Formulations of voltage-gated sodium channel inhibitors and methods of making the same

Abstract

Formulations of voltage-gated sodium channel inhibitors and methods of making the same, the present invention relates to solid dispersions and methods of making the same, wherein the solid dispersions comprise a compound of formula (I), an enantiomer thereof, or a pharmaceutically acceptable salt thereof, and a polymeric carrier. The present invention further relates to solid dispersion compositions comprising the solid dispersions and excipients.(I)

Description

Technical Field

[0001] This invention relates to solid dispersions of compounds used as voltage-gated sodium channel inhibitors, oral formulations containing the same, methods of their preparation, and their use in treating diseases. Background Technology

[0002] Studies have shown that alterations in ion channels are the molecular basis for peripheral sensitization, central sensitization, and disinhibition following inflammation or neuropathological injury, and are also an important molecular mechanism in the development of pain. Currently, Nav inhibitors have proven effective; for example, the local anesthetic lidocaine relieves pain by inhibiting Nav, and non-selective Nav inhibitors such as lamotrigine, lacocillin, and mexiletine have been successfully used to treat chronic pain. However, currently used Nav inhibitors lack subtype selectivity, inhibiting sodium ion channels expressed in the heart and central nervous system, resulting in a narrow therapeutic window and limited application.

[0003] Highly selective Nav inhibitors are one of the key research directions for voltage-gated sodium ion channels. Nav1.8 is mainly distributed in the peripheral nervous system and is limited to pain-sensing neurons, making it a highly selective target for pain treatment. Therefore, selectively inhibiting Nav1.8 shows good promise in reducing potential toxic side effects.

[0004] Nav1.8 is a subtype of voltage-gated sodium channels (VGSC / Nav).

[0005] NaV1.8 participates in the conduction and transmission of nociceptive action potentials. Due to its dependence on depolarization voltage, NaV1.8 is the main mediator during the rising phase of the action potential. Furthermore, NaV1.8's rapid recovery from inactivation also contributes to repetitive high-frequency firing. Inhibiting NaV1.8 activity can block the transmission of pain signals. Since NaV1.8 is mainly expressed in neurons transmitting pain signals in the dorsal root ganglia (DRG) of the peripheral nervous system, selective inhibition of NaV1.8 can also effectively reduce potential toxic side effects.

[0006] This invention develops solid dispersions containing compounds used as voltage-gated sodium channel inhibitors and their oral formulations to improve the solubility, stability, processability, and bioavailability of the compounds. Summary of the Invention

[0007] In one aspect, the present invention provides an oral formulation of a compound used as a voltage-gated sodium channel inhibitor, the formulation comprising a solid dispersion of the compound and an excipient.

[0008] In one aspect, the present invention provides a solid dispersion of a compound used as a voltage-gated sodium channel inhibitor, and provides the composition of the solid dispersion, a method for its preparation, and a type of polymer carrier.

[0009] In one aspect, the present invention provides a composition comprising the solid dispersion of the present invention and an excipient.

[0010] In one aspect, the present invention provides methods and uses for treating diseases using the oral formulation, solid dispersion, or solid dispersion composition.

[0011] In one aspect, the present invention provides a solid dispersion comprising a compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof and a polymeric carrier:

[0012] (I), (Ia), (Ib).

[0013] In one respect, the compound is substantially amorphous.

[0014] Other objects of the present invention will become apparent to those skilled in the art through the context and through the examples.

[0015] The dispersions of the present invention and formulations containing them have excellent solubility, stability, processability and bioavailability. Invention Details

[0017] definition

[0018] As used herein, the term "about" includes a specified amount or a range of values ​​that are recognized by those skilled 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 in a particular value as determined by those skilled 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 implementations, the term "about" means within 0.5% of a given value or range.

[0019] wt% (weight %) represents the percentage of the total weight of the solid dispersion.

[0020] Solid dispersions (SDs) are dispersion systems in which a drug is highly dispersed in a solid carrier, existing in solid form. The drug exists in the carrier in molecular, colloidal, microcrystalline, amorphous, or mixed forms. Types of solid dispersions include: eutectic mixtures; solid solutions (including continuous and discontinuous solutions); substitutional crystallization solutions; interstitial crystallization solutions; amorphous solid solutions; glass solutions; and glass suspensions.

[0021] As used herein, the term "amorphous" refers to a solid material that does not possess long-range order in its molecular positions. The molecules in an amorphous solid are typically arranged randomly, without a defined order. Amorphous solids are generally isotropic, meaning they exhibit similar properties in all directions and do not have a definite 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., it is not crystalline as determined by XRPD). Instead, one or more broad peaks appear in its XRPD pattern.

[0022] The term "effective amount" or "therapeutic effective amount" refers to an amount of reagent sufficient to provide a desired biological outcome. This outcome may be a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, "effective amount" for therapeutic use refers to an amount of composition comprising the compound that is the active ingredient of the invention, which is clinically necessary to significantly reduce disease. In any case, an appropriate "effective" amount can be determined by a person skilled in the art using conventional experiments. Therefore, the expression "effective amount" generally refers to the amount at which the active substance has a therapeutic effect.

[0023] The terms "treat" or "treatment" as used in this application are synonymous with the term "prevent" and are intended to indicate delaying the development of a disease, preventing the development of a disease, and / or reducing the severity of said symptoms that will develop or are expected to develop. Therefore, these terms include improving existing disease symptoms, preventing additional symptoms, improving or preventing the underlying metabolic causes of symptoms, inhibiting a disorder or disease, for example, preventing the development of a disorder or disease, alleviating a disorder or disease, regressing a disorder or disease, reducing symptoms caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

[0024] "Pharmaceutical" means a substance that is not biologically or otherwise substantially undesirable, that is, a substance that can be administered to an individual without causing any undesirable biological effects or interacting in a harmful manner with any component of a composition containing such a substance.

[0025] The term "subject" as used in this application includes both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the invention, the mammal is a human.

[0026] Compounds that serve as voltage-gated sodium channel inhibitors and are active ingredients of the present invention can form salts. Unless otherwise stated, references to the presence of said compounds in this application should be understood to include references to their salts. The term "salt (one or more)" as used in this application refers to acidic salts formed with inorganic and / or organic acids and basic salts formed with inorganic and / or organic bases. Additionally, when said compounds contain a basic moiety (e.g., but not limited to, pyridine or imidazole) and an acidic moiety (e.g., but not limited to, carboxylic acid), zwitterions ("internal salts") can be formed, and said zwitterions ("internal salts") are included in the term "salt (one or more)" as used in this application. Pharmaceutical (i.e., non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful. Salts containing said compounds can be formed, for example, by reacting said compounds with a certain amount (e.g., an equal amount) of acid or base in a medium, said medium being, for example, a medium in which the salt precipitates or an aqueous medium (lyophilized after reaction).

[0027] Polymorphic forms of compounds, their salts, solvates, esters, and prodrugs are intended to be included in this invention.

[0028] Cyclodextrins and their derivatives are a class of functional excipients that improve the solubility and bioavailability of poorly soluble drug molecules by encapsulating them (forming inclusion complexes). Cyclodextrins include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, and their derivatives include sulfobutyl ether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-modified β-cyclodextrin, and carboxymethyl-β-cyclodextrin.

[0029] Eudragit is a trade name for synthetic pharmaceutical excipients, including methacrylic acid copolymers and methacrylate copolymers, commonly known as polyacrylic acid resins. Polyacrylic acid resin excipients are classified into different types according to their composition, proportions, and degree of polymerization. Specifically, Eudragit E is a polymer of dimethylaminoethyl methacrylate and methacrylate; Eudragit L is a polymer of methacrylic acid and methyl methacrylate with a free carboxyl group:ester ratio of 1:1; Eudragit S is a polymer of methacrylic acid and methyl methacrylate with a free carboxyl group:ester ratio of 1:2; Eudragit RL is a polymer of acrylic acid and methacrylate containing 10% quaternary ammonium groups; and Eudragit RS is a polymer of acrylic acid and methacrylate containing 5% quaternary ammonium groups. Specifically, the Eudragit polymer carrier is selected from Eudragit L100, Eudragit S 100, Eudragit E PO, Eudragit E 100, or Eudragit L 100-55.

