subject has a baseline pain score of at least 4 according to the 11-point digital pain rating scale prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
50. The method of any one of clauses 1 to 48, wherein prior to administering compound 1, or a pharmaceutically acceptable salt thereof, the subject has a baseline pain level of moderate or severe according to a speech classification rating scale.
51. The method of any one of clauses 1 to 50, wherein the method comprises administering to the subject compound 1 in a non-salt form.
52. The method of any one of clauses 1 to 51, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously, before or after treatment with the compound or pharmaceutically acceptable salt.
53. Use of compound 1 or a pharmaceutically acceptable salt thereof as a medicament in any of the foregoing methods.
54. A solid dispersion, the solid dispersion comprising:
(2R, 3S,4S, 5R) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; and
At least one polymer.
55. The solid dispersion of clause 54, wherein compound 1 or a pharmaceutically acceptable salt thereof and the polymer are co-spray dried with a solvent.
56. The solid dispersion of any one of clauses 54 to 55, wherein the polymer is selected from the group consisting of: hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof.
57. The solid dispersion of any one of clauses 54 to 56, wherein the polymer is HPMCAS.
58. The solid dispersion of any one of clauses 54 to 57, wherein the solid dispersion comprises:
about 20% to about 50% by weight of compound 1 or a pharmaceutically acceptable salt thereof; and
about 50% to about 80% by weight of the polymer.
59. The solid dispersion of any one of clauses 54 to 58, wherein the solid dispersion comprises:
about 25% by weight of compound 1 or a pharmaceutically acceptable salt thereof; and
about 75% by weight of said polymer.
60. The solid dispersion of any one of clauses 54 to 59, wherein compound 1 is substantially amorphous.
61. A pharmaceutical composition comprising the solid dispersion of any one of claims 54 to 60.
62. The pharmaceutical composition of clause 61, wherein the pharmaceutical composition is a tablet.
63. The pharmaceutical composition of clause 61 or 62, wherein the pharmaceutical composition further comprises one or more excipients selected from the group consisting of: at least one filler, at least one disintegrant, at least one lubricant, and any combination thereof.
64. The pharmaceutical composition of clause 61 or 62, wherein the pharmaceutical composition further comprises at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant.
65. The pharmaceutical composition of clause 63, wherein the pharmaceutical composition comprises about 72.5 weight percent of the filler, about 4.5 weight percent of the disintegrant, and about 3 weight percent of the lubricant.
66. The pharmaceutical composition of any one of clauses 63-65, wherein the filler is selected from the group consisting of: microcrystalline cellulose, lactose monohydrate, mannitol, and any combination thereof.
67. The pharmaceutical composition of any one of clauses 63-66, wherein the disintegrant is selected from the group consisting of: croscarmellose sodium, crospovidone, and any combination thereof.
68. The pharmaceutical composition of any one of clauses 63 to 67, wherein the lubricant is selected from the group consisting of: sodium stearyl fumarate, magnesium stearate, and any combination thereof.
69. The pharmaceutical composition of any one of clauses 63-68, wherein the filler comprises microcrystalline cellulose and lactose monohydrate, wherein the disintegrant comprises croscarmellose sodium, and wherein the lubricant comprises sodium stearyl fumarate.
70. The pharmaceutical composition of any one of clauses 61 to 69, wherein the pharmaceutical composition comprises about 1 to about 50mg of compound 1 or a pharmaceutically acceptable salt thereof.
71. The pharmaceutical composition of any one of clauses 61 to 69, wherein the pharmaceutical composition comprises about 10mg of compound 1 or a pharmaceutically acceptable salt thereof.
72. The method of any one of clauses 1 to 52, wherein administering compound 1 or a pharmaceutically acceptable salt thereof to the subject comprises administering the pharmaceutical composition of any one of claims 61 to 71.
Synthesis of Compounds of the invention
Compound 1 can be prepared from known materials by the methods described in the examples, other similar methods, and other methods known to those skilled in the art. As will be appreciated by those skilled in the art, the functional groups of intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed according to standard techniques well known to those skilled in the art. The use of protecting groups is described in detail in T.G.M.Wuts et al, greene's Protective Groups in Organic Synthesis (4 th edition, 2006).
Examples
Abbreviations (abbreviations)
Unless otherwise indicated, or the context indicates otherwise, the following abbreviations should be understood to have the following meanings:
example 1
(2R, 3S,4S, 5R) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) phenyl- ] and tetrahydrofuran-2-carbonyl group]Amino group]Preparation of pyridine-2-carboxamide (Compound 1)
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Step 1:
NEt was stirred under nitrogen at 0deg.C 3 (7.7 mL,55.2 mmol) was added to a solution of ethyl 2-diazo-3-oxo-pentanoate (6.69 g,39.3 mmol) in DCM (80 mL). Trimethylsilyl triflate (8.5 mL,47.0 mmol) was added dropwise over 5 min and the mixture stirred at 0deg.C for an additional 30 min. The reaction mixture was diluted with pentane (100 mL), the layers separated, and the organic phase was washed with dilute aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried (MgSO 4 ) And concentrated in vacuo to give ethyl (Z) -2-diazonium-3-trimethylsilyloxy-pent-3-enoate (9.4 g, 99%) as a red oil. 1 H NMR (500 MHz, chloroform-d) delta 5.33 (q, j=7.0 hz, 1H), 4.25 (q, j=7.1 hz, 2H), 1.67 (d, j=7.0 hz, 3H), 1.29 (t, j=7.1 hz, 3H), 0.22 (s, 9H) ppm.
Step 2:
to a solution of 1, 1-trifluoropropan-2-one (8 mL,89.4 mmol) in DCM (80 mL) stirred at-78deg.C was added TiCl via cannula 4 (70 mL,1M in DCM, 70.00 mmol). To the resulting solution was added dropwise a solution of (Z) -2-diazonium-3-trimethylsilyloxy-pent-3-enoic acid ethyl ester (36.1 g,31.3% w/w,46.6 mmol) in 40mL DCM over 15 min. After 100 min, the reaction was carefully quenched with water, the temperature was slowly raised, and then extracted with DCM. The combined organic layers were dried (MgSO 4 ) Filtered and concentrated in vacuo. By flash chromatography (330 g SiO) 2 0 to 20% EtOAc/heptane) to give ethyl 2-diazo-6, 6-trifluoro-5-hydroxy-4, 5-dimethyl-3-oxo-hexanoate (8.82 g, 67%) which was stored as a solution in toluene. 1 H NMR (500 MHz, chloroform-d) δ4.33 (q, J=7.1 Hz, 2H), 4.14 (q, J=7.0 Hz, 1H), 3.98 (s, 1H), 1.43 (q, J=1.2 Hz, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.31 (dq, J=7.0, 1.4Hz, 3H) ppm ESI-MS M/z calculated 282.08273, experimental value 283.1 (M+1) + ；281.0(M-1) - 。
Step 3:
a solution of rhodium tetraacetate (248 mg,0.55 mmol) in benzene (32 mL) was heated at reflux for 10min, then a solution of ethyl 2-diazonium-6, 6-trifluoro-5-hydroxy-4, 5-dimethyl-3-oxo-hexanoate (10 g,35.4 mmol) in benzene (13 mL) was slowly added via an addition funnel while refluxing for 60 min. The mixture was then concentrated in vacuo to give rac- (4 r,5 r) -4, 5-dimethyl-3-oxo-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid ethyl ester (9.0 g, 100%) as a green residue containing residual catalyst and as a mixture of epimers adjacent to the ester. The material was used without further purification. 1 H NMR (500 MHz, chloroform-d) delta 4.83-4.57 (m, 1H), 4.38-4.16 (m, 2H), 2.60 (dddd, j=9.3, 8.2,5.6,1.4hz, 1H), 1.73-1.63 (m, 3H), 1.30 (t, j=7.1 hz, 3H), 1.24 (ddq, j=6.4, 4.1,1.9hz, 3H) ppm.
Step 4:
to a solution of rac- (4 r,5 r) -4, 5-dimethyl-3-oxo-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid ethyl ester (48 g,188.83 mmol) in DCM (400 mL) stirred at-78 ℃ was added DIPEA (29.680 g,40mL,229.64 mmol). A solution of trifluoromethylsulfonyl triflate (53.440 g,32mL,189.41 mmol) in DCM (200 mL) was added to the reaction mixture over 1h at the same temperature. The reaction mixture was stirred at 0deg.C for 30 min, then with 100mL saturated NaHCO 3 Quenching with water solution. The organic layer was separated and the aqueous layer was extracted with DCM (160 mL). The combined organic layers were dried (MgSO 4 ) And concentrated in vacuo to give rac- (4 r,5 r) -2, 3-dimethyl-2- (trifluoromethyl) -4- (trifluoromethylsulfonyloxy) -3H-furan-5-carboxylic acid ethyl ester (71 g, 97%). 1 H NMR (400 MHz, chloroform-d) delta 4.38-4.32 (m, 2H), 3.29-3.23 (m, 1H), 1.64 (s, 3H), 1.37-1.33 (m, 6H) ppm.
