Solid dispersion of a P2X4 inhibitor, method of manufacture, and use.

Abstract

A solid dispersion of a P2X4 inhibitor comprising an active ingredient and a carrier is disclosed. The resulting solid dispersion can improve the solubility and dissolution effect of the active ingredient, has good stability, and does not show a significant increase in impurities under conditions of 25°C / 60%RH (open) and 40°C / 75%RH (open). The method for producing the solid dispersion is simple and can be used by spray drying, solvent method, or hot melt extrusion, and the solvent residue of the resulting product is suitable. Furthermore, the resulting solid dispersion effectively improves the pharmacokinetic effect of the active ingredient. A pharmaceutical composition comprising the solid dispersion is disclosed, the pharmaceutical composition having good disintegration effect, and the disintegration time is within the limits of the pharmacopoeia. Therefore, the pharmaceutical composition provides convenience for the subsequent development of dosage forms of the active ingredient.

Description

[Technical Field]

[0001] This application claims priority to two prior applications: one filed with the China National Intellectual Property Administration on June 16, 2023, with patent application number 2023107248878, titled "Solid dispersion of P2X4 inhibitor, method for manufacturing the same, and use thereof"; and another filed with the China National Intellectual Property Administration on May 9, 2024, with patent application number 2024105673321, titled "Solid dispersion of P2X4 inhibitor, method for manufacturing the same, and use thereof". The entire contents of these two prior applications are incorporated into this application by reference.

[0002] [Technical field] This invention belongs to the field of medical technology and specifically relates to a solid dispersion of a P2X4 inhibitor, and a method for producing and using the same. [Background technology]

[0003] Purine receptors are widely present in the membranes of almost all mammalian cells and are involved in regulating multiple biological signaling pathways. Purine receptors can be classified into adenosine receptors and ATP receptors. ATP receptors are broadly divided into the P2X family of ion channel receptors and the P2Y family of G protein-coupled receptors. P2X receptors are widely distributed in various tissues throughout the body, including the brain, lungs, neurons, glial cells, heart, and blood vessels. To date, seven subtypes of P2X receptors (P2X1 to P2X7) have been disclosed. Here, the P2X4 receptor is the only subtype in the P2X family whose crystal structure has been elucidated, with a high resolution of 2.8 Å. Furthermore, research has shown that P2X4 is Ca2 + It was found to be the P2X subtype with the highest permeability to [the specified substance].

[0004] Currently, P2X4 inhibitors are a focus of research for many companies.

[0005] Patent document WO2016198374A1 discloses several P2X4 inhibitory compounds that are P2X4 antagonists or negative allosteric modulators. Such compounds are used for the treatment or prevention of pain-related disorders, or for the treatment or prevention of pain syndromes (acute and chronic), pro-inflammatory pain, neuropathic pain, pelvic pain, cancer-related pain, endometriosis-related pain and endometriosis itself, cancer itself, and proliferative disorders similar to endometriosis itself, and can be used alone or in combination with other active ingredients.

[0006] Patent document WO2017191000A1 discloses several P2X4 inhibitor compounds used alone or in combination with other active ingredients for the manufacture of pharmaceutical compositions, which are used for the treatment or prevention of diseases (in particular mammalian diseases, such as pain-related disorders, etc.), or for the treatment or prevention of brain or bone marrow pain or nerve injury, and inflammation or arthritis or spondylitis syndromes (acute and chronic), pro-inflammatory pain, neuropathic pain, pelvic pain, cancer-related pain, endometriosis-related pain and endometriosis itself, cancer itself, multiple sclerosis itself, bone marrow or ischemic brain injury itself.

[0007] Patent document WO2019081573A1 discloses several P2X4 inhibitor compounds used in the manufacture of pharmaceuticals for the treatment of hemorrhagic stroke and traumatic brain injury.

[0008] Patent documents WO2022002859A1 and WO2022002860A1 disclose several phenethylamide compounds having P2X4 receptor antagonistic activity, and the use of several phenethylamide compounds having P2X4 receptor antagonistic activity in the manufacture of pharmaceuticals for treating certain eye diseases.