[0030] Hydroxypropyl methylcellulose acetate succinate, abbreviated as HPMCAS, is classified into L (LF / LG), M (MF / MG), and H (HF / HG) grades, differing in the ratio of acetyl (Ac) and succinyl (Su): MG type: balanced solubility and film-forming properties (Ac: 8-11%, Su: 14-18%); LF / LG type: low acetyl (Ac: 7-10%, Su: 12-15%); HF / HG type: high acetyl (10-14%, Su: 10-15%).

[0031] As used herein and unless otherwise stated, the terms “daily” and “total daily dose” when referring to the amount of the compound or its pharmaceutically acceptable salt administered to a subject mean the amount of the compound or its pharmaceutically acceptable salt administered to the subject over at least one 24-hour period during treatment. Unless otherwise stated, it should be understood that the compound or its pharmaceutically acceptable salt may be administered to the subject in different amounts on one or more other days during treatment.

[0032] It should be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting. Furthermore, although any methods, apparatus, and materials similar to or equivalent to those described herein may be used in the practice or testing of the invention, preferred methods, apparatus, and materials are now described.

[0033] The dosage of the compound, which is the active ingredient of the present invention, depends on many factors, such as the route of administration, the age and weight of the subject, and the condition of the patient to be treated, and will ultimately be determined by the attending physician or veterinarian. Such an amount of the active compound, determined by the attending physician or veterinarian, is referred to herein and in the claims as a “therapeutic effective amount.” For example, the dosage of the compound is typically in the range of about 1 to about 1000 mg / day. Preferably, the therapeutic effective amount is about 1 mg to about 500 mg / day.

[0034] Spray drying is a method of drying liquid materials using fluidization technology. The basic principle is that a liquid material system (solution, suspension, emulsion, etc.) is atomized by gas in a drying tower (chamber). Upon contact with hot air, the water (solvent) rapidly vaporizes, resulting in a dried powder product. This method can directly and rapidly dry solutions, suspensions, emulsions, etc., into powder or granular products, eliminating the need for evaporation and pulverization processes.

[0035] Spray drying methods include pressure spray drying, centrifugal spray drying, and airflow spray drying.

[0036] (1) Pressure spray drying method:

[0037] Principle: Using a high-pressure pump, the material is atomized into 10-200 microns at a pressure of 70-200 atmospheres and brought into direct contact with hot air for heat exchange, thus completing the drying process in a short time.

[0038] (2) Centrifugal spray drying method:

[0039] Principle: A horizontally rotating disk at high speed applies centrifugal force to the solution, causing it to be ejected at high speed, forming a thin film, filaments, or droplets. Due to friction, obstruction, and tearing effects from the air, the tangential acceleration generated by the disk's rotation and the radial acceleration generated by centrifugal force result in a combined velocity as the liquid moves along the disk in a spiral trajectory. After being ejected from the disk along this spiral, the liquid disperses into very small droplets that move at an average speed along the tangential direction of the disk. Simultaneously, the droplets are pulled down by gravity. Because the sprayed particles vary in size, their flight distances also differ. Therefore, the particles falling at different distances form a cylinder symmetrical about the axis of rotation.

[0040] (3) Airflow spray drying method:

[0041] Principle: Wet materials are conveyed and heated natural air enters the dryer simultaneously. The two are fully mixed, and due to the large heat and mass exchange area, the purpose of evaporation and drying is achieved in a very short time.

[0042] Spray drying is widely used in the food industry (e.g., milk powder), pharmaceutical industry (drying traditional Chinese medicine, preparing solid dispersions, reducing particle size, etc.), chemical industry, plastics industry, and ceramics production.

[0043] The techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th edition, edited by R.P. Perry, D.W. Green & J.O. Maloney, McGraw-Hill book co. (1984); and Marshall, “Atomization and Spray-Drying”, 50, Chem. Eng. Prog. Monogr. Series 2 (1954). All three references are incorporated herein by reference in their entirety.

[0044] Additional drying steps may be required after spray drying to ensure solvent removal. Other drying techniques include, but are not limited to, disc drying, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying, microwave drying, drum drying, or double-cone vacuum drying (e.g., from about room temperature to about 200°C).

[0045] The solvents used in spray drying are volatile solvents. For example, volatile solvents may have a boiling point below 100°C. Mixtures of volatile solvents or mixtures of volatile and non-volatile solvents may be used.

[0046] Exemplary testable solvents include acetone, cyclohexane, dichloromethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolinone (DMI), dimethyl sulfoxide (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, anhydrous ethanol, isopropanol, isobutanol, isopropyl acetate, n-hexane, dichloromethane, benzene, and toluene. In a dual-solvent system, the solvent may be present from about 0.1% to about 99.9%. In some embodiments, methanol and dichloromethane are co-solvents in a volume ratio of 1:2 to 2:1, for example, 1:2, 1:1, or 2:1. Attached Figure Description

[0047] Figure 1 This is a process flow diagram for the production of solid dispersions.

[0048] Figure 2 This is a flowchart of the tablet manufacturing process.

[0049] Figure 3This is the XRPD diagram of the amorphous (Ia) compound.

[0050] Figure 4 The image shows the XRPD plot of solid dispersion 1.

[0051] Figure 5 The image shows the XRPD plot of solid dispersion 2.

[0052] Figure 6 The image shows the XRPD plot of solid dispersion 3.

[0053] Figure 7 The image shows the XRPD plot of solid dispersion 4.

[0054] Figure 8 The image shows the XRPD plot of solid dispersion 5.

[0055] Figure 9 The image shows the XRPD plot of solid dispersion 6.

[0056] Figure 10 The image shows the XRPD plot of solid dispersion 7.

[0057] Figure 11 Dissolution diagram for 10mg (coated tablets) process optimization.

[0058] Figure 12 A comparison chart of dissolution during the process study of 50mg (coated tablets). Detailed Implementation

[0059] This invention relates to solid dispersions of compounds used as voltage-gated sodium channel inhibitors, and oral formulations containing the same. Specifically, the invention develops solid dispersions of compounds containing formula (I) or their enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof, and oral formulations thereof.

[0060] In one embodiment, the present invention provides a solid dispersion comprising:

[0061] (1) A compound of formula (I) or its enantiomer (Ia) or enantiomer (Ib) or pharmaceutically acceptable salt thereof:

[0062] (I), (Ia), (Ib); and

[0063] (2) Polymer carrier.

[0064] In one embodiment, the compound in the solid dispersion of the present invention is (R)-5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the compound in the solid dispersion of the present invention is of formula (Ia):

[0066] (Ia).

[0067] In one embodiment, the compound in the solid dispersion of the present invention is substantially amorphous.

[0068] In one embodiment, the polymer carrier in the solid dispersion of the present invention is selected from cyclodextrins and their derivatives, polyethylene glycols, polyvinylpyrrolidone, Eudragit, copolyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, and any combination thereof.

[0069] In one embodiment, the polymer carrier in the solid dispersion of the present invention is a cyclodextrin and its derivatives, preferably selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-modified β-cyclodextrin and carboxymethyl-β-cyclodextrin; preferably hydroxypropyl-β-cyclodextrin.

[0070] In one embodiment, the weight ratio of the compound in the solid dispersion of the present invention to the polymer carrier is 1:20 to 20:1.

[0071] In one embodiment, the weight ratio of the compound to the polymer carrier in the solid dispersion of the present invention is 1:19 to 19:1, 1:15 to 15:1, 1:10 to 10:1, 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, 4:5 to 5:4, 5:6 to 6:5, or 1:1. Preferably, the weight ratio of the compound to the polymer carrier is 1:9.

[0072] In one embodiment, the compound in the solid dispersion of the present invention is present in an amount of about 1% to about 99% by weight, about 5% to about 95% by weight, about 10% to about 90% by weight, about 20% to about 80% by weight, about 30% to about 70% by weight, about 40% to about 60% by weight, or about 10% to about 20% by weight; preferably, the compound is present in an amount of about 10% by weight.

[0073] In one embodiment, the solid dispersion of the present invention is prepared by a method selected from: melt drying, solvent drying, solvent-melt drying, spray drying, freeze drying, grinding, and hot melt extrusion. In a further embodiment, the solid dispersion of the present invention is prepared by spray drying.

[0074] In one embodiment, the present invention provides a composition of the solid dispersion and excipients of the present invention.