Step 5:
to a solution of rac- (4R, 5R) -2, 3-dimethyl-2- (trifluoromethyl) -4- (trifluoromethylsulfonyloxy) -3H-furan-5-carboxylic acid ethyl ester (26 g,67.311 mmol) in toluene (130.00 mL) was added (3, 4-difluoro-2-methoxy-phenyl) boronic acid (14 g,74.5 mmol) followed by K under an argon atmosphere 3 PO 4 (100 mL,2M,200.00 mmol) the reaction was degassed before adding tetrakis (triphenylphosphine) palladium (0) (4 g,3.46 mmol). After further degassing, the reaction was heated at 100 ℃ for 2 hours. The reaction was diluted in water and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were concentrated in vacuo. By flash chromatography (SiO 2 0 to 10% EtOAc/heptane) to give 4- (3, 4-difluoro-2-methoxy-phenyl) -2, 3-dimethyl-2- (trifluoromethyl) -3H-furan-5-carboxylic acid ethyl ester (24.4 g, 93%) as a 6:1 diastereomer mixture, believed to be the major isomer rac- (4 r,5 r) -4- (3, 4-difluoro-2-methoxy-phenyl) -2, 3-dimethyl-2- (trifluoromethyl) -3H-furan-5-carboxylic acid ethyl ester. Major isomer: 1 h NMR (400 MHz, chloroform-d) delta 6.88-6.79 (m, 2H), 4.17-4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, j=7.4 hz, 1H), 1.67 (s, 3H), 1.12 (t, j=7.4 hz, 3H), 1.06 (dd, j=5.4, 2.7hz, 3H) ppm 1 H NMR (400 MHz, chloroform-d) delta 6.88-6.79 (m, 2H), 4.17-4.09 (m, 2H), 3.88 (s, 3H), 3.76-3.71 (m, 1H)1.51 (s, 3H), 1.12 (t, J=7.4 Hz, 3H), 0.99 (dd, J=5.4, 2.7Hz, 3H) ppm ESI-MS M/z calculated 380.1047, experimental 381.02 (M+1) + 。
Step 6:
to an ice-cooled solution of 4- (3, 4-difluoro-2-methoxy-phenyl) -2, 3-dimethyl-2- (trifluoromethyl) -3H-furan-5-carboxylic acid ethyl ester (110 g,243.0 mmol) in DCM (360 mL) was added BBr dropwise 3 (370 mL,1M,370.0 mmol). Upon completion, the mixture was quenched by addition of water and aqueous sodium bicarbonate, the aqueous layer was extracted with DCM, and the combined organic layers were dried (MgSO 4 ) And concentrated in vacuo. The residue was dissolved in DCM (430 mL) at ambient temperature and TFA (40 mL,519.2 mmol) was added, then the reaction was heated to 45 ℃. Upon completion, the mixture was quenched by addition of aqueous sodium bicarbonate and the aqueous layer was extracted with DCM, dried (MgSO 4 ) And concentrated in vacuo to afford the desired product as a 5:1 diastereomer mixture. Recrystallization (liquid-liquid diffusion) was performed by dissolving the crude product in the smallest possible amount of DCM and adding a layer of heptane on top of the solution. After about 1 hour, 56.5g (d.r.97: 3 cis: trans) was obtained from the first and second crystallization, and 4.6g (d.r.96: 4 cis: trans) was obtained from the third crystallization. Combining the first to third batches to obtain 6, 7-difluoro-1, 2-dimethyl-2- (trifluoromethyl) -1H-furo [2,3-c ]]Chromen-4-one (61 g, 78%) believed to be the major isomer rac- (1S, 2R) -6, 7-difluoro-1, 2-dimethyl-2- (trifluoromethyl) -1H-furo [2,3-c]Chromen-4-one. ESI-MS M/z calculated 320.04718, experimental value 321.5 (M+1) + ；319.6(M-1) - 。
Step 7:
to the racemic- (1S, 2R) -6, 7-difluoro-1, 2-dimethyl-2- (trifluoromethyl) -1H-furo [2,3-c]Chromen-4-one (30 g,93.69 mmol) was dissolved in EtOAc (400 mL) and stirred with activated carbon (6 g,499.6 mmol) (0.2 g/g substrate) at ambient temperature for 4 hours 30 minutes. The mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo to give a white solid. The white solid was suspended in MeOH (600 mL) and added to Pd (OH) in a 2.25L Parr bottle (Parr bottle) 2 (13.62 g,20% w/w,19.40 mmol) inIn suspension in MeOH (150 mL). The resulting mixture was shaken in a Parr hydrogenator under 60psi hydrogen pressure overnight. The suspension was filtered through celite under nitrogen, rinsed with MeOH, and then EtOAc, and the resulting filtrate was concentrated in vacuo to give rac- (2 r,3s,4s,5 r) -3- (3, 4-difluoro-2-hydroxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid methyl ester (32.75 g, 99%). 1 H NMR (400 MHz, methanol-d 4) delta 7.05 (ddq, J=9.4, 5.9,1.9Hz, 1H), 6.57 (ddd, J=10.0, 9.0,7.6Hz, 1H), 5.01 (d, J=6.0 Hz, 1H), 4.34 (dd, J=8.4, 6.0Hz, 1H), 3.49 (s, 3H), 3.01-2.86 (M, 1H), 1.50 (q, J=1.2 Hz, 3H), 0.89 (dq, J=7.6, 1.9Hz, 3H) ppm ESI-MS M/z calculated 354.08905, experimental value 353.3 (M-1) - 。
Step 8:
a solution of racemic- (2R, 3S,4S, 5R) -3- (3, 4-difluoro-2-hydroxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid methyl ester (60.8 g,171.6 mmol) in THF (620 mL) was cooled to 1℃and potassium tert-butoxide (65.0472 g,579.7 mmol) was added over 10 minutes maintaining the internal temperature below 10 ℃. The mixture was stirred at 0 ℃ for an additional 5min and then the mixture was slightly heated. When the temperature reached 13 ℃, the reaction was cooled again with an ice bath, keeping the internal temperature below 15 ℃ before adding 2M HCl (365 mL, to pH 1). Water (300 mL) was added, the layers separated, and the aqueous layer extracted with EtOAc (110 mL). The combined organic extracts were washed with brine (300 mL), dried (MgSO 4 ) Filtration and concentration in vacuo afforded rac- (2 r,3s,4s,5 r) -3- (3, 4-difluoro-2-hydroxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid (58.22 g, 100%). 1 H NMR (400 MHz, methanol-d) 4 ) Delta 7.00 (ddd, j=8.4, 5.6,2.3hz,1 h), 6.69 (ddd, j=10.1, 8.8,7.5hz,1 h), 4.98 (d, j=10.5 hz,1 h), 4.18 (dd, j=10.5, 7.6hz,1 h), 2.83 (p, j=7.5 hz,1 h), 1.59 (q, j=1.2 hz,3 h), 0.76 (dq, j=7.2, 2.2hz,3 h) ppm esi-MS M/z calculated 340.0734, experimental 339.0 (M-1) - 。
Step 9:
racemic- (2R, 3S,4S, 5R) -3- (3, 4-difluoro-2-hydroxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid (58.39 g,171.6 mmol) in acetonitrile (3)00 mL) of K was added to the solution 2 CO 3 (82.6 g,597.7 mmol) and MeI (37 mL,594.3 mmol) the reaction was heated to 80deg.C (internal temperature reached 61 ℃ C.) for 5 hours, then cooled to ambient temperature and diluted with DCM (350 mL). The mixture was filtered, the filter cake was washed with more DCM (350 mL) and the filtrate concentrated in vacuo to give rac- (2 r,3s,4s,5 r) -3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid methyl ester (64.7 g, 100%) as an orange oil containing some residual K 2 CO 3 . The material was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) delta 6.91 (ddd, j=7.6, 5.7,1.9hz, 1H), 6.85 (td, j=9.1, 7.2hz, 1H), 4.91 (d, j=10.2 hz, 1H), 4.13 (dd, j=10.2, 8.0hz, 1H), 4.00 (d, j=2.7 hz, 3H), 3.71 (s, 3H), 2.72 (p, j=7.7 hz, 1H), 1.62 (q, j=1.2 hz, 3H), 0.76 (dq, j=7.5, 2.4hz, 3H) ppm.