[0009] Patent document WO2021104486A1 discloses benzene ring-containing compounds and their uses, disclosing several benzene ring-containing compounds as P2X4 inhibitors, and further disclosing the use of these compounds for the treatment of P2X4-mediated diseases. It also discloses compounds 1 to 48 that exhibit high inhibitory activity, good selectivity, low toxicity, and good metabolic stability against P2X4. However, since such compounds have poor solubility, it is necessary to develop formulations for these compounds to improve the aforementioned problems. [Overview of the project]

[0010] The object of the present invention is to provide a solid dispersion of a P2X4 inhibitor comprising an active ingredient and a carrier in order to solve the shortcomings of the prior art, wherein the active ingredient is selected from at least one of the following compounds 1 to 48 or pharmaceutically acceptable salts thereof.

[0011] [ka]

[0012] [ka]

[0013] [ka]

[0014] [ka]

[0015] The carrier is selected from one or more of the following: copovidone, povidone, hypromellose acetate succinate, hypromellose phthalate (HPMPCP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl cellulose, hypromellose, polyacrylic acid resin, cellulose acetate phthalate (CAP), methacrylic acid-methyl methacrylate copolymer, or polyethylene oxide (PEO). Preferably, it is copovidone, hypromellose acetate succinate, or povidone, and most preferably, it is copovidone.

[0016] According to embodiments of the present invention, in the carrier, copovidone is PVP-VA64, copovidone is also called polyvinylpyrrolidone / vinyl acetate copolymer, polyvinylpyrrolidone / vinyl acetate copolymer is a linear copolymer of a series of N-vinylpyrrolidone (NVP) and vinyl acetate (VA), and commercially available common copovidones include PVP-VA64, Coridone VA64, Plasdone S-630, etc., and the povidone is PVP-K30, here povidone is a homopolymer of a series of water-soluble N-vinylpyrrolidone (NVP), and commonly used povidones include PVP-K30, PVP-K90, etc., the hypromellose is HPMC E3, and the polyacrylic resin is Eudragit L100.

[0017] According to embodiments of the present invention, the solid dispersion further comprises a surfactant.

[0018] According to an embodiment of the present invention, the surfactant is sodium lauryl sulfate (abbreviation: SLS or SDS), sodium cetyl sulfate, sodium stearyl sulfate, Tween (for example, Tween 80, 60, 40 and 20), hydrogenated castor oil (for example, Cremophor EL), glycerol monostearate, vitamin E polyethylene glycol succinate (VE-TPGS), polyoxyethylene castor oil derivative (for example, Cremophor RH40), poloxamer (for example, poloxamer F68, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407), or polyethylene glycol (15)-hydroxystearic acid (Solutol HS15), and is a mixture obtained by mixing one or more selected therefrom in an arbitrary ratio. Preferably, it is a mixture obtained by mixing one or more of sodium lauryl sulfate, vitamin E polyethylene glycol succinate, and Cremophor RH40 in an arbitrary ratio.

[0019] In one preferred embodiment, the active ingredient is compound 1 or a pharmaceutically acceptable salt thereof.

[0020] According to an embodiment of the present invention, compounds 1 to 48 can refer to the compounds disclosed in Patent Document WO2021104486A1, the whole of which is incorporated herein by reference.

[0021] According to an embodiment of the present invention, the mass ratio of the active ingredient to the carrier is 1:(1 to 7), preferably 1:(2 to 5), more preferably 3:(6 to 7), and most preferably 3:7.

[0022] According to some embodiments of the present invention, the mass ratio of the active ingredient to the carrier is 1:(1 to 7), preferably 1:(2 to 5), more preferably 3:(6 to 9), and most preferably 1:2.8.

[0023] According to embodiments of the present invention, the solid dispersion comprises an active ingredient, a carrier, and a surfactant, and the mass ratio of the active ingredient, carrier, and surfactant is 1:(1~7):(0.1~1), preferably 1:(2~5):(0.1~1), for example 3:6.5:0.5.

[0024] In some embodiments of the present invention, the solid dispersion comprises compound 1 and copovidone. Alternatively, containing compound 1 and povidone, Alternatively, the compound comprises compound 1 and hypromellose acetate succinate. Alternatively, compound 1 contains copovidone and cremofol RH40, Alternatively, compound 1 contains copovidone and SLS, Alternatively, compound 1 contains copovidone and VE-TPGS, Alternatively, compound 1 contains copovidone and cremofol RH40, Alternatively, compound 1 contains copovidone and SLS, Alternatively, the compound may contain compound 1, copovidone, and VE-TPGS.