[0075] In one embodiment, the excipient in the composition of the present invention is selected from one or more of fillers, disintegrants, disintegration aids, surfactants, and lubricants.

[0076] In one embodiment, the filler in the composition of the present invention is selected from microcrystalline cellulose, lactose, mannitol, sodium bicarbonate, and any combination thereof; the disintegrant is selected from crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and any combination thereof; the disintegration aid is selected from anhydrous citric acid, sodium chloride, and any combination thereof; the surfactant is sodium dodecyl sulfate; and the lubricant is selected from magnesium stearate, sodium stearoyl fumarate, and any combination thereof.

[0077] In one embodiment, the solid dispersion in the composition of the present invention is present in an amount of about 1% to about 99% by weight; preferably about 10% to about 90% by weight; preferably about 20% to about 80% by weight; preferably about 30% to about 70% by weight; preferably about 40% to about 60% by weight; preferably about 40%, about 45.5% by weight, about 50% by weight, about 55.5% by weight, or about 60% by weight.

[0078] In one embodiment, the present invention provides an oral formulation comprising the solid dispersion or composition described herein. In a further embodiment, the oral formulation is selected from tablets, capsules, granules, powders, lozenges, and pills.

[0079] In one embodiment, the present invention provides a tablet comprising the solid dispersion described herein and one or more excipients selected from fillers, disintegrants, disintegration aids, surfactants, and lubricants.

[0080] In one embodiment, the present invention provides a tablet comprising about 1% to about 99% by weight of the solid dispersion, about 1% to about 99% by weight of a filler, about 0.5% to about 20% by weight of a disintegrant, about 0% to about 5% by weight of a disintegrating agent, about 0% to about 5% by weight of a surfactant, and about 0.25% to about 5% by weight of a lubricant. In a further embodiment, the filler is selected from microcrystalline cellulose, lactose, mannitol, sodium bicarbonate, and any combination thereof, preferably lactose or mannitol, or mixtures thereof; the disintegrant is selected from crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and any combination thereof, preferably crospovidone sodium carboxymethyl cellulose; the disintegrating agent is selected from anhydrous citric acid, sodium chloride, and any combination thereof; the surfactant is sodium dodecyl sulfate; and the lubricant is selected from magnesium stearate, sodium stearoyl fumarate, and any combination thereof, preferably magnesium stearate.

[0081] In one embodiment, the present invention provides a tablet in which the content of the compound in a unit tablet is from about 1 mg to about 200 mg, from about 2 mg to about 150 mg, from about 2.5 mg to about 150 mg, from about 5 mg to about 150 mg, from about 5 mg to about 100 mg, or from about 10 mg to about 50 mg, preferably 10 mg or 50 mg; preferably, the compound is a compound of formula (Ia).

[0082] In a further embodiment, the tablet is a coated tablet. In one embodiment, the coating agent is selected from: sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, gelatin, pharmaceutical enamel, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein, and omeprazole; preferably, the coating agent is a gastrointestinal coating agent.

[0083] In one embodiment, the present invention provides a unit tablet comprising about 50.0 mg to about 1000.0 mg of the solid dispersion, about 20.0 mg to about 80.0 mg of lactose, about 20.0 mg to about 80.0 mg of mannitol, about 5 mg to about 50.0 mg of croscarmellose sodium, about 1.0 mg to about 10.0 mg of magnesium stearate and about 1 mg to about 20.0 mg of coating agent, wherein the content of the compound in the solid dispersion is about 10% to about 20% by weight, preferably the compound is a compound of formula (Ia).

[0084] In one embodiment, the present invention provides a unit tablet comprising about 100.0 mg of the solid dispersion, about 40.0 mg of lactose, about 40 mg of mannitol, about 16.0 mg of croscarmellose sodium, about 4.0 mg of magnesium stearate and about 7.0 mg of coating agent, wherein the content of the compound in the solid dispersion is about 10% by weight, preferably the compound is a compound of formula (Ia).

[0085] In one embodiment, the present invention provides a unit tablet comprising about 500.0 mg of the solid dispersion, about 200.0 mg of lactose, about 200.0 mg of mannitol, about 80.0 mg of croscarmellose sodium, about 20.0 mg of magnesium stearate and about 35.0 mg of coating agent, wherein the content of the compound in the solid dispersion is about 10% by weight, preferably the compound is a compound of formula (Ia).

[0086] In one embodiment, the present invention provides the use of the solid dispersion, composition, oral formulation, or tablet of the present invention in the preparation of a medicament used as a voltage-gated sodium channel inhibitor; preferably, the voltage-gated sodium channel inhibitor is a sodium ion channel 1.8 (NaV1.8) inhibitor; preferably, the voltage-gated sodium channel inhibitor is used to treat diseases selected from: acute, chronic, neurogenic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or epilepsy syndrome, neurodegenerative diseases, mental disorders such as anxiety and depression, bipolar disorder, myotonia, arrhythmia, and exercise. Movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetrating pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal activity; preferably, the diseases are selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain.

[0087] In one embodiment, the present invention provides a method for treating a subject for a disease mediated by voltage-gated sodium channels, preferably by sodium ion channels 1.8 (NaV1.8), comprising administering to the patient a therapeutically effective amount of the solid dispersion, composition, oral formulation, or tablet of the present invention, preferably wherein said disease is selected from acute, chronic, neurogenic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or epilepsy syndrome, neurodegenerative diseases, mental disorders such as anxiety and depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders. Disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetrating pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal activity; preferably, the diseases are selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain.

[0088] In one embodiment, the present invention provides the above-described solid dispersion, composition, oral formulation, or tablet for treating a subject with a disease mediated by a voltage-gated sodium channel, preferably a disease mediated by sodium ion channel 1.8 (NaV1.8), preferably, wherein said disease is selected from: acute, chronic, neurogenic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or epilepsy syndrome, neurodegenerative diseases, mental disorders such as anxiety and depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, etc. Multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetrating pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal activity; preferably, the diseases are selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain.

[0089] In one embodiment, the present invention provides a method for preparing a solid dispersion as described herein, selected from melting, solvent, solvent-melt, spray drying, freeze drying, and grinding methods, preferably spray drying.

[0090] In one embodiment, the present invention provides a method for preparing a solid dispersion as described herein, comprising the following steps:

[0091] (1) Preparing a spray-drying solution, comprising dissolving the polymer carrier and the compound in a solvent;

[0092] (2) Spray drying,

[0093] The solvent is selected from anhydrous ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene, and toluene, or mixtures thereof, or mixtures thereof with water.

[0094] In one embodiment, the present invention provides a method for preparing an oral formulation as described herein, comprising wet granulation or dry granulation. In a further embodiment, the oral formulation is prepared by dry granulation.

[0095] In one embodiment, the present invention provides a method for preparing a tablet as described herein, comprising the following steps:

[0096] (1) Premix the solid dispersion and a portion of the excipient;

[0097] (2) Dry granulation;

[0098] (3) Add the remaining excipients and mix;

[0099] (4) Add lubricant;

[0100] (5) Tableting; and

[0101] (6) Coating.

[0102] In one embodiment, the present invention provides a method for treating a subject's pain or reducing its severity, the method comprising administering to the subject a compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions thereof in an amount equivalent to about 10 mg to about 600 mg per day, optionally in an amount equivalent to about 20 mg to 300 mg per day.

[0103] In one embodiment, the present invention provides a method for treating pain in a subject or reducing its severity, wherein on the first day, an amount equivalent to about 10 mg to about 600 mg of the compound of formula (I) is administered, optionally on the first day, an amount equivalent to about 20 mg to about 300 mg of the compound of formula (I) is administered, optionally on the first day, an amount equivalent to about 20 mg to about 30 mg of the compound of formula (I) is administered, optionally on the first day, an amount equivalent to about 60 mg to about 90 mg of the compound of formula (I) is administered, optionally on the first day, an amount equivalent to about 100 mg to about 150 mg of the compound of formula (I) is administered, optionally after said first day, an amount equivalent to about 5 mg to about 200 mg of the compound of formula (I) is administered daily, consisting of the compound of formula (I) or its enantiomers (Ia) or (Ib), or pharmaceutically acceptable salts thereof or solid dispersions comprising them.