Step 10:
racemic- (2R, 3S,4S, 5R) -3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid methyl ester (63.2 g,171.6 mmol) was dissolved in MeOH (500 mL) and water (300 mL). Adding LiOH H 2 O (14.8882 g,354.8 mmol) and the resulting mixture was stirred at ambient temperature for 2 hours. MeOH was removed in vacuo and the mixture was diluted in MTBE (320 mL). 2M HCl (440 mL) was added to reach pH 1, the layers were separated, and the aqueous layer was extracted twice with MTBE (100 mL). The combined organic layers were dried (MgSO 4 ) Filtration and concentration in vacuo afforded rac- (2 r,3s,4s,5 r) -3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid (60.3 g, 99%) as an orange oil. 1 H NMR(400MHz,DMSO-d 6 ) Delta 12.96 (s, 1H), 7.40-6.82 (M, 2H), 4.96 (dd, J=15.5, 10.5Hz, 1H), 4.08 (dd, J=10.4, 7.6Hz, 1H), 3.93 (d, J=2.2 Hz, 3H), 2.67 (p, J=7.7 Hz, 1H), 1.59-1.49 (M, 3H), 0.77-0.63 (M, 3H) ppm.ESI-MS M/z calculated 354.08905, experimental 353.1 (M-1) - 。
Step 11:
racemic- (2 r,3s,4s,5 r) -3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) stirred at 0 ℃ under nitrogen via an addition funnel over 30 minutes) To a solution of tetrahydrofuran-2-carboxylic acid (158.6 g,447.7 mmol) and DMF (135. Mu.L, 1.74 mmol) in DCM (1.5L) was added oxalyl chloride (79 mL,905.6 mmol). The ice bath was removed partway through the addition and the mixture was warmed to ambient temperature during the rest of the addition. The mixture was stirred at ambient temperature for an additional 1 hour and then evaporated in vacuo. The residue was dissolved in DCM (700 mL) and added via a dropping funnel to 4-aminopyridine-2-carboxylic acid methyl ester (81.5 g,535.7 mmol), DMF (135. Mu.L, 1.744 mmol) and Et stirred at-10 ℃ 3 N (95 mL,681.6 mmol) in DCM (780 mL). The rate of addition was controlled to maintain the internal temperature below 5 ℃ (about 15 minutes). After addition, the mixture was diluted with water (600 mL), the layers were separated, and the aqueous phase was further extracted with DCM (100 mL). A solid formed at the interface between the layers and was collected by filtration to give the filtered desired product (43.2 g). The filtrate was further washed with water (600 mL), dried (MgSO) 4 ) Filtered and concentrated in vacuo. The residue was suspended in MeOH (360 mL) and stirred rapidly for 20 min. The mixture was filtered and the solid was washed with MeOH and dried under vacuum for 30 minutes. This material was combined with the previously obtained product to give rac- (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] as a white solid]Amino group]Pyridine-2-carboxylic acid methyl ester (166.2 g, 76%). 1 H NMR(500MHz,DMSO-d 6 ) δ10.74 (s, 1H), 8.57 (d, j=5.4 hz, 1H), 8.36 (d, j=2.0 hz, 1H), 7.85 (dd, j=5.5, 2.2hz, 1H), 7.16 (qd, j=9.2, 6.3hz, 2H), 5.11 (d, j=10.1 hz, 1H), 4.25 (dd, j=10.2, 7.7hz, 1H), 3.95 (d, j=2.0 hz, 3H), 3.87 (s, 3H), 2.77 (p, j=7.6 hz, 1H), 1.61 (s, 3H), 0.81-0.65 (m, 3H) ppm. ESI-MS M/z calculated 488.13705, experimental 489.6 (M+1) + ；487.6(M-1) - 。
Step 12:
methanolic ammonia (3L, 7M,21.00 mol) is added to racemic- (2R, 3S,4S, 5R) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl]Amino group]Pyridine-2-carboxylic acid methyl ester (166 g,339.9 mmol) and the reaction was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give rac- (2R, 3S,4S, 5R) -4-[ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ]]Amino group]Pyridine-2-carboxamide (173 g), which is used in the next step without further purification. ESI-MS M/z calculated 473.1374, experimental 474.6 (M+1) + ；472.6(M-1) - 。
Step 13:
rac- (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl]Amino group]Pyridine-2-carboxamide (640 mg,1.415 mmol) was purified by chiral SFC (using (R' R) Whelk O-1 column from Regis Technologies on a UPC2-SFC instrument from Waters Corp., 3-5 μm particle size, 5.0 cm. Times.3.0 mm, solvent A: liquid CO) 2 [58-60 bar/40 DEG C]The method comprises the steps of carrying out a first treatment on the surface of the Solvent B: methanol HPLC grade with 20mM NH 3 ) Purifying to obtain:
first eluting isomer: (2S, 3R,4R, 5S) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ]Amino group]Pyridine-2-carboxamide (6, 198 mg): 1 HNMR (500 MHz, methanol-d) 4 ) δ8.52 (d, j=5.5 hz,1 h), 8.30 (d, j=2.0 hz,1 h), 7.94 (dd, j=5.5, 2.2hz,1 h), 7.16 (ddd, j=8.2, 5.6,2.3hz,1 h), 7.02 (ddd, j=9.9, 8.9,7.5hz,1 h), 5.12 (d, j=10.4 hz,1 h), 4.37 (dd, j=10.4, 8.0hz,1 h), 4.03 (d, j=2.2 hz,3 h), 2.84 (p, j=7.6 hz,1 h), 1.70 (d, j=1.1 hz,3 h), 0.86 (dq, j=7.4, 2.4hz,3 h) ppm.esi-MS/z calculated 473.1374, experimental value 474.6 (m+1) + ；472.7(M-1) - 。
Second eluting isomer: (2R, 3S,4S, 5R) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl]Amino group]Pyridine-2-carboxamide (compound 1, 195 mg): 1 h NMR (500 MHz, methanol-d) 4 ) δ8.39 (d, j=5.5 hz,1 h), 8.16 (d, j=2.0 hz,1 h), 7.80 (dd, j=5.5, 2.0hz,1 h), 7.02 (ddd, j=8.2, 5.7,2.4hz,1 h), 6.88 (ddd, j=9.9, 8.8,7.5hz,1 h), 4.98 (d, j=10.4 hz,1 h), 4.23 (dd, j=10.4, 7.9hz,1 h), 3.89 (d, j=2.2 hz,3 h), 2.70 (p, j=7.6 hz,1 h), 1.56 (d, j=1.1 hz,3 h), 0.72 (dq, j=7.6, 2.4hz,3 h) ppm.esi-MS/z calculated 473.1374, experimental value 474.6 (m+1) + ；472.8(M-1) - 。
The absolute stereochemistry of the first eluting isomer and the second eluting isomer was determined by single crystal X-ray crystallography of compound 1.
Compound 1-solid form A
Crystallization of compound 1 in methanol at 60 ℃ yields a crystalline form of compound 1, which is referred to herein as form a. Form a was characterized by XRPD, TGA and DSC analysis.
XRPD patterns of form a are depicted in fig. 1, and the corresponding data are summarized in the following table:
angle (° 2θ±0.2) Relative intensity (%)
7.3 19.9
9.9 28.3
13.9 100.0
15.7 20.1
19.0 50.4
20.1 31.8
20.3 19.3
25.4 14.7
The TGA thermogram of form a is depicted in fig. 2 and shows negligible weight loss from ambient temperature until thermal degradation.
The DSC thermogram of form a is depicted in figure 3 and shows a melting onset temperature of 186 ℃ with a peak at 187 ℃.
Compound 1-solid form B
Compound 1 was dissolved in ethyl acetate (6 volumes) at 68 ℃. The mixture was cooled to 50 ℃ over 1 hour and n-heptane (6 volumes) was added over 5 hours. The mixture was then cooled to 20 ℃ over a further 5 hours and kept overnight. The resulting solid material was filtered, washed with heptane (3 volumes) and dried to yield the crystalline form of compound 1, referred to herein as form B. Form B by XRPD and solid state NMR 13 C and C 19 F) TGA, DSC, IR and single crystal X-ray analysis.
XRPD patterns of form B are depicted in fig. 4, and the corresponding data are summarized in the following table:
Angle (° 2θ±0.2) Relative intensity (%)
7.6 11.3
9.2 10.5
12.0 10.0
12.8 36.7
14.1 59.3
15.1 24.0
15.2 39.4
16.2 23.9
16.9 31.9
17.6 15.1
18.4 63.1
18.5 100.0
18.7 51.7
19.3 64.2
20.3 64.6
21.7 11.6
22.0 29.3
22.2 29.7
22.9 15.1
23.6 27.3
24.0 10.9
24.2 16.8
25.2 30.0
26.9 15.6
27.0 10.7
27.4 17.0
28.6 10.8
28.9 20.9
Solid state of form B 13 The C NMR spectrum is depicted in FIG. 5, and the corresponding numbersSummarized in the following table:
solid state of form B 19 The F NMR spectrum is depicted in fig. 6, and the corresponding data is summarized in the following table:
chemical shift [ ppm ]] Relative intensity
-137.1 12.5
-152.8 5.8
The TGA thermogram of form B is depicted in fig. 7 and shows negligible weight loss from ambient temperature until thermal degradation.
The DSC thermogram of form B is depicted in fig. 8 and shows a melting onset temperature of 182 ℃ with a peak at 183 ℃.
The IR spectrum of form B is depicted in FIG. 9 and is included at 3501, 3356, 1684, 1565, 1505, and 1122cm -1 Peak at.
Crystals with form B were grown for single crystal X-ray analysis by dissolving 1mg of compound 1 material in 500 μl ethanol, which was allowed to evaporate slowly over several days. A thermal ellipsoid plot of 50% probability is depicted in fig. 10, and unit cell parameters are reported in the following table:
example 2
V E-VIPR assay to detect and measure Na inhibition properties
Sodium ion channels are voltage dependent proteins that can be activated by application of an electric field to induce a change in membrane voltage. An electro-stimulation apparatus known as E-VIPR and methods of use thereof are described in International publication No. WO 2002/008748A3 and C. -J.Huang et al, characterization of voltage-gated sodium channel blockers by electrical stimulation and fluorescence detection of membrane potential,24Nature Biotech.439-46 (2006), both of which are incorporated herein by reference in their entirety. The instrument includes a microtiter plate processor, an optical system for exciting coumarin dyes while recording coumarin and oxyborol emissions, a waveform generator, a current or voltage controlled amplifier, and a parallel electrode pair inserted into a assay plate well. Under integrated computer control, the instrument delivers a user-programmed electrical stimulation protocol to the cells within the microtiter plate wells.