[0025] In some embodiments of the present invention, the solid dispersion comprises compound 1, copovidone, and cremofol RH40. Alternatively, compound 1 contains copovidone and SLS, Alternatively, compound 1 contains copovidone and VE-TPGS, Alternatively, compound 1 contains povidone and cremofol RH40, Alternatively, compound 1 contains povidone and SLS, Alternatively, it may contain compound 1, povidone, and VE-TPGS.

[0026] In some embodiments of the present invention, the solid dispersion comprises compound 1, copovidone, and cremofol RH40. Alternatively, compound 1 contains copovidone and SLS, Alternatively, the compound may contain compound 1, copovidone, and VE-TPGS.

[0027] In some embodiments of the present invention, the solid dispersion comprises compound 1, copovidone and SLS, Alternatively, it may contain compound 1, copovidone, and vitamin E polyethylene glycol succinate (VE-TPGS).

[0028] In some specific embodiments of the present invention, the solid dispersion comprises compound 1, PVP-VA64 and SLS, Alternatively, it may contain compound 1, PVP-VA64, and vitamin E polyethylene glycol succinate (VE-TPGS).

[0029] In some specific embodiments of the present invention, the solid dispersion comprises, by weight, 1 part by weight of compound 1, 1 to 7 parts by weight of a carrier, and 0.1 to 1 part by weight of a surfactant, wherein the carrier is selected from one of copovidone, povidone, or hypromellose acetate succinate, and the surfactant is selected from one of sodium lauryl sulfate, vitamin E polyethylene glycol succinate (VE-TPGS), or polyoxyethylene castor oil derivative (such as cremofor RH40).

[0030] In some specific embodiments of the present invention, the solid dispersion comprises, by weight, 1 part by weight of compound 1, 1 to 7 parts by weight of PVP-VA64 and 0.1 to 1 part by weight of SLS, or 1 part by weight of compound 1, 1 to 7 parts by weight of PVP-VA64 and 0.1 to 1 part by weight of vitamin E polyethylene glycol succinate (VE-TPGS).

[0031] The present invention further provides a method for producing the solid dispersion using a spray drying method, a solvent method, or a hot melt extrusion method, comprising the following steps.

[0032] Spray drying method: This method involves adding raw materials to solvent S1 to produce a solution, followed by spray drying. In formulations containing surfactants, the active ingredient, carrier, and surfactant are added to solvent S1 to produce a solution, which is then spray dried.

[0033] Solvent method: The raw materials are added to solvent S2 and stirred uniformly until the raw materials are completely dissolved to obtain a solution. Then, the solvent is removed from the obtained solution, and the solution is dried and pulverized to obtain a solid dispersion.

[0034] Hot melt extrusion method: A step in which raw materials are mixed, and then an appropriate amount of lubricant is optionally added and the mixture is extruded using the hot melt method.

[0035] The solvent S1 is a ketone-based solvent, or a mixed solvent consisting of a ketone-based solvent and a halogenated alkane-based solvent, water, or an alcohol-based solvent.

[0036] The solvent S2 is a ketone-based solvent, or a mixed solvent consisting of a ketone-based solvent, a halogenated alkane-based solvent, or an alcohol-based solvent.

[0037] In the method for producing the solid dispersion described above, the "raw materials" include an active ingredient and a carrier, and if the solid dispersion further contains a surfactant, the raw materials include the active ingredient, the carrier and the surfactant.

[0038] According to embodiments of the present invention, the raw materials in the method for producing the solid dispersion described above may include the active ingredient compound 1 and a carrier, or may include the active ingredient compound 1, a carrier, and optionally a surfactant, depending on the specific requirements for producing various solid dispersions.

[0039] The phrase "optionally" includes not choosing it, or choosing one, two, or more of them.

[0040] According to embodiments of the present invention, the ketone solvent is one or more of acetone, butanone, and methyl isobutyl ketone, and is preferably acetone.

[0041] According to embodiments of this disclosure, the halogenated alkane solvent is dichloromethane.

[0042] According to embodiments of this disclosure, the alcohol-based solvent is methanol, ethanol, or propanol.

[0043] According to embodiments of the present disclosure, the solvent S1 is a two-component mixed solvent consisting of a ketone solvent and a halogenated alkane solvent, water, and an alcohol solvent, wherein the volume ratio of the ketone solvent to the other solvents is (1-10):1, for example, (1-5):1.