[0104] In one embodiment, the present invention provides a method for treating a subject’s pain or reducing its severity, wherein a compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions containing them are administered daily at two doses, or on the first day at a first dose and a subsequent dose, wherein the first dose is greater than the subsequent dose, optionally wherein the subsequent dose is administered 12 hours after the first dose.

[0105] In a further embodiment, the first dose is equivalent to about 20 mg to about 100 mg of a compound of formula (I), optionally the first dose is equivalent to about 20 mg of a compound of formula (I), or optionally the first dose is equivalent to about 60 mg of a compound of formula (I), or the first dose is equivalent to about 100 mg of a compound of formula (I) of formula (I) or its enantiomers of formula (Ia) or enantiomers of formula (Ib) or their pharmaceutically acceptable salts or solid dispersions containing them.

[0106] In a further embodiment, the subsequent dose is a compound of formula (I) equivalent to about 10 mg to about 100 mg, or the subsequent dose is a compound of formula (I) equivalent to about 10 mg to about 50 mg, or the subsequent dose is a compound of formula (I) equivalent to about 10 mg, or the subsequent dose is a compound of formula (I) equivalent to about 30 mg, or the subsequent dose is a compound of formula (I) equivalent to about 50 mg, or an enantiomer of formula (Ia) or enantiomer of formula (Ib) or their pharmaceutically acceptable salts or solid dispersions comprising them.

[0107] In a further embodiment, the compound of formula (I) or its enantiomers (Ia) or (Ib), or pharmaceutically acceptable salts thereof, or solid dispersions comprising them, are administered at two doses daily after the first day, or at two doses daily equivalent to about 10 mg to 50 mg of the compound of formula (I) after the first day, or at two doses daily equivalent to about 30 mg of the compound of formula (I) after the first day, or at two doses daily equivalent to about 50 mg of the compound of formula (I) after the first day. In a further embodiment, a 12-hour period is elapsed between each of the two doses administered.

[0108] In one embodiment, the present invention provides a method for treating a subject’s pain or reducing its severity, wherein a compound of formula (I) or its enantiomers of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions comprising them are administered at a daily dose.

[0109] In one embodiment, the present invention provides a method for treating a subject’s pain or reducing its severity, wherein a compound of formula (I) or its enantiomer (Ia) or enantiomer (Ib) or their pharmaceutically acceptable salts or solid dispersions comprising them are administered for at least one week, or at least six weeks, or at least two days.

[0110] In one embodiment, the present invention provides a method for treating a subject’s pain or reducing its severity, wherein a compound of formula (I) or its enantiomer (Ia) or enantiomer (Ib) or a pharmaceutically acceptable salt thereof or a solid dispersion comprising thereof is administered orally.

[0111] Dosing regimen

[0112] Any amount of a compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof may be administered to treat pain in a subject or to reduce its severity. In some embodiments, the dosage may be from 20 mg to 5000 mg daily, or from 20 mg to 4500 mg daily, or from 20 mg to 4000 mg daily, or from 20 mg to 3500 mg daily, or from 20 mg to 3000 mg daily, or from 20 mg to 2500 mg daily, or from 20 mg daily. Up to 2000 mg daily, or 20 mg to 1500 mg daily, or 20 mg to 1000 mg daily, or 20 mg to 800 mg daily, or 20 mg to 700 mg daily, or 20 mg to 600 mg daily, or 20 mg to 500 mg daily, or 20 mg to 450 mg daily, or 20 mg to 400 mg daily, or 20 mg to 350 mg daily, or 20 mg to 300 mg daily, or 20 mg to 250 mg daily. g, or 20 mg to 200 mg daily, or 20 mg to 150 mg daily, or 20 mg to 30 mg daily, or 90 mg to 120 mg daily, or 100 mg to 5000 mg daily, or 100 mg to 4500 mg daily, or 100 mg to 4000 mg daily, or 100 mg to 3500 mg daily, or 100 mg to 3000 mg daily, or 100 mg to 2500 mg daily, or 100 mg to 2000mg, or 100mg to 1500mg daily, or 100mg to 1000mg daily, or 100mg to 800mg daily, or 100mg to 600mg daily, or 100mg to 500mg daily, or 100mg to 400mg daily, or 100mg to 300mg daily, or 100mg to 200mg daily, or 100mg to 150mg daily, or 60mg to 2500mg daily, or daily 60mg to 2400mg daily, or 60mg to 2300mg daily, or 60mg to 2200mg daily, or 60mg to 2100mg daily, or 60mg to 2000mg daily, or 60mg to 1900mg daily, or 60mg to 1800mg daily, or 60mg to 1700mg daily, or 60mg to 1200mg daily, or 60mg to 800mg daily, or about 60mg daily, or 60mg to 700mg daily, or 60mg to 600mg daily, or 60mg to 500mg daily, or 60mg to 300mg daily, or 60mg to 200mg daily, or 60mg to 150mg daily, or 60mg to 90mg daily, or about 10mg daily, or about 20mg daily, or aboutApply a compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions thereof in amounts of 23 mg, or about 30 mg, or about 46 mg, or about 50 mg, or about 60 mg, or about 69 mg, or about 70 mg, or about 90 mg, or about 100 mg, or about 150 mg, or about 200 mg per day.

[0113] When administered over multiple days, the compound of formula (I) or its enantiomers (Ia) or (Ib) or their pharmaceutically acceptable salts or solid dispersions containing them may be administered daily in the same or different amounts.

[0114] In some embodiments, a compound of formula (I) or its enantiomers (Ia) or (Ib), or pharmaceutically acceptable salts thereof, or solid dispersions containing the enantiomers, are administered in different amounts on the first day and after the first day. In some embodiments, the dosage on the first day is 10 mg to 3000 mg, or 10 mg to 2000 mg, or 10 mg to 1000 mg, or 10 mg to 500 mg, or 10 mg to 400 mg, or 10 mg to 350 mg, or 10 mg to 300 mg, or 10 mg to 250 mg, or 10 mg... The compound of formula (I) or its enantiomers (Ia) or (Ib) or their pharmaceutically acceptable salts or solid dispersions comprising the thereof may be administered in amounts up to 200 mg, or about 100 mg, or about 150 mg, or about 120 mg, or about 90 mg, or about 30 mg, and after the first day in amounts from 10 mg to 2000 mg daily, or 10 mg to 1500 mg daily, or 10 mg to 1000 mg daily, or 10 mg to 500 mg daily, or 10 mg to 400 mg daily, or 10 mg to 300 mg daily, or 20 mg to 100 mg daily, or about 20 mg daily, or about 60 mg daily, or about 100 mg daily, or about 30 mg daily, or about 20 mg daily, or about 50 mg daily.

[0115] The compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof may be administered by any means known in the art. In some embodiments, the compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions comprising the thereof may be administered orally.

[0116] The compound of formula (I) or its enantiomers (Ia) or (Ib) or their pharmaceutically acceptable salts or solid dispersions containing them may be administered to a subject for any number of days necessary or desired to treat the subject's pain or reduce its severity, depending on the type of pain experienced by the subject. In some embodiments, the compound of formula (I) or its enantiomers (Ia) or (Ib) or their pharmaceutically acceptable salts or solid dispersions containing them are administered for at least two days. In some embodiments, the compound of formula (I) or its enantiomers (Ia) or (Ib) or their pharmaceutically acceptable salts or solid dispersions containing them are 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.

[0117] Pharmaceutically acceptable salts, pharmaceutical compositions, dosage forms and routes of administration

[0118] This article describes compounds of formula (I) or their enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof, administered to a subject.

[0119] As used herein, the term "pharmaceutically acceptable salt" means that, within reasonable medical judgment, it is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of a compound of formula (I) or its enantiomers (Ia) or (Ib) includes any non-toxic salt that, when administered to a recipient, directly or indirectly provides a compound of formula (I) or its enantiomers (Ia) or (Ib) or its inhibitory metabolites or residues (e.g., the parent compound of a prodrug). As used herein, the term "inhibitory metabolites or residues" means that its metabolites or residues are also inhibitors of voltage-gated sodium channels.

[0120] Pharmaceutically acceptable salts of compounds of formula (I) or their enantiomers of formula (Ia) or (Ib) include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate-heptanoate, glycerol phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate-pentanoate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, and ammonium salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate.