Human Na, which expresses a truncated form with full channel activity, will be expressed 16-20 hours prior to running the assay on E-VIPR V HEK cells of 1.8 were seeded at a density of 25,000 cells per well into microtiter 384-well plates pre-coated with matrigel. 2.5% -5% kir2.1 Bacmam virus was added to the final cell suspension prior to inoculation into the cell plates. HEK cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% FBS (fetal bovine serum, eligibility; sigma #F4135), 1% NEAA (non-essential amino acids, gibco # 11140), 1% HEPES (Gibco # 15630), 1% pen-Strep (penicillin-streptomycin; gibco # 15140) and 5 μg/ml Blasticidin (Blticin) (Gibco #R210-01). At a humidity of 90% -95% and 5% CO 2 Is used for expanding cells in the aeration cover cell culture flask.
Reagents and stock solutions:
100mg/mL Pluronic F-127 (Sigma #P2443) in anhydrous DMSO
Compound plate: corning 384 well polypropylene round bottom #3656
Cell plates: 384 well tissue culture treatment plate (Greiner # 781091-2B)
2.5% -5% KIR2.1 Bacmam virus (produced internally) was prepared as described in section 3.3 of J.A. Fornwald et al, gene Expression in Mammalian Cells Using BacMam, a Modified Baculovirus System,1350Methods in Molecular Biology95-116 (2016), the entire contents of which are incorporated by reference. The concentration used may depend on the viral titer of each batch.
5mM DiSBAC 6 (3) Voltage-sensitive oxynuoro receptor (CAS number 169211-44-3;5- [3- (1, 3-dihexylhexahydro-4, 6-dioxo-2-thio-5-pyrimidinyl) -2-propen-1-ylidene)]-1, 3-dihexyldihydro-2-thio-4, 6 (1 h,5 h) -pyrimidinedione in anhydrous DMSO. DiSBAC 6 (3) Is similar to DiSBAC 4 (3) As described in Voltage Sensing by Fluorescence Resonance Energy Transfer in Single Cells, gonzalez, j.e. and Tsien, r.y. (1995) biophys.j.69, 1272-1280.
5mM CC2-DMPE, a commercially available membrane-bound coumarin phospholipid FRET donor (ThermoFisher Scientific catalog number K1017, CAS number 393782-57-5; tetradecanoic acid, 1' - [ (1R) -1- [8- (6-chloro-7-hydroxy-2-oxo-2H-1-benzopyran-3-yl) -3-hydroxy-3-oxo-8-oxo-2, 4-dioxa-7-aza-3-phosphaoct-1-yl ] -1, 2-ethanediyl ] ester) was prepared in anhydrous DMSO. See also Improved indicators of cell membrane potential that use fluorescence resonance energy transfer, gonzalez, J.E. and Tsien, R.Y. (1997) chem. Biol.4,269-277.
At H 2 Preparation of a voltmetric background inhibiting Compound (VABSC-1) (89-363 mM, range for maintaining solubility) in O
Human serum (HS, millipore #S1P1-01KL, or Sigma SLBR5469V and SLBR5470V, in the form of a 50%/50% mixture for 25% determination of final concentration)
Bath 1 buffer:
an aqueous solution of 160mM (9.35 g/L) of sodium chloride, 4.5mM (0.335 g/L) of potassium chloride, 10mM (1.8 g/L) of glucose, 1mM (0.095 g/L) of magnesium chloride (anhydrous), 2mM (0.222 g/L) of calcium chloride, and 10mM (2.38 g/L) of HEPES.
Na/TMACL bath 1 buffer:
aqueous solutions of 96mM (5.61 g/L) of sodium chloride, 4.5mM (0.335 g/L) of potassium chloride, 64mM (7.01 g/L) of Tetramethylammonium (TMA) -Cl, 10mM (1.8 g/L) of glucose, 1mM (0.095 g/L) of magnesium chloride (anhydrous), 2mM (0.222 g/L) of calcium chloride, and 10mM (2.38 g/L) of HEPES.
Hexyl dye solution (2X concentration):
contains 0.5% beta-cyclodextrin (freshly prepared before each use, sigma #C4767), 8. Mu. MCC2-DMPE and 2. Mu.M DiSBAC 6 (3) Is a bath 1 buffer solution. By adding a component equal to CC2-DMPE and DiSBAC 6 (3) 10% Pluronic F127 stock solution by volume of the combination of (c). The preparation sequence is that Pluronic and CC2-DMPE are mixed first, and DiSBAC is added 6 (3) Bath 1/beta-cyclodextrin was then added while swirling.
Compound loading buffer (2X concentration): a Na/TMACL bath 1 buffer containing 50% HS (omitted from experiments performed in the absence of Human Serum (HS)), 1mM VABSC-1, 0.2mg/ml BSA (in bath 1), 9mM KCl, and 0.625% DMSO.
Assay protocol (7 key steps):
1) To reach the final concentration in each well, 375nL of each compound (in pure DMSO) was pre-spotted into polypropylene plates from an intermediate stock concentration of 0.075mM at the desired final concentration of 240x, 3-fold dilution in an 11-point dose response resulting in the highest dose in the cell plate with a final concentration of 300 nM. Vehicle control (pure DMSO) and positive control (established Na V 1.8 inhibitors, final 25. Mu.M in DMSO in the assay) were manually added to the outermost column of each plate, respectively. The compound plates were backfilled with 45 μl of compound loading buffer per well, yielding 240-fold dilutions of the compound after 1:1 transfer to the cell plates (see step 6). The final DMSO concentration was 0.625% for all wells in the assay (0.75% DMSO was added to compound loading buffer, final DMSO concentration was 0.62)5%). The assay dilution scheme is adjusted to be able to test higher dose ranges in the presence of HS or in the event of a final assay volume change.
2) A hexyl dye solution was prepared.
3) Cell plates were prepared. On the day of assay, the medium was aspirated and the cells were washed three times with 80 μl of bath 1 buffer, maintaining a residual volume of 25 μl in each well.
4) mu.L of hexyl dye solution per well was dispensed into the cell plates. Cells were incubated for 20 minutes in the dark at room or ambient conditions.
5) mu.L of compound loading buffer per well was dispensed into the compound plates.
6) The cell plates were washed three times with 80 μl of bath 1 buffer per well, leaving a residual volume of 25 μl. Then 25 μl per well from the compound plate was transferred to each cell plate. The mixture was incubated at room temperature/ambient conditions for 30 minutes.
7) Cell plates containing compounds were read on E-VIPR using a current controlled amplifier to deliver stimulation wave pulses using a symmetrical biphasic waveform. The user programmed electrical stimulation protocol was 1.25-4 amps and a 4 millisecond pulse width (depending on the electrode composition) was delivered at 10Hz for 10 seconds. A 0.5 second pre-stimulus record was made for each well to obtain an unstimulated intensity baseline. The stimulus waveform was followed by a post-stimulus recording of 0.5 seconds to check for relaxation to a resting state. All E-VIPR reactions were measured at a 200Hz acquisition rate.
Data analysis:
the data were analyzed and reported as normalized ratios of the measured emission intensities in the 460nm and 580nm channels. The response as a function of time is reported as a ratio obtained using the following formula:
By calculating the initial (R i ) And finally (R) f ) The ratio further simplifies (i.e., normalizes) the data. These are during some or all of the pre-stimulation period and during the stimulation periodAverage ratio values during sampling points. Then calculate the fluorescence ratio (R f /R i ) And reported as a function of time.
The control reaction was obtained by performing the assay in the presence of a positive control and in the absence of a drug (DMSO vehicle negative control). The response to negative (N) and positive (P) controls was calculated as above. The% compound antagonist activity a is then defined as:
where X is the ratio response of the test compound (i.e., the maximum magnitude of the ratio response or the number of action potential peaks at the beginning of the pulse sequence in the presence of the test compound). Using this assay protocol, a dose response curve was plotted and IC for compound 1 of the present invention was determined 50 Value of<0.01μM。
Example 3
SDD tablet process
Step 1: preparation of Compound 1 Spray Dried Dispersion (SDD)
About 2466.7gm of methylene chloride and about 2466.7gm of methanol were mixed in a glass vessel. To the resulting mixture was added about 100gm of compound 1 at room temperature. Approximately 300gm HPMCAS was added to the mixture at room temperature when compound 1 was completely dissolved. When HPMCAS was completely dissolved, the resulting mixture was spray dried using a MicraSpray (MS-35) spray dryer with a 0.8mm two-fluid nozzle, a 3mm gasket, a 2.6mm air cap, a 150 mesh PTFE in-line filter and a collection vessel attached to the circulation and pulse counter filter. The following table summarizes the process parameters for an MS-35 spray dryer:
Spray dryer process parameters
To begin spray drying, MS-35 was preheated and when the target outlet temperature of 48℃was reached, the equilibration solution was sprayed until all parameters were stable and within the target range. Once all parameters have stabilized and are within the target range, the MS-35 spray dryer begins spraying the solution containing compound 1 and polymer. The process parameters may be adjusted during operation to keep them within the operating range.
The wet SDD is transferred to a tray of appropriate size. Each tray was filled with powder to a depth of about 1 inch and placed in a vacuum oven at 40 ℃ under a nitrogen purge. After 12-72 hours, samples were removed from the trays to check residual solvent levels. Once the solvent level was below specification (dichloromethane (< 600 ppm) and methanol (< 3000 ppm)), all the powders from the trays were mixed.