[0044] According to embodiments of the present invention, the solvent S1 is a two-component mixed solvent consisting of acetone and a solvent comprising dichloromethane, ethanol, and water, and the volume ratio of acetone to the other solvents is (1-5):1.

[0045] According to embodiments of the present invention, the solvent S1 is a two-component mixed solvent of acetone and dichloromethane, with a volume ratio of acetone to dichloromethane of 6:4, or the solvent S1 is a two-component mixed solvent of acetone and water, with a volume ratio of acetone to water of 7:3, or the solvent S1 is a two-component mixed solvent of acetone and ethanol, with a volume ratio of acetone to ethanol of 1:1.

[0046] According to embodiments of the present invention, the solvent S1 is a mixed solvent consisting of acetone, ethanol, and water.

[0047] According to a specific embodiment of the present invention, the solvent S1 is a mixed solvent consisting of acetone, ethanol, and water, where the volume ratio of acetone, ethanol, and water is 1:(0.8~1):(0.2~0.7), preferably 8:7:5, 2:2:1, 5:4:1, 4:3:3, and most preferably 8:7:5.

[0048] According to embodiments of the present invention, when the solvent S2 is a two-component mixed solvent, the volume ratio of the ketone solvent to the other solvent is (1-10):1, for example, (5-9):1.

[0049] According to embodiments of the present invention, when a spray drying method is used, the concentration of the active ingredient in the obtained solution is 5 to 50 mg / mL, for example, 15 to 25 mg / mL.

[0050] According to embodiments of the present invention, when the solvent method is used, the mass fraction of the active ingredient in the resulting solution is 5% to 50%, for example, 10% to 40%.

[0051] According to embodiments of the present invention, in a method for producing a solid dispersion by the hot-melt extrusion method, the lubricant is selected from a mixture obtained by mixing one or more of the following in any proportion: talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, hydrated silicon dioxide, hydrophobic silicon dioxide, sodium stearyl fumarate, polyethylene glycol, sodium stearyl fumarate, glycerol monostearate, and hydrogenated vegetable oil.

[0052] The present invention further provides a pharmaceutical composition comprising the above-mentioned solid dispersion and a pharmaceutically acceptable excipient.

[0053] According to embodiments of the present invention, the pharmaceutical composition can be formulated into tablets, powders, granules, capsules, intravenous pills, or pellets by conventional manufacturing processes, and preferably into tablets.

[0054] The administration routes of the pharmaceutical composition of the present invention include oral, rectal, vaginal, and sublingual administration.

[0055] According to embodiments of the present invention, the excipient comprises one or more of fillers, lubricants, and disintegrants.

[0056] According to embodiments of the present invention, the filler is selected from a mixture obtained by mixing one or more of lactose, dextrin, mannitol, microcrystalline cellulose, starch, pregelatinized starch, cellulose lactose, calcium hydrogen phosphate, and mannitol-starch complex in any proportion, and is preferably a mixture obtained by mixing one or more of microcrystalline cellulose, mannitol, and starch in any proportion.

[0057] According to embodiments of the present invention, the lubricant is selected from a mixture obtained by mixing one or more of the following in any proportion: talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, hydrated silicon dioxide, hydrophobic silicon dioxide, sodium stearyl fumarate, polyethylene glycol, sodium stearyl fumarate, glycerol monostearate, and hydrogenated vegetable oil. Preferably, it is a mixture obtained by mixing one or more of the following in any proportion: magnesium stearate, colloidal silicon dioxide, and hydrophobic silicon dioxide.

[0058] According to embodiments of the present invention, the disintegrant is selected from a mixture obtained by mixing one or more of the following in any proportion: dried starch, croscarmellose sodium, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, methylcellulose, low-substituted hydroxypropylcellulose, crospovidone, chitosan, and microcrystalline cellulose. Preferably, it is a mixture obtained by mixing one or more of the following in any proportion: croscarmellose sodium, carboxymethylcellulose, and carboxymethylcellulose calcium.

[0059] According to embodiments of the present invention, calculated by weight percentage, the content of the pharmaceutical composition is 30% to 50% of the solid dispersion, 20% to 50% of the filler, 1% to 15% of the disintegrant, and 1% to 15% of the lubricant. Preferably, calculated by weight percentage, the content of the solid dispersion is 35% to 45%, the content of the filler is 35% to 45%, the content of the disintegrant is 1% to 10%, and the content of the lubricant is 1% to 10%. More preferably, calculated by weight percentage, the content of the solid dispersion is 40% to 45%, the content of the filler is 40% to 45%, the content of the disintegrant is 5% to 10%, and the content of the lubricant is 1% to 5%.