[0121] The amount of the compound of formula (I) or its enantiomer of formula (Ia) or enantiomer of formula (Ib) or its pharmaceutically acceptable salt used in the solid dispersion of the present invention may vary from about 1% by weight to about 99% by weight, based on the total weight of the solid dispersion. In one embodiment, the amount of the compound ranges from about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, 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%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%. %, approximately 50% by weight, approximately 51% by weight, approximately 52% by weight, approximately 53% by weight, approximately 54% by weight, approximately 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, approximately 60% by weight, approximately 61% by weight, approximately 62% by weight, approximately 63% by weight, approximately 64% by weight, approximately 65% ​​by weight, approximately 66% by weight, approximately 67% by weight, approximately 68% by weight, approximately 69% by weight, approximately 70% by weight, approximately 71% by weight, approximately 72% by weight, approximately 73% by weight, approximately 74% by weight The dosage is approximately 75% by weight, approximately 76% by weight, approximately 77% by weight, approximately 78% by weight, approximately 79% by weight, approximately 80% by weight, approximately 81% by weight, approximately 82% by weight, approximately 83% by weight, approximately 84% by weight, approximately 85% by weight, approximately 86% by weight, approximately 87% by weight, approximately 88% by weight, approximately 89% by weight, approximately 90% by weight, approximately 91% by weight, approximately 92% by weight, approximately 93% by weight, approximately 94% by weight, approximately 95% by weight, approximately 96% by weight, approximately 97% by weight, approximately 98% by weight, or approximately 99% by weight, or any range therebetween. In one embodiment, the dosage of the glucokinase activator ranges from approximately 1% by weight to approximately 20% by weight. In another embodiment, the dosage of the glucokinase activator ranges from approximately 2% by weight to approximately 40% by weight. In a further embodiment, the dosage of the glucokinase activator ranges from approximately 30% by weight to approximately 60% by weight. In yet another embodiment, the dosage of the glucokinase activator ranges from approximately 60% by weight to approximately 80% by weight. In yet another embodiment, the amount of glucokinase activator ranges from about 70% to about 90% by weight.In yet another embodiment, the amount of glucokinase activator ranges from about 80% by weight to about 100% by weight.

[0122] The amount of polymer carrier used in the solid dispersion of the present invention, based on the total weight of the solid dispersion, can vary from about 1 wt% to about 99 wt%. In one embodiment, the amount of polymer carrier ranges from about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, 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%. Approximately 25% by weight, approximately 26% by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 31% by weight, approximately 32% by weight, approximately 33% by weight, approximately 34% by weight, approximately 35% by weight, approximately 36% by weight, approximately 37% by weight, approximately 38% by weight, approximately 39% by weight, approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, approximately 50% by weight. % by weight, approximately 51% by weight, approximately 52% by weight, approximately 53% by weight, approximately 54% by weight, approximately 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, approximately 60% by weight, approximately 61% by weight, approximately 62% by weight, approximately 63% by weight, approximately 64% by weight, approximately 65% ​​by weight, approximately 66% by weight, approximately 67% by weight, approximately 68% by weight, approximately 69% by weight, approximately 70% by weight, approximately 71% by weight, approximately 72% by weight, approximately 73% by weight, approximately 74% by weight, approximately 75% by weight The amount of polymer carrier ranges from about 76% by weight, about 77% by weight, about 78% by weight, about 79% by weight, about 80% by weight, about 81% by weight, about 82% by weight, about 83% by weight, about 84% by weight, about 85% by weight, about 86% by weight, about 87% by weight, about 88% by weight, about 89% by weight, about 90% by weight, about 91% by weight, about 92% by weight, about 93% by weight, about 94% by weight, about 95% by weight, about 96% by weight, about 97% by weight, about 98% by weight, or about 99% by weight, or any range between these values. In one embodiment, the amount of polymer carrier ranges from about 1% by weight to about 20% by weight. In another embodiment, the amount ranges from about 2% by weight to about 40% by weight. In a further embodiment, the amount ranges from about 30% by weight to about 60% by weight. In yet another embodiment, the amount ranges from about 60% by weight to about 80% by weight. In yet another embodiment, the amount ranges from about 70% by weight to about 90% by weight. In yet another embodiment, the amount ranges from about 80% by weight to about 100% by weight.

[0123] It is understood that examples of other excipients used in the solid dispersion compositions and formulations of the present invention include, but are not limited to: diluents such as tablet and / or capsule diluents; sweeteners or flavorings; antioxidants; surfactants; compatibilizers or fillers or compressors; binders; disintegrants such as tablet disintegrants; lubricants such as tablet and / or capsule lubricants; flow aids / anti-adhesion agents; release modifiers; stabilizers; coating agents; colorants; complexing agents; emulsifiers and / or solubilizers; flavoring agents and fragrances.

[0124] Examples of diluents suitable for use in this invention include, but are not limited to, ω-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose including silicified microcrystalline cellulose SMCC 90, sodium saccharin, glucose, and / or glycine. Furthermore, tablet and / or capsule diluents suitable for use in this invention, in addition to the diluents described above, include, but are not limited to, calcium carbonate, dicalcium phosphate, calcium phosphate, calcium sulfate, cellulose powder, dextran binders, fructose, kaolin, starch, pregelatinized starch, compressible sugars and sugars for confectionery, and combinations thereof.

[0125] Examples of sweeteners or flavorings suitable for use in this invention include, but are not limited to, essential oils, water-soluble extracts, sugars, monosaccharides, oligosaccharides, aldoses, ketoses, dextrose, maltose, lactose, glucose, fructose, sucrose, mannitol, xylitol, D-sorbitol, erythritol, pentitol, hexitol, maltitol, potassium butyrate, sweet protein, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, sodium cyclohexylsulfamate, eugenol formate flavorings, and combinations thereof.

[0126] Examples of antioxidants suitable for use in this invention include, but are not limited to, α-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite, as well as combinations thereof.

[0127] Examples of surfactants suitable for use in this invention include, but are not limited to, salts of alkyl sulfate esters, such as lauryl sulfate diethanolamine salt; alkyl aryl sulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol-oxidized olefin adducts, such as nonylphenol-C18 ethoxylate; alcohol-oxidized olefin adducts, such as tridecyl alcohol-C16 ethoxylate; soaps, such as sodium stearate; alkyl naphthalene-sulfonates, such as sodium dibutylnaphthalenesulfonate; and dialkyl esters of sulfosuccinates, such as di(2-ethylhexyl) Sodium sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary ammonium compounds, such as lauryl methyl ammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; salts of monoalkyl phosphate esters and dialkyl phosphate esters; vegetable oils, such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil, etc.; and esters of the above vegetable oils and combinations thereof.

[0128] Examples of fillers suitable for use in this invention include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose (including microcrystalline cellulose 302 and silicified microcrystalline cellulose SMCC 90), lactose, anhydrous lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol (including mannitol Pearlitol SD 200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin / glucose binders, maltodextrin, compressible sugars and other known compatibilizers or fillers and / or mixtures of two or more of them.

[0129] Examples of adhesives suitable for use in this invention include, but are not limited to, carboxymethyl cellulose (including sodium carboxymethyl cellulose), hydroxypropyl cellulose (including hydroxypropyl cellulose EXF), corn starch, pregelatinized starch, modified corn starch, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) (including hydroxypropyl methylcellulose 2208), lactose, gum arabic, ethyl cellulose, cellulose acetate, and wax adhesives such as carnauba wax, paraffin wax, cetyl wax, polyethylene or microcrystalline wax, and other conventional adhesives and / or mixtures of two or more of them. Furthermore, in addition to the adhesives described above, tablet adhesives suitable for use in this invention also include, but are not limited to, alginate, microcrystalline cellulose, dextrin, gelatin, liquid glucose, guar gum, methylcellulose, polyethylene oxide, povidone, and syrups, and combinations thereof.

[0130] Examples of disintegrants suitable for use in this invention include, but are not limited to, croscarmellose sodium, cropovidone, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and other known disintegrants. Several specific types of disintegrants are suitable for the formulations described in this application. For example, any grade of cropovidone, including, for example, cropovidone XL-10, selected from Kollidon CL®, Polyplasdone XL®, Kollidon CL-M®, Polyplasdone XL-10®, and Polyplasdone INF-10®, can be used. Furthermore, tablet disintegrants suitable for use in this invention, in addition to the above-described disintegrants, include, but are not limited to, alginate, polacolin potassium, sodium starch glycolate, and pregelatinized starch, as well as combinations thereof.