The SDD is transferred to a secondary drying chamber for further drying. At the completion of the drying, X-ray powder diffraction (XRPD) analysis was performed in reflection mode at room temperature using a PANalytical Empyrean system (Malvern PANalytical Inc, westborough, massachusetts) equipped with a sealed tube source and PIXcel 1D Medipix-3 detector. By copper radiation The X-ray generator was operated at a voltage of 45kV and a current of 40 mA. The powder sample is placed in a back-loaded sample holder and loaded into the instrument. The sample was scanned over a range of about 3 ° to about 40 ° 2θ, with a step size of 0.0131 ° and 48.195s per step. The obtained XRPD diffractogram is depicted in figure 11.
The composition of the SDD is summarized in table 1:
table 1 composition of spray dried dispersion of compound 1
Step 2: preparation of tablets comprising Compound 1SDD
Compound 1SDD, microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium from step 1 were each passed through a 20 mesh screen and mixed in a 10L Bohle mixer. The mixture was mixed at 32rpm for about 2.5 minutes. Sodium stearyl fumarate was passed through a 60 mesh screen and added to the blended mixture and further blended at 32rpm for about 1.5 minutes.
UsingThe resulting blended mixture was dry granulated by a roll press and an in-line mill. The resulting abrasive particles were added to a 5L Bohle mixer along with microcrystalline cellulose and croscarmellose sodium that passed through a 20 mesh screen. The resulting mixture was blended at 32rpm for 8.5 minutes. After blending, sodium stearyl fumarate passing through a 60 mesh screen was added to the blended mixture and mixed for an additional 2 minutes at 32 rpm. The process parameters of the roll press and the online mill are summarized in table 2:
Table 2 process parameters
And then useThe resulting mixture was compressed into tablets by a tablet press to obtain tablets each containing 10mg of compound 1. The press had an 8mm standard round concave tool and a paddle feeder. The turret speed was set to 30rpm and the paddle speed was set to 25rpm. The target weights and hardness of the tablets are summarized in table 3:
TABLE 3 Table 3
After milling to a uniform powder, the resulting tablets were analyzed by X-ray powder diffraction (XRPD) and solid state nuclear magnetic resonance (ssNMR). XRPD analysis was performed in reflection mode at room temperature using a PANalytical Empyrean system (Malvern PANalytical Inc, westborough, massachusetts) equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector. By copper radiationThe X-ray generator was operated at a voltage of 45kV and a current of 40 mA. The powder sample is placed in a back-loaded sample holder and loaded into the instrument. Scanning the sample over a range of about 3 ° to about 40 ° 2θ, wherein the step size is 0.0131 ° and each step is 48.195s; and scanning is performed in the range of about 14 ° to about 16 ° 2θ, with a step size of 0.0131 ° and 1497.870s per step. The obtained XRPD diffractograms are depicted in fig. 12A and 12B.
Solid state NMR analysis was performed on a Bruker-Biospin 400MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe. The sample was packed to 4mm ZrO 2 In the rotor and under Magic Angle Spinning (MAS) conditions at a rotational speed typically set to 12.5 kHz. Using 1 H MAS T 1 Saturation recovery relaxation experiment proton relaxation time was measured to set 13 Appropriate cyclic delay for C cross-polarization (CP) MAS experiments. Using 19 F MAS T 1 Saturation recovery relaxation experiment measurement of fluorine relaxation time to set 19 Appropriate cycle delay for the F MAS experiments. The CP contact time of the carbon CPMAS experiment was set to 2 milliseconds. CP proton pulses with linear slopes (50% to 100%) were used. The carbon Hartmann-Hahn match was optimized on an external reference sample (glycine). Both carbon and fluorine spectra were recorded using proton decoupling at a field strength of about 100kHz using a TPPM15 decoupling sequence. The fluorine and carbon NMR spectra obtained are depicted in fig. 13A and 13B, respectively, and the peak lists are presented in tables 4 and 5.
Table 4. 19 List of F MAS peaks:
peak numbering δ[ppm] Strength of
1 -40.1 1.51E0
2 -73.2 1.23E1
3 -105.9 4.26E0
4 -121.8 3.33E0
5 -137.9 4.80E0
6 -155.6 6.33E0
7 -171.1 8.30E0
8 -220.6 1.49E0
Table 5. 13 C CPMAS peak list:
peak numbering δ[ppm] Strength of
1 170.6 8.85E0
2 151.5 4.48E0
3 125.2 3.23E0
4 92.6 3.24E0
5 89.2 2.87E1
6 84.3 2.33E1
7 75.1 9.99E1
8 72.7 9.87E1
9 65.3 3.92E1
10 61.7 3.37E1
11 44.5 3.52E0
12 33.2 1.92E1
13 31.0 4.74E0
14 27.4 4.85E0
15 20.7 1.11E1
TABLE 6 tablet composition, 10mg
* Avicel PH101 has a particle size of about 50 microns.
* Avicel PH200 has a particle size of about 180 microns.
Example 3A
SDD (25% DL) tablet
TABLE 7 tablet compositions, 10mg, 20mg and 50mg
TABLE 8 tablet compositions, 10mg and 50mg
CCS IG/EG ratio: 75/25
MgST IG/EG ratio 25/75
Particle weight% in the final blend: 75 percent of
Example 4: efficacy and safety study of compound 1 in subjects with pain following bunion excision
A randomized, double-blind, placebo-controlled, 5-group parallel design study was performed to evaluate the efficacy and safety of compound 1 against acute surgical pain. Bunion excision is a mature, multi-dose surgical acute pain model. A randomized, double-blind study design was used to avoid observer bias and reduce symptoms or outcomes due to subject knowledge of treatment. An opioid reference group evaluating standard of care treatment (hydrocodone bitartrate (5 mg)/acetaminophen (325 mg) (HB/APAP)) was included to determine the ability of the study to successfully observe the therapeutic effect of compound 1.
Study subjects
Male and female patients with pain of 18 to 75 years (inclusive) age according to 11-score pain rating scale (NPRS) > 4 and moderate or severe according to speech classification rating scale (VRS) after bunaectomy were included in this study.
Research medicament
Study drug: compound 1. Study drug was administered orally in 10mg tablets. Tablets were prepared according to example 3. Study drug was administered every 12 hours (q 12 h). Low, medium and high dose regimens were tested. The first dose in the low dose regimen was 20mg and the subsequent dose was 10mg q12h. The first dose in the medium dose regimen was 60mg and the subsequent dose was 30mg q12h. The first dose in the high dose regimen was 100mg and the subsequent dose was 50mg q12h.
Reference drug: HB/APAP. The reference drug was orally administered in 5mg/325mg capsules, provided in the form of 5mg/325mg tablets that were over-encapsulated. The reference drug was administered every 6 hours (q 6 h) at a dose of 5mg/325 mg.
Study protocol
The schedule of this study is summarized in table 9. Following the screening period, subjects received primary Shan Cedi one-metatarsal bunyatis excision repair on the negative day under local anesthesia (meyo) and popliteal block. Infusion of popliteal sciatic nerve block (0.2% ropivacaine) was initiated post-operatively and held in place until around 3 a.m. on day 1. The popliteal sciatic nerve block lag was removed and each subject was randomized when the subject required a first dose of study drug for pain relief and reported pain ∈4 according to NPRS and moderate or severe pain according to VRS. NPRS and VRS criteria were designed to ensure that the subject had enough pain to determine if the study drug was effective. Subjects that did not meet the NPRS and VRS criteria within 9 hours of removal of the popliteal sciatic nerve block did not participate in the study.
TABLE 9 study protocol
Study days Event(s)
Day-28 The screening period begins
Day-1 Bunion excision of bunions
Day 1 (about 3 am) Removal of the popliteal block
Day 1 Random grouping
Day 1-3 Administration of study drugs
Day 12-16 Security follow-up phone follow-up
264 subjects were randomized into five treatment groups at approximately 2:2:1:2:2: compound 1 (high dose); compound 1 (medium dose); compound 1 (low dose); HB/APAP (opioid reference); or placebo (see table 2). Random groupings were stratified by location and baseline NPRS (< 8 vs. 8). To maintain blindness, all subjects received the same number of capsules in a double simulation design.
TABLE 10 Compound 1 treatment group
Compound 1 was administered every 12 hours (q 12 h). The final dose of compound 1 was administered 36 hours after the first dose. HB/APAP placebo capsules were administered every 6 hours (q 6 h).
In the reference group, HB/APAP was administered at a dose of 5mg/325mg every 6 hours (q 6 h). The final dose of HB/APAP was given 42 hours after the first dose. Compound 1 placebo capsules were administered every 12 hours (q 12 h).
In the placebo group, compound 1 placebo capsules were administered every 12 hours (q 12 h) and HB/APAP placebo capsules were administered every 6 hours (q 6 h).
Subjects underwent a safety follow-up telephone interview 14 (+2) days after the last study drug dose, with the aim of collecting information on adverse events, drugs, and treatments and procedures.
Efficacy assessment
11 points (0 to 10) digital pain rating scale: NPRS scores are often used in bunaectomy studies and are approved by the FDA as an effective pain intensity indicator. In the 11-point NPRS, a score of 0 indicates no pain, and a score of 10 indicates the highest pain intensity conceivable. Subjects reported their pain according to 11-point NPRS immediately prior to their first dose of study drug (baseline NPRS score) and at time intervals (i.e., 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours (±5 minutes) within a period of 48 hours after the first dose of study drug. Immediately prior to each administration of the rescue medication, pain intensity was also recorded according to NPRS. Pain intensity scores collected 4 hours after a dose of drug were considered missing and the missing value was estimated as the intensity recorded immediately prior to administration of rescue drug.