[0060] According to embodiments of the present invention, the pharmaceutical composition further comprises a disintegration aid.

[0061] According to embodiments of the present invention, the disintegration accelerator is selected from a mixture obtained by mixing one or more of the following in any proportion: sodium chloride, sodium carbonate, calcium carbonate, potassium carbonate, calcium magnesium carbonate, zinc carbonate, magnesium carbonate, ammonium carbonate, sodium glycine carbonate, sodium sesquicarbonate, sodium bicarbonate, calcium bicarbonate, potassium bicarbonate, and ammonium bicarbonate. Preferably, it is a mixture obtained by mixing one or more of the following in any proportion: sodium chloride, sodium carbonate, and sodium bicarbonate.

[0062] According to embodiments of the present invention, when a disintegration accelerator is further included, the content of the pharmaceutical composition is calculated by weight percentage as follows: the solid dispersion content is 30% to 50%, the filler content is 20% to 50%, the disintegrant content is 1% to 15%, the lubricant content is 1% to 15%, and the disintegration accelerator content is 0.1% to 10%.

[0063] Preferably, calculated by weight percentage, the content of the solid dispersion is 35% to 45%, the content of the filler is 35% to 45%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 1% to 10%, and the content of the disintegration accelerator is 1% to 10%. More preferably, calculated by weight percentage, the content of the solid dispersion is 40% to 45%, the content of the filler is 40% to 45%, the content of the disintegrant is 5% to 10%, the content of the lubricant is 1% to 5%, and the content of the disintegration accelerator is 5% to 10%.

[0064] According to embodiments of the present invention, the pharmaceutical composition is a solid dosage form, for example, a tablet.

[0065] The present invention further provides a method for producing the above-mentioned pharmaceutical composition, comprising the step of mixing a solid dispersion with a pharmaceutically acceptable excipient.

[0066] According to embodiments of the present invention, the excipients may be sieved before mixing.

[0067] According to embodiments of the present invention, the pharmaceutical composition is manufactured by a dry granulation process, the manufacturing method of which involves weighing the ingredients in the amounts to be blended, where the solid dispersion is not sieved, other excipients are sieved for later use, premixing the granular filler, disintegrant, flow promoter and solid dispersion, then crushing and sieving, adding a lubricant and dry granulation, then adding the granular filler, disintegrant, leavening agent and lubricant, and finally mixing. Preferably, after the final mixing, the required amount of active ingredient is packaged, and then the mixture is compressed into tablets conforming to pharmaceutical standards.

[0068] The active ingredients used in this disclosure have inhibitory, antagonistic, and negatively allosteric modulating effects on the P2X4 receptor. Therefore, when a predetermined amount of the solid dispersion or pharmaceutical composition of the present invention is administered to a mammal (including a human), it has inhibitory, antagonistic, and negatively allosteric modulating effects on the P2X4 receptor, and can effectively treat related diseases.

[0069] The present invention further provides the use of the above-mentioned solid dispersion or pharmaceutical composition in the manufacture of a P2X4 receptor antagonist.

[0070] According to embodiments of this disclosure, the P2X4 receptor antagonist is used to treat respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative disorders, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related disorders, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue developmental disorders, or systemic disorders. The aforementioned respiratory system diseases include, for example, respiratory disorders, and include idiopathic pulmonary fibrosis, respiratory failure, chronic obstructive pulmonary disease, asthma, bronchospasm, cough (e.g., acute cough, chronic cough), refractory chronic cough, and idiopathic chronic cough. The aforementioned urinary tract diseases include, for example, urinary incontinence, overactive bladder, voiding dysfunction, benign prostatic hyperplasia, cystitis (e.g., interstitial cystitis), bladder pain syndrome, and prostatitis. The aforementioned gynecological diseases include, for example, endometriosis, primary and secondary dysmenorrhea, dyspareunia, and adenomyosis. The aforementioned ophthalmic diseases include, for example, dry eye syndrome, neuropathic pain of the eye, eye trauma, and postoperative eye pain. The aforementioned