[0131] Examples of lubricants suitable for use in this invention include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitate stearate, palmitic acid, myristic acid, and hydrogenated vegetable oils and fats, as well as other known lubricants and / or mixtures of two or more thereof. Furthermore, tablet and / or capsule lubricants suitable for use in this invention, in addition to the aforementioned lubricants, include, but are not limited to, glyceryl docosanoate, light mineral oil, polyethylene glycol, hard purified stearic acid, and combinations thereof.

[0132] Examples of flow aids and / or anti-adhesion agents suitable for use in this invention include, but are not limited to, silica, colloidal silica, magnesium silicate, magnesium trisilicate, talc and other forms of silica such as aggregated silicates and hydrated silica gel.

[0133] Examples of release modifiers suitable for use in this invention include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylate polymers, hydroxypropyl cellulose, starch, gums, cellulose ethers, protein-derived substances, nylon, acrylic resins, polylactic acid, polyvinyl chloride, polyvinylpyrrolidone, and cellulose acetate phthalate, as well as combinations thereof.

[0134] Stabilizers suitable for use in this invention include, but are not limited to, fatty acids such as oleic acid and its sodium salt, cholic acid and deoxycholic acid, cationic lipids such as stearamide, and anionic stabilizers such as phosphatidylethanolamine, phosphatidylserine, phosphatidic acid and phosphatidylglycerol, and combinations thereof. In one embodiment, the stabilizer is oleic acid.

[0135] Coating agents suitable for use in this invention include, but are not limited to, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein, and omega-3, such as omega-3 03K12429, and combinations thereof.

[0136] Colorants suitable for use in this invention include, but are not limited to, caramel, red colorants, yellow colorants, black colorants or blends, iron oxide, and combinations thereof.

[0137] Examples of complexing agents suitable for use in this invention include, but are not limited to, ethylenediaminetetraacetic acid and its salt (EDTA), edetate, gentian acid ethanolamide, hydroxyquinoline sulfate, and combinations thereof.

[0138] Emulsifiers and / or solubilizers suitable for use in this invention include, but are not limited to, gum arabic, cholesterol, diethanolamine, glyceryl monostearate, lanolin alcohol, lecithin, mono- and di-glycerides, monoethanolamine, oleic acid, oleyl alcohol, poloxamer, polyoxyethylene 50 stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol 10 oleate ether, polyoxyethylene (20) hexadecyl-octadecyl ether, polyoxyethylene (40) monostearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitol monolaurate, sorbitol monooleate, sorbitol monopalmitate, sorbitol monostearate, stearic acid, triethanolamine, emulsifying waxes, and combinations thereof.

[0139] Flavoring agents and fragrances applicable to this invention include, but are not limited to, anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, neroli oil, peppermint, peppermint oil, peppermint spirit, rose oil, concentrated rose water, thymol, toluene tincture, vanilla, vanilla tincture, vanillin, and combinations thereof.

[0140] Solvents suitable for use in this invention include, but are not limited to, acetone, alcohols, anhydrous ethanol, dilute alcohols, hydrated pentene, benzyl benzoate, butanol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerol, hexanediol, isopropanol, methanol, dichloromethane, methyl isobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylene carbonate, propylene glycol, sesame oil, water for injection, sterile water for injection, sterile rinsing water, purified water, and combinations thereof.

[0141] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, the present invention is not limited to the embodiments. Any modifications and substitutions made on the basis of the present invention shall fall within the protection scope of the present invention.

[0142] Example

[0143] Active pharmaceutical ingredient (API)

[0144] The preparation of compounds of formula (I), their enantiomers of formula (Ia), compounds of formula (Ib), or pharmaceutically acceptable salts thereof, as described in this application, may be referenced to Chinese application CN202311015650.9. The entire contents of CN202311015650.9 are incorporated herein by reference.

[0145] The compound of formula (I) is 5-chloro-2-(4,4-difluoroazacyclohept-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide.

[0146] The compound of formula (Ia) is (R)-5-chloro-2-(4,4-difluoroazacyclohept-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide.

[0147] Compound of formula (Ib) is (S)-5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0148] (I), (Ia), (Ib)

[0149] Reagents and Instruments

[0150] The chemicals used in this invention are manufactured by companies such as STA, Roquette Freres, DuPont Nutrition USA, Inc., Kerry Inc., BASF, JRS, Merck, Avantor, Peter Greven Nederland, and Shanghai Calcare Coating Technology Co., Ltd.

[0151] The models and manufacturers of the equipment used in this invention are shown in the table below:

[0152]

[0153] Characterization

[0154] The solid dispersion was characterized by X-ray powder diffraction (XRPD).

[0155] Procedure: Place the sample (approximately 10 mg) on ​​the sample holder and test it using the following method via X-ray diffraction (Bruker D8 Advance).

[0156]

[0157] I. Preparation and Testing of Solid Dispersions (SDDs)

[0158] 1.1 Preparation of solid dispersions

[0159] The production process of solid dispersions is as follows: Figure 1 As shown in the image.

[0160] Example 1: Solid Dispersion 1 (10DL-API-HP-β-CD-SDD)

[0161] The preparation includes the following steps:

[0162] (1) Material dispensing: Weigh the hydroxypropyl-β-cyclodextrin (HP-β-CD) and compound (Ia) according to the prescription amount. Weigh the methanol into the dispensing tank according to the prescription amount and stir at an appropriate speed.

[0163] (2) Solution preparation of the solid dispersion: First, the prescribed amount of hydroxypropyl β-cyclodextrin was slowly and uniformly added to methanol and stirred and circulated until the solid dissolved. Then, the compound of formula (Ia) was slowly added and stirred and circulated until the solid dissolved. Finally, it was stirred and set aside for use.

[0164] (3) Filter the solution from step (2).

[0165] (4) Preparation of wet solid dispersion: The solution obtained in step (3) is spray-dried (the gas used is nitrogen, with a purity of 99.999%), and the spray drying control is recorded every half hour; after the solid dispersion solution is sprayed, switch to blank solvent and spray for ≥1 hour, and then collect the wet solid dispersion.

[0166] (5) Preparation of solid dispersion: The wet solid dispersion was dried in an oven at 50-60°C. When the methanol content in the intermediate control test was <2500ppm, the product was unloaded, sieved, and then solid dispersion 1 was obtained.

[0167] Solid dispersion 1 was prepared according to the above procedure, and its formulation is as follows:

[0168]

[0169] Remark: *Solution preparation: Solid content 20%; methanol is removed during the process.

[0170] Example 2: Solid dispersion 2 (20DL-API-HP-β-CD-SDD)

[0171] Solid dispersion 2 was prepared using the same procedure as in Example 1, and its formulation is as follows:

[0172]

[0173] The same solid dispersion was prepared using methanol:dichloromethane = 1:1, v / v as the solvent:

[0174]

[0175] Example 3: Solid dispersion 3 (5DL-API-HP-β-CD-SDD)

[0176] Solid dispersion 3 was prepared using the same procedure as in Example 1, and its formulation is as follows:

[0177]

[0178] Example 4: Solid Dispersion 4 (20DL-API-MG-SDD)

[0179] Solid dispersion 4 was prepared using the same procedure as in Example 1, with HPMCAS MG used as the polymer carrier, and its formulation is as follows:

[0180]

[0181] Example 5: Solid dispersion 5 (20DL-API-L100-55-SDD)

[0182] Solid dispersion 5 was prepared using the same procedure as in Example 1, with Eudragit L100 used as the polymer carrier, and its formulation is as follows:

[0183]

[0184] Example 6: Solid Dispersion 6 (50DL-API-MG-SDD)

[0185] Solid dispersion 6 was prepared using the same procedure as in Example 1, and its formulation is as follows:

[0186]

[0187] Example 7: Solid Dispersion 7 (50DL-API-HP-β-CD-SDD)

[0188] Solid dispersion 7 was prepared using the same procedure as in Example 1, and its formulation is as follows:

[0189]

[0190] 1.2 Test

[0191] A. Solubility test using the Biopharmaceutics Classification System (BCS)

[0192] The solubility of solid dispersion 1 was studied in buffer solutions with different pH values.