SPID-48 is the sum of Pain Intensity Differences (PID) over a 48 hour period. Pain intensity scores of 0 (no pain) to 10 (possibly more severe pain) were obtained before starting the study and throughout the 48 hour period. The pain score at each assessment was subtracted from the baseline pain score to give a total score or SPID-48. Higher SPID-48 is better and indicates a decrease in pain intensity compared to the baseline score.
Score 4 speech classification rating scale: subjects reported their pain (baseline VRS) according to 4 points of VRS (none, mild, moderate or severe) immediately prior to their first dose of study drug.
Efficacy results
SPID48 score. SPID scores for subjects in placebo, study and reference groups are presented in table 11 below.
TABLE 11 results of efficacy of bunion excision
The bunaectomy study reached its primary endpoint, showing a statistically significant improvement in SPID48 for those patients treated with high doses of compound 1 compared to placebo, as recorded on the digital pain rating scale (NPRS). The higher the SPID48 value, the better the pain relief effect. The effect was rapid and continued throughout the evaluation period.
Security results
Safety assessments include adverse events, clinical laboratory assessments, clinical assessments of vital signs, electrocardiography and physical examinations. No patients stopped treatment due to AE, nor did patients present with SAE. All AEs were mild or moderate. The most common AEs (incidence >10% of placebo, HB/APAP or compound 1 high dose groups, respectively) were headache (12%, 7%, 8%) and nausea (9%, 18%, 8%).
Compound 1 was also studied in patients receiving abdominal wall plastic surgery and demonstrated a statistically significant improvement in SPID48 (NCT 05034952).
Example 5: predictive of
Efficacy and safety study of compound 1 in subjects with painful diabetic peripheral neuropathy
A randomized, double-blind, active control, dose range, 4-group, parallel design study was performed to assess the safety and efficacy of compound 1 in treating subjects with painful diabetic peripheral neuropathy. A randomized, double-blind study design was chosen to avoid observer bias and reduce symptoms or outcomes due to subject knowledge of treatment. A pregabalin reference group evaluating standard of care treatment (100 mg tid) was included to determine the ability of the study to successfully observe the therapeutic effect of compound 1.
Study subjects
Subjects meeting the qualification criteria during the 1 st and 2 nd screening visit entered a 7 day lead-in period to establish their baseline digital pain rating scale (NPRS) pain scores. The study included male and female patients aged 18 to 75 years (inclusive) and had a pain of ∈4 according to 11 minutes NPRS. A total of about 150 subjects were randomized to the 4 treatment groups at 2:1:1:2: compound 1 (high, medium or low dose) or pregabalin (reference group) (table 3). Random grouping is by gender (female and male) and body mass index (not less than 30 and) <30kg/m 2 ) Layering. To maintain blindness, in a double simulation design, all subjects received the same amount of pharmaceutical composition once daily (qd) in the morning and the same dosage form 3 times daily. After the end of the treatment period, subjects gradually reduced the capsule (pregabalin reference drug or matched placebo) study drug for 7 days (4 days every 12 hours followed by qd administration for 3 days) and were followed for safety follow-up after an additional 7 (±2) days.
Table 12 treatment group
Table 12 treatment group
qd: once a day; tid: 3 times per day: to maintain blindness, all subjects received the same number of tablets and the same number of capsules in a double simulation design at the same frequency (i.e., qd took tablets and tid took capsules during treatment).
Research medicament
Study drug: compound 1. The study drug was administered orally in a tablet containing 23mg of active ingredient. Study medication was administered once daily. Low, medium and high dose regimens were tested. The low dose was 23mg, the medium dose was 46mg, and the high dose was 69mg.
Reference drug: pregabalin. The reference drug was orally administered as 100mg of tid in capsule form. The doses and dose frequency are summarized in table 4 below.
Table 13 study drug
Compound 1 was administered once daily (qd) and pregabalin was administered three times daily.
In the placebo group, compound 1 placebo capsules were administered once daily.
After the end of the treatment period, subjects gradually reduced the capsule (pregabalin reference drug or matched placebo) study drug over 7 days; no tablets (compound 1 or matched placebo) study drug were provided during the taper period. Subjects received safety follow-up 14 (±2) days after the end of the treatment period.
Efficacy assessment
11 points (0 to 10) digital pain rating scale: the FDA considers NPRS scores as an effective pain intensity indicator. In the 11-point NPRS, a score of 0 indicates no pain, and a score of 10 indicates the highest pain intensity conceivable. The subjects reported their pain according to the 11-point NPRS immediately prior to (baseline NPRS score) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours (±5 minutes) after the first dose of study drug.
From day-7 to week 12, the subject reported his average daily pain over the past 24 hours on NPRS via an electronic diary; during the treatment period, NPRS was completed in the morning prior to the first daily dose. Subjects reported their current pain scores prior to each administration of rescue medication. The NPRS score in the daily electronic diary was used in primary endpoint analysis and the subject proportion of > 30%, > 50% and > 70% decrease in weekly average score reported in the daily electronic diary was used in secondary endpoint analysis.
Daily sleep disturbance scale (DSIS): pain often interferes with sleep, which is important for quality of life. FDA recommends evaluating the effect of analgesics on sleep. DSIS is commonly used in neuropathic pain studies and is evaluated according to 11-point NPRS and is therefore evaluated in this study. 11 minutes is in the range of 0 (none) to 10 (severe).
Patient Global Impression of Change (PGIC): PGICs are commonly used in neuropathic pain studies, and the method, measurement and pain assessment Initiative (IMMPACT) panel of clinical trials recommended it as a core outcome indicator for chronic pain studies, and thus evaluated in this study. There is evidence that PGIC may be more sensitive than pain intensity assessment in neuropathic pain studies, as it can assess additional quality of life metrics. The assessment consisted of a single item of 7 minutes, from 1 (very improved) to 7 (very poor).
Neuropathic pain symptom questionnaire (NPSI): NPSI is a well-characterized method for quantifying the different symptoms and therapeutic effects experienced by various neuropathic pain patients and is therefore evaluated in this study. In addition, it is used to study the underlying basis of individual symptom quality.
Simple Mejil pain questionnaire-2 (SF-MPQ-2): SF-MPQ-2 is designed to provide an overall assessment of pain-related symptoms by including a series of neuropathic and non-neuropathic pain descriptors, and is therefore evaluated in this study. It evaluates 15 specific sensory and emotional pain descriptors and provides a total score as well as a sensory and emotional component table score.
Columbia suicide severity rating scale (C-SSRS): FDA suggests that suicidal tendencies are assessed in clinical studies and thus are assessed in this study. The C-SSRS evaluates this through a series of questions about suicide ideas and behaviors.
SF-36: SF-36 is included because it is a common health questionnaire measuring 8 areas: physical function, character limitation due to physical problems, social function, physical pain, mental health, character limitation due to emotional problems, vitality, and general health perception. A physical and mental component composite score may be calculated.
BDI: BDI is recommended as a core outcome indicator of emotional function in chronic pain clinical trials and is therefore evaluated in this study. It has very positive reliability and effectiveness and can address the less severe depression scores after treatment.
Bedside feel test suite (BSTK): BSTK was used for standardized assessment and phenotyping of pain in subjects, using common components of neurosensory examination, and was therefore evaluated in this study.
Efficacy results
Baseline NPRS score. Baseline NPRS scores for subjects in placebo, study and reference groups are reported. The NPRS score reflects the mean (and standard deviation) of the NPRS scores for the subjects in each group.
Security results
Safety assessments include adverse events, clinical laboratory assessments, clinical assessments of vital signs, electrocardiography and physical examinations.
Example 6: predictive of
Pharmacokinetic study of Compound 1 in a subject with painful diabetic peripheral neuropathy
Population PK analysis was performed on the plasma concentrations of compound 1 and compound 1a (compound 1 metabolite) versus time data using a nonlinear mixed effect modeling method. Population methods can also be used to study the exposure-response relationship of efficacy and safety variables. PK samples were collected during the clinical visit during the study described in example 4.
All efforts were made to obtain a suitable PK sample at the exact nominal time relative to the administration of the first daily dose. Acceptable sampling time windows are shown in table 14. Samples collected outside these acceptable windows are considered protocol bias.
TABLE 14 acceptable pharmacokinetic sampling window
Example 7: predictive of
Efficacy and safety study of compound 1 in subjects with painful diabetic peripheral neuropathy
A randomized, double-blind, active control, dose range, 4-group, parallel design study was performed to assess the safety and efficacy of compound 1 in treating subjects with painful diabetic peripheral neuropathy. Random, double-blind study designs were chosen to avoid observer bias, reduce the likelihood of blinding, and reduce symptoms or outcomes due to subject knowledge of treatment. A pregabalin reference group evaluating standard of care treatment (100 mg tid) was included to determine the ability of the study to successfully observe the therapeutic effect of compound 1.
Study subjects
Subjects meeting the qualification criteria during the 1 st and 2 nd screening visit entered a 7 day lead-in period to determine their baseline digital pain rating scale (NPRS) pain scores and daily sleep disturbance scale (DSIS) scores. In the case of a plausible scenario, the day 1 window period may be extended by up to 3 days (i.e., there may be up to 3 days between the end of the lead-in period and the beginning of the treatment period). Male and female patients aged 18 to 80 years (inclusive) and having a pain of > 4 according to 11 NPRS were included in this study, provided they had bilateral lower limb pain due to diabetic peripheral neuropathy for at least one year, and a weekly average NPRS pain score of > 4 according to 11 NPRS and limited variation over a 7 day lead-in period (SD <25% of the average). Optionally, to avoid confounding medical history, subjects receiving hormone replacement therapy may be excluded. A total of about 175 subjects were randomized into 4 treatment groups at 2:2:1:2: compound 1 (high, medium or low dose) or pregabalin (reference group) (table 6). The random groupings were stratified by gender (female and male) and body mass index (body mass index of one group is less than given)Cut-off values, and a further group of body mass indices greater than or equal to the cut-off value, the cut-off value may be between 30 and 35kg/m 2 And, inclusive). To maintain blindness, in a double simulation design, all subjects will receive the same number of tablets once a day (qd) in the morning and the same number of capsules 3 times a day (tid). After the end of the treatment period, subjects gradually reduced the capsule (pregabalin reference drug or matched placebo) study drug for 7 days (4 days every 12 hours followed by qd administration for 3 days) and were followed for safety follow-up after an additional 7 (±2) days.
Table 15 treatment group
qd: once a day; tid: 3 times per day: to maintain blindness, all subjects received the same number of tablets and the same number of capsules in a double simulation design at the same frequency (i.e., qd took tablets and tid took capsules during treatment).
Research medicament
Study drug: compound 1. The study drug was administered orally in a tablet containing 23mg of active ingredient. Study medication was administered once daily. Low, medium and high dose regimens were tested as described in table 6.
Reference drug: pregabalin. Pregabalin is an anticonvulsant approved for use in the treatment of painful diabetic neuropathy; in most international clinical guidelines, it is considered as first line therapy and constitutes a critical part of neuropathic pain management. The reference drug was orally administered as 100mg of tid in capsule form. The doses and dose frequency are summarized in table 7 below.
Table 16 study drug
Compound 1 was administered once daily (qd) and pregabalin was administered three times daily.
In the placebo group, compound 1 placebo capsules were administered once daily.
After the end of the treatment period, subjects gradually reduced the capsule (pregabalin reference drug or matched placebo) study drug over 7 days; no tablets (compound 1 or matched placebo) study drug were provided during the taper period. Subjects received safety follow-up 14 (±2) days after the end of the treatment period.
Efficacy and safety assessment
11 points (0 to 10) digital pain rating scale: the FDA considers NPRS scores as an effective pain intensity indicator and is used as a standard pain rating scale in many pain enrollment studies. In the 11-point NPRS, a score of 0 indicates no pain, and a score of 10 indicates the highest pain intensity conceivable. The subjects reported their pain according to the 11-point NPRS immediately prior to (baseline NPRS score) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours (±5 minutes) after the first dose of study drug.
From day-7 to week 12, the subject reported his average daily pain over the past 24 hours on NPRS via an electronic diary; during the treatment period, NPRS was completed in the morning prior to the first daily dose. Subjects reported their current pain scores prior to each administration of rescue medication. The NPRS score in the daily electronic diary, especially the change from baseline in weekly averages at week 12, was used in the primary endpoint analysis, and the subject proportion of > 30%, > 50% and > 70% decrease in weekly average score reported in the daily electronic diary, especially at week 12, was used in the secondary endpoint analysis. For the primary endpoint, daily NPRS scores were averaged over a week to reduce the impact of individual high or low pain scores, and the change in weekly averages from baseline could be used as an additional endpoint.
Daily sleep disturbance scale (DSIS): pain often interferes with sleep, which is important for quality of life. FDA recommends evaluating the effect of analgesics on sleep. DSIS is commonly used in neuropathic pain studies and is evaluated according to 11-point NPRS and is therefore evaluated in this study. 11 minutes is in the range of 0 (none) to 10 (severe). DSIS is completed daily in the morning before the first daily dose in the electronic diary to describe how pain interferes with the subject's sleep. The weekly average of DSIS (especially at week 12) from baseline changes can be used for secondary endpoint analysis.
Patient Global Impression of Change (PGIC): PGICs are commonly used in neuropathic pain studies, and the method, measurement and pain assessment Initiative (IMMPACT) panel of clinical trials recommended it as a core outcome indicator for chronic pain studies, and thus evaluated in this study. There is evidence that PGIC may be more sensitive than pain intensity assessment in neuropathic pain studies, as it can assess additional quality of life metrics. The assessment consisted of a single item of 7 minutes, from 1 (very improved) to 7 (very poor). PGIC was completed in selected study visits to quantify changes in overall condition of subjects. The proportion of subjects categorized as improved according to PGIC assessment (especially at week 12) can be used for secondary endpoint analysis.
Neuropathic pain symptom questionnaire (NPSI): NPSI is a well-characterized method for quantifying the different symptoms and therapeutic effects experienced by various neuropathic pain patients and is therefore evaluated in this study. In addition, it is used to study the underlying basis of individual symptom quality. NPSI was completed in selected study visits to quantify the change in the subject's different pain symptoms. The change in the total intensity score of NPSI (especially at week 12) from baseline can be used as an endpoint.
Simple Mejil pain questionnaire-2 (SF-MPQ-2): SF-MPQ-2 is designed to provide an overall assessment of pain-related symptoms by including a series of neuropathic and non-neuropathic pain descriptors, and is therefore evaluated in this study. It evaluates 15 specific sensory and emotional pain descriptors and provides a total score as well as a sensory and emotional component table score. SF-MPQ-2 is completed in selected on-site visits to quantify the overall and specific pain symptom changes in the subject. Changes in pain characteristics and intensity (especially at week 2) from baseline using SF-MPQ-2 can be used as an endpoint.
SF-36: SF-36 is included because it is a common health questionnaire measuring 8 areas: physical function, character limitation due to physical problems, social function, physical pain, mental health, character limitation due to emotional problems, vitality, and general health perception. A physical and mental component composite score may be calculated. Changes in SF-36 (especially at week 12) from baseline can be used as an endpoint.
BDI: BDI is recommended as a core outcome indicator of emotional function in chronic pain clinical trials and is therefore evaluated in this study. It has very positive reliability and effectiveness and can address the less severe depression scores after treatment. Changes in BDI (especially at week 12) from baseline can be used as endpoint.
Bedside feel test suite (BSTK): BSTK was used for standardized assessment and phenotyping of pain in subjects, using common components of neurosensory examination, and was therefore evaluated in this study.
Subject ratio and total drug dose with rescue drug: acetaminophen was allowed as an analgesic drug as needed (prn) throughout the study. In the electronic diary, subjects recorded the usage of rescue drugs and their current pain scores according to NPRS immediately prior to each administration of rescue drugs. Data on rescue drug use was collected for descriptive analysis in 4 treatment groups, and subject proportion and total drug usage using rescue drugs was used as endpoints.
Pharmacokinetic analysis
Blood samples will be collected from subjects administered any dose level of compound 1 at different time points to assess the plasma concentrations of compound 1 and its metabolite compound 1 a.
Efficacy results
Baseline scores. Baseline NPRS scores for subjects in placebo, study and reference groups are reported. The NPRS score reflects the mean (and standard deviation) of the NPRS scores for the subjects in each group. The NPRS daily pain intensity score and baseline value of DSIS were defined as the average score from day-7 to day-1. For ECG, baseline values are defined as the average of non-missing pre-treatment measurements (in triplicate) on day 1. For all other variables, baseline values were defined as the most recent non-missing measurements collected prior to the first dose of study medication. The change from baseline (absolute change) is calculated as the post-baseline value.
And (5) carrying out statistical analysis. The primary efficacy endpoint was the change from baseline in weekly averages of daily pain intensity of NPRS at week 12. The primary analysis will be an intra-group comparison of any compound 1 dose group. Primary efficacy analysis will be based on a mixed effect model (MMRM) of repeated measures, with the change from baseline in the weekly average of the daily pain intensity scores as a dependent variable; and the fixed effects of treatment group, time (class), treatment group-to-time interactions, baseline weekly averages of daily pain intensity, and baseline weekly averages of daily pain intensity-to-time interactions. The Least Squares (LS) mean change from baseline for each group at week 12 will be presented with the corresponding SE and the corresponding 95% confidence interval and P value. This study was not used for comparison between compound 1 dose and pregabalin reference group. Additional analysis of primary endpoints will be performed based on the same MMRM as described above to estimate the mean difference between each compound 1 dose and pregabalin. Differences in LS mean from baseline changes in Shi Purui balms at week 12 will be presented with corresponding 80% confidence intervals. The proportion of subjects whose weekly average decrease in daily pain intensity by > 30% at week 12 of NPRS will be summarized descriptive by treatment group and analyzed using the Cochran-Mantel-Hanzel test (stratified by gender and BMI). The proportion of subjects decreasing by > 50% and > 70% will be analyzed similarly. The proportion of subjects categorized as improved according to PGIC assessment at week 12 will be summarized descriptive by treatment group and analyzed using the Cochran-Mantel-Hanzel test (stratified by gender and BMI). The change in weekly averages of DSIS at week 12 from baseline will be analyzed similarly to the primary endpoint. The change in weekly NPRS pain scores from baseline will be analyzed using MMRM in a similar manner to the primary analysis. Changes in NPSI, SF-36, SF-MPQ-2, and BDI-2 from baseline at week 12 will be analyzed by an analysis of covariance (ANOVA) model. The use of rescue medication will be summarized descriptively by the percentage of subjects using rescue medication and the total medication usage. No statistical test is performed on the security endpoint.