[0193] Approximately 100 mg of solid dispersion 1 was weighed and placed into a 40-mL vial. Buffer solutions of different pH values ​​(Table 2) were then added to the vial to achieve a concentration of the target active pharmaceutical ingredient (i.e., compound (Ia)) of 10 mg / mL (based on the active pharmaceutical ingredient). For these clear solutions, excess solid dispersion 1 was added to obtain a suspension. The resulting suspension was stirred at 150 rpm at 37°C for 24 hours. Samples were then taken at 2 hours, 4 hours, and 24 hours, and centrifuged at 14,000 rpm for 3 minutes.

[0194] According to the results, it provided similar values ​​of 2.5-3.5 mg / mL in the pH range of 3.0-7.4, but the highest value appeared at pH 1.2, reaching 28 mg / mL.

[0195] Table 1: Solubility results of solid dispersion 1 in pH buffer solution

[0196]

[0197] B. Two-stage dissolution test

[0198] Two-stage dissolution tests were performed in SGF and cFaSSIF to evaluate the in vitro release profiles of the solid dispersions.

[0199] A certain amount of solid dispersion (equivalent to 36 mg of compound (Ia)) was weighed into a 40 mL glass vial and suspended in 6.6 mL of SGF at 37 °C and 150 rpm for 30 minutes on a magnetic stirrer. At each time point of 10, 30, and 60 minutes, 200 μL of the suspension was transferred and centrifuged at 14,000 rpm for 3 minutes to separate the supernatant, which was then diluted appropriately for analysis.

[0200] 12 mL of cFaSSIF (concentrated FaSSIF) was added to the suspension, and the mixture was stirred at 37°C and 150 rpm for 4 hours on a magnetic stirrer. At each time point of 10, 30, 45, 60, 90, 120, 180, and 240 minutes, 200 μL of the suspension was pipetted and centrifuged at 14,000 rpm for 3 minutes to separate the supernatant. The supernatant was then diluted appropriately for analysis. The pH of the solution was measured using a pH meter before and after sampling, and the results are summarized in Table 2 below.

[0201] Table 2: Stage 2 Dissolution Results

[0202]

[0203] The results showed that, in the Grade 2 dissolution test, the dissolution results of the solid dispersion formulation were significantly better than those of the amorphous (Ia) compound.

[0204] C Stability Study

[0205] A certain amount of solid dispersion was weighed into 40 mL vials and then stored for 4 weeks in stabilization chambers at 25℃ / 60%RH (closed), 40℃ / 75%RH (open), and 40℃ / 75%RH (closed). The samples were analyzed at different time points (initial and 1 week) (appearance, XRPD, HPLC), and the results are summarized in Tables 3 and 4.

[0206] Table 3 Short-term stability of solid dispersions

[0207]

[0208]

[0209] Note: Only the purity of impurities exceeding 0.05% was calculated.

[0210] Table 4 Results of impurities in the dispersion

[0211]

[0212]

[0213] Note: * Impurities exceeding 0.05% and impurities with continuous variations but less than 0.05% are listed.

[0214] Based on the results, the amorphous (Ia) compound exhibited a slight increase in impurities under certain conditions. The solid dispersion formulation showed good stability.

[0215] II. Tablet preparation and dissolution measurement

[0216] 2.1 Tablet Preparation

[0217] The tablet manufacturing process includes premixing, dry granulation, external mixing, lubrication, tableting, coating, and bottling.

[0218] (1) Premixed 1

[0219] - Weigh the following components according to the formula: solid dispersion 1, lactose (part 1), lactose (part 2), mannitol, croscarmellose sodium (internal), magnesium stearate (internal), croscarmellose sodium (external) and magnesium stearate (external).

[0220] - Add lactose (part 1) and solid dispersion 1 to a mixing tank and premix to obtain premix 1.

[0221] (2) Premixed 2

[0222] - Sift mannitol, premix 1, lactose (part 2), and croscarmellose sodium (added internally) separately.

[0223] - Add the sieved mannitol, premix 1, lactose (part 2), and croscarmellose sodium (added internally) to the mixed premix in sequence to obtain premix 2.

[0224] (3) Premixed 3

[0225] Magnesium stearate (added internally) was sieved and then premixed to obtain premix 3.

[0226] (4) Dry granulation

[0227] Premix 3 was granulated using a dry granulator to obtain granules 1.

[0228] (5) Addition of mixture

[0229] - After sieving the sodium croscarmellose (added) and magnesium stearate (added) separately, weigh the prescription amount.

[0230] - Add the prescribed amount of sieved cross-linked carboxymethyl cellulose sodium (added) and granules 1 to a mixing tank and mix to obtain the added mixture.

[0231] (6) Lubrication

[0232] Add the prescribed amount of sieved magnesium stearate (added externally), mix, and obtain total mixed particles.

[0233] (7) Tableting

[0234] Tablets are prepared using a tablet compressor.

[0235] (8) Coating

[0236] - Prepare a 20% solids content coated powder suspension using purified water, and stir for at least 45 minutes.

[0237] - Coat the resulting tablets using a coating machine.

[0238] 10mg and 50mg tablets were prepared according to the above method. The production process is as follows: Figure 2 As shown.

[0239] Table 5: Tablet Prescription Composition Information

[0240]

[0241] 2.2 Dissolution Measurement

[0242] Tablet dissolution was determined using the paddle method as described in the Chinese Pharmacopoeia (2010 edition), with 10 mM sodium dihydrogen phosphate buffer solution (pH=6.8) as the dissolution medium and a paddle speed of 50 rpm. 5 ml samples were taken at 5, 10, 20, 30, 45, and 60 minutes for HPLC analysis.

[0243] Following the above test method, the dissolution rate of 10mg and 50mg tablets was measured, and the dissolution rate results are as follows: Figure 11 and 12 As shown in the image.

[0244] The dissolution results of the process study for 50mg coated tablets are shown below:

[0245]

[0246] The dissolution results of the process study for 10mg coated tablets are shown below:

[0247]

[0248] 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 provided by way of example only.

Claims

1. A solid dispersion comprising: (1) A compound of formula (I) or its enantiomer (Ia) or enantiomer (Ib) or pharmaceutically acceptable salt thereof: (I), (Ia), (Ib); and (2) Polymer carrier; Preferably, the compound is (R)-5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof; Preferably, the compound is of formula (Ia): (It); Preferably, the polymer carrier is selected from cyclodextrin and its derivatives, polyethylene glycols, polyvinylpyrrolidone, Eudragit, copovidone, hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, and any combination thereof. Preferably, the polymer carrier is a cyclodextrin and its derivatives, preferably selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfonyl butyl ether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-modified β-cyclodextrin and carboxymethyl-β-cyclodextrin; preferably hydroxypropyl-β-cyclodextrin. Preferably, the weight ratio of the compound to the polymer carrier is 1:20 to 20:1; Preferably, the weight ratio of the compound to the polymer carrier is 1:19 to 19:1, 1:15 to 15:1, 1:10 to 10:1, 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, 4:5 to 5:4, 5:6 to 6:5 or 1:1; Preferably, the weight ratio of the compound to the polymer carrier is 1:9; Preferably, the compound is present in the solid dispersion at a content of about 1% to about 99% by weight, about 5% to about 95% by weight, about 10% to about 90% by weight, about 20% to about 80% by weight, about 30% to about 70% by weight, about 40% to about 60% by weight, or about 10% to about 20% by weight; preferably, the compound is present in the solid dispersion at a content of about 10% by weight. Preferably, the solid dispersion is prepared by a method selected from: melt drying, solvent drying, solvent-melt drying, spray drying, freeze drying, grinding, and hot melt extrusion. Preferably, it is prepared by spray drying.