Security results
Safety assessments include adverse events, clinical laboratory assessments, clinical assessments of vital signs, electrocardiography, physical examination, and C-SSRS. Safety and tolerability based on the incidence and type of adverse events, clinically significant laboratory test results at each visit, vital signs, and changes in ECG from baseline can be used for secondary endpoint analysis.
Example 8SDD tablet Process
The spray-dried dispersion (SDD) of compound 1, microcrystalline cellulose and croscarmellose sodium were weighed and sieved. The bulk (SDD), microcrystalline cellulose and croscarmellose sodium were weighed and sieved. The sieved material is then added to a box mixer and blended to form an intra-granular (IG) mixture. The magnesium stearate was weighed and sieved. The sieved magnesium stearate is then added to the IG mixture and the resulting IG blend is dry granulated using a roller compactor and an in-line mill to produce abrasive particles.
Microcrystalline cellulose and croscarmellose sodium (for extra-granular (EG) mixtures) were weighed and sieved. The sieved material was added to a box mixer containing abrasive particles and the resulting mixture was blended to form an EG mixture. The magnesium stearate was weighed and sieved. The sieved magnesium stearate is then added to the EG blend, which is further mixed. The resulting blend was compressed using a tablet press into tablets containing an equivalent amount of 50mg of compound 1. The tablets were then film coated using an Opadry blue (85F 105173).
Tablets of the present disclosure were prepared according to this method, including the tablets described in tables 6, 7 and the tablets of example 3.
Example 9: predictive SDD tablet process
Compound 1 spray-dried dispersion (SDD), microcrystalline cellulose and croscarmellose sodium, which can be prepared according to example 3, were weighed and sieved. The sieved material is then added to a box mixer and blended to form an intra-granular (IG) mixture. The magnesium stearate was weighed and sieved. The sieved magnesium stearate is then added to the IG mixture and the resulting IG blend is dry granulated using a roller compactor and an in-line mill to produce abrasive particles.
Microcrystalline cellulose and croscarmellose sodium (for extra-granular (EG) mixtures) were weighed and sieved. The sieved material was added to a box mixer containing abrasive particles and the resulting mixture was blended to form an EG mixture. The magnesium stearate was weighed and sieved. The sieved magnesium stearate is then added to the EG blend, which is further mixed. The resulting blend was compressed using a tablet press into tablets containing the desired amount of compound 1. The tablets are then optionally film coated.
Tablets of the present disclosure, including those described in tables 6, 7 and 8 of example 3, can be prepared according to this method.
It will be apparent to those skilled in the art that many modifications and variations can be made to the embodiments described herein without departing from the scope. The specific embodiments described herein are offered by way of example only.

Claims (28)

1. A method of treating pain or lessening the severity of pain in a subject, said method comprising administering compound 1 to said subject in an amount of from about 10mg to about 300mg per day, optionally in an amount of from about 20mg to 200mg per day,
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10mg to about 300mg on the first day, optionally in an amount of about 20mg to about 200mg on the first day, optionally in an amount of about 20mg to about 30mg on the first day, optionally in an amount of about 60mg to about 90mg on the first day, optionally in an amount of about 100mg to about 150mg on the first day, optionally in an amount of about 5mg to about 200mg per day after the first day.
3. The method of any one of claims 1-2, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered at two doses per day, or at a first dose and a subsequent dose on the first day, wherein the first dose is greater than the subsequent dose, optionally wherein the subsequent dose is administered 12 hours after the first dose.
4. The method of claim 3, wherein the first dose is about 20mg to about 100mg, optionally the first dose is about 20mg, or optionally wherein the first dose is about 60mg, or wherein the first dose is about 100mg.
5. The method of any one of claims 3 to 4, wherein the subsequent dose is from about 10mg to about 100mg, or wherein the subsequent dose is from about 10mg to about 50mg, or wherein the subsequent dose is about 10mg, or wherein the subsequent dose is about 30mg, or wherein the subsequent dose is about 50mg.
6. The method of any one of claims 2 to 5, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered at two doses per day after the first day, or at two doses of about 10mg to 50mg per day after the first day, or at two doses of about 10mg per day after the first day, or at two doses of about 30mg per day after the first day, or at two doses of about 50mg per day after the first day.
7. The method of claim 6, wherein a period of 12 hours passes between administration of each of the two doses.
8. The method of claim 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at one dose per day.
9. The method of any one of claims 1 to 8, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least 1 week, or at least 6 weeks, or at least two days.
10. The method of any one of claims 1 to 9, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered orally or intravenously.
11. The method of any one of claims 1 to 10, wherein the pain comprises chronic pain; intestinal pain; neuropathic pain, optionally post-herpetic neuralgia; small fiber neuropathy; idiopathic small fiber neuropathy; diabetic neuropathy or diabetic peripheral neuropathy; musculoskeletal pain, optionally osteoarthritis pain; acute pain, optionally acute postoperative pain; inflammatory pain; cancer pain; idiopathic pain; postoperative pain, optionally bunion excision pain, abdominal wall plastic pain or hernia repair pain; or visceral pain, optionally wherein the pain is associated with multiple sclerosis, xia Matu trise syndrome, incontinence, pathological cough or arrhythmia.
12. The method of any one of claims 1 to 11, wherein the subject has a baseline pain score of at least 4 according to the 11-point digital pain rating scale prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
13. The method of any one of claims 1 to 11, wherein the subject has a baseline pain level of moderate or severe according to a speech classification rating scale prior to administration of compound 1 or a pharmaceutically acceptable salt thereof.
14. The method of any one of claims 1 to 13, wherein the method comprises administering to the subject compound 1 in non-salt form.
15. The method of any one of claims 1 to 14, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously, prior to, or after treatment with the compound or pharmaceutically acceptable salt.
16. Use of compound 1 or a pharmaceutically acceptable salt thereof as a medicament in any of the foregoing methods.
17. A solid dispersion, the solid dispersion comprising:
(2R, 3S,4S, 5R) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; and
at least one polymer.
18. The solid dispersion of claim 17, wherein compound 1 or a pharmaceutically acceptable salt thereof and the polymer are co-spray dried with a solvent, optionally wherein the polymer is selected from the group consisting of: hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof, optionally wherein the polymer is HPMCAS.
19. The solid dispersion of any one of claims 17 to 18, wherein the solid dispersion comprises:
about 20% to about 50% by weight of compound 1 or a pharmaceutically acceptable salt thereof; and from about 50% to about 80% by weight of said polymer,
optionally about 25% by weight of compound 1 or a pharmaceutically acceptable salt thereof; and
optionally about 75% by weight of the polymer.
20. The solid dispersion of any one of claims 17 to 19, wherein compound 1 is substantially amorphous.
21. A pharmaceutical composition comprising the solid dispersion of any one of claims 17 to 20, optionally wherein the pharmaceutical composition is a tablet.
22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition further comprises one or more excipients selected from the group consisting of: optionally 72.5 wt% of at least one filler, optionally 4.5 wt% of at least one disintegrant, optionally 3 wt% of at least one lubricant, and any combination thereof.
23. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition further comprises at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant.
24. The pharmaceutical composition of claim 22, wherein the filler is selected from the group consisting of: microcrystalline cellulose, lactose monohydrate, mannitol, and any combination thereof;
optionally wherein the disintegrant is selected from: croscarmellose sodium, crospovidone, and any combination thereof;
optionally wherein the lubricant is selected from: sodium stearyl fumarate, magnesium stearate, and any combination thereof;
optionally wherein the filler comprises microcrystalline cellulose and lactose monohydrate and the disintegrant comprises croscarmellose sodium, and wherein the lubricant comprises sodium stearyl fumarate.
25. The pharmaceutical composition of any one of claims 21 to 24, wherein the pharmaceutical composition comprises about 1 to about 50mg, optionally about 10mg, of compound 1 or a pharmaceutically acceptable salt thereof.
26. The method of any one of claims 1 to 15, wherein administering compound 1 or a pharmaceutically acceptable salt thereof to the subject comprises administering the pharmaceutical composition of any one of claims 21 to 25.
27. The method of claim 1, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 150mg on the first day.
28. The method of claim 1, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20mg to about 100mg on the first day.
CN202280052433.4A 2021-06-04 2022-06-03 Solid dosage forms and dosing regimens comprising (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide Pending CN117794537A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US63/196,933 2021-06-04
US63/196,937 2021-06-04
US202163285201P 2021-12-02 2021-12-02
US63/285,201 2021-12-02
US63/285,197 2021-12-02
PCT/US2022/032253 WO2022256708A1 (en) 2021-06-04 2022-06-03 Solid dosage forms and dosing regimens comprising (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

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CN117794537A true CN117794537A (en) 2024-03-29

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CN202280052433.4A Pending CN117794537A (en) 2021-06-04 2022-06-03 Solid dosage forms and dosing regimens comprising (2 r,3s,4s,5 r) -4- [ [3- (3, 4-difluoro-2-methoxy-phenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carbonyl ] amino ] pyridine-2-carboxamide

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