2. A composition comprising the solid dispersion and excipient as described in claim 1; Preferably, the excipient is selected from one or more of fillers, disintegrants, disintegration aids, surfactants, and lubricants; Preferably, the filler is selected from microcrystalline cellulose, lactose, mannitol, sodium bicarbonate, and any combination thereof; the disintegrant is selected from crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and any combination thereof; the disintegration aid is selected from anhydrous citric acid, sodium chloride, and any combination thereof; the surfactant is sodium dodecyl sulfate; and the lubricant is selected from magnesium stearate, sodium stearoyl fumarate, and any combination thereof. Preferably, the solid dispersion is present in the composition at a content of about 1% to about 99% by weight; preferably about 10% to about 90% by weight; preferably about 20% to about 80% by weight; preferably about 30% to about 70% by weight; preferably about 40% to about 60% by weight; preferably about 40%, about 45.5% by weight, about 50% by weight, about 55.5% by weight, or about 60% by weight.

3. An oral formulation comprising the solid dispersion of claim 1 or the composition of claim 2; Preferably, it is selected from tablets, capsules, granules, powders, lozenges and pills.

4. A tablet comprising the solid dispersion of claim 1 and an excipient selected from one or more of fillers, disintegrants, disintegration aids, surfactants, and lubricants; Preferably, the tablet comprises about 1% to about 99% by weight of the solid dispersion, about 1% to about 99% by weight of the filler, about 0.5% to about 20% by weight of the disintegrant, about 0% to about 5% by weight of the disintegration aid, about 0% to about 5% by weight of the surfactant, and about 0.25% to about 5% by weight of the lubricant. Preferably, the filler is selected from microcrystalline cellulose, lactose, mannitol, sodium bicarbonate, and any combination thereof, preferably lactose or mannitol or a mixture thereof; the disintegrant is selected from crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and any combination thereof, preferably crospovidone sodium carboxymethyl cellulose; the disintegration aid is selected from anhydrous citric acid, sodium chloride, and any combination thereof; the surfactant is sodium dodecyl sulfate; the lubricant is selected from magnesium stearate, sodium stearoyl fumarate, and any combination thereof, preferably magnesium stearate; Preferably, the content of the compound in a unit tablet is about 1 mg to about 200 mg, about 2 mg to about 150 mg, about 2.5 mg to about 150 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, or about 10 mg to about 50 mg, preferably 10 mg or 50 mg; preferably, the compound is a compound of formula (Ia). Preferably, it is a coated tablet; Preferably, the coated tablet comprises a coating agent selected from: sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, gelatin, pharmaceutical enamel, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein, and omeprazole; preferably, the coating agent is a gastrointestinal coating agent. Preferably, each tablet comprises about 50.0 mg to about 1000.0 mg of the solid dispersion, about 20.0 mg to about 80.0 mg of lactose, about 20.0 mg to about 80.0 mg of mannitol, about 5 mg to about 50.0 mg of croscarmellose sodium, about 1.0 mg to about 10.0 mg of magnesium stearate and about 1 mg to about 20.0 mg of coating agent, wherein the content of the compound in the solid dispersion is about 10% by weight to about 20% by weight, preferably the compound is a compound of formula (Ia); Preferably, each tablet comprises about 100.0 mg of the solid dispersion, about 40.0 mg of lactose, about 40 mg of mannitol, about 16.0 mg of croscarmellose sodium, about 4.0 mg of magnesium stearate and about 7.0 mg of coating agent, wherein the content of the compound in the solid dispersion is about 10% by weight, preferably the compound is a compound of formula (Ia); Preferably, each tablet comprises about 500.0 mg of the solid dispersion, about 200.0 mg of lactose, about 200.0 mg of mannitol, about 80.0 mg of croscarmellose sodium, about 20.0 mg of magnesium stearate and about 35.0 mg of coating agent, wherein the content of the compound in the solid dispersion is about 10% by weight, preferably the compound is a compound of formula (Ia).

5. Use of the solid dispersion of claim 1, the composition of claim 2, the oral formulation of claim 3, or the tablet of claim 4 in the preparation of a medicament used as a voltage-gated sodium channel inhibitor; preferably, the voltage-gated sodium channel inhibitor is a sodium ion channel 1.8 (NaV1.8) inhibitor; preferably, the voltage-gated sodium channel inhibitor is used to treat diseases selected from: acute, chronic, neurogenic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or epilepsy syndrome, neurodegenerative diseases, mental disorders such as anxiety and depression, bipolar disorder, myotonia, Arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetrating pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal activity; preferably, the diseases are selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain.

6. A method for preparing the solid dispersion of claim 1, selected from the melting method, solvent method, solvent-melt method, spray drying method, freeze drying method and grinding method, preferably the spray drying method.

7. A method for preparing the solid dispersion as described in claim 1, comprising the following steps: (1) Preparing a spray-drying solution, comprising dissolving the polymer carrier and the compound in a solvent; (2) Spray drying, The solvent is selected from anhydrous ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene, and toluene, or mixtures thereof, or mixtures thereof with water.

8. A method for preparing the oral formulation of claim 3, comprising wet granulation or dry granulation; Preferably, the oral formulation is prepared by dry granulation.

9. A method for preparing a tablet as claimed in claim 4, comprising the following steps: (1) Premix the solid dispersion and a portion of the excipient; (2) Dry granulation; (3) Add the remaining excipients and mix; (4) Add lubricant; (5) Tableting; and (6) Coating.

10. A method for treating pain in a subject or reducing its severity, the method comprising administering to the subject a compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions thereof in an amount equivalent to about 10 mg to about 600 mg per day, optionally in an amount equivalent to about 20 mg to 300 mg per day. Preferably, the compound of formula (I) or its enantiomers (Ia) or (Ib) or their pharmaceutically acceptable salts or solid dispersions comprising them are administered on the first day in an amount equivalent to about 10 mg to about 600 mg of the compound of formula (I), optionally on the first day in an amount equivalent to about 20 mg to about 30 mg of the compound of formula (I), optionally on the first day in an amount equivalent to about 20 mg to about 30 mg of the compound of formula (I), optionally on the first day in an amount equivalent to about 60 mg to about 90 mg of the compound of formula (I), optionally on the first day in an amount equivalent to about 100 mg to about 150 mg of the compound of formula (I), optionally after the first day in an amount equivalent to about 5 mg to about 200 mg of the compound of formula (I) per day. Preferably, the compound of formula (I) or its enantiomers (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions containing them are administered daily in two doses, or in a first dose and a subsequent dose on the first day, wherein the first dose is greater than the subsequent dose, and optionally the subsequent dose is administered 12 hours after the first dose. Preferably, the first dose is a compound of formula (I) equivalent to about 20 mg to about 100 mg, optionally the first dose is a compound of formula (I) equivalent to about 20 mg, or optionally the first dose is a compound of formula (I) equivalent to about 60 mg, or the first dose is a compound of formula (I) equivalent to about 100 mg, or its enantiomers of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof or solid dispersions containing them; Preferably, the subsequent dose is a compound of formula (I) equivalent to about 10 mg to about 100 mg, or the subsequent dose is a compound of formula (I) equivalent to about 10 mg to about 50 mg, or the subsequent dose is a compound of formula (I) equivalent to about 10 mg, or the subsequent dose is a compound of formula (I) equivalent to about 30 mg, or the subsequent dose is a compound of formula (I) equivalent to about 50 mg, or an enantiomer of formula (Ia) or enantiomer of formula (Ib) or their pharmaceutically acceptable salts or solid dispersions containing them; Preferably, the compound of formula (I) or its enantiomers (Ia) or (Ib) or their pharmaceutically acceptable salts or solid dispersions comprising them are administered at two doses per day after the first day, or at two doses per day equivalent to about 10 mg to 50 mg of the compound of formula (I) after the first day, or at two doses per day equivalent to about 30 mg of the compound of formula (I) after the first day, or at two doses per day equivalent to about 50 mg of the compound of formula (I) after the first day. Preferably, a 12-hour time interval is elapsed between the administration of each of the two doses; Preferably, the compound of formula (I) or its enantiomer of formula (Ia) or enantiomer of formula (Ib) or pharmaceutically acceptable salt thereof or solid dispersion comprising thereof is administered at one dose per day. Preferably, the compound of formula (I) or its enantiomer (Ia) or enantiomer (Ib) or their pharmaceutically acceptable salts or solid dispersions containing them are administered for at least 1 week, at least 6 weeks, or at least 2 days. Preferably, the compound of formula (I) orally administered orally, or its enantiomer of formula (Ia) or enantiomer of formula (Ib), or their pharmaceutically acceptable salts or solid dispersions containing them, are preferred.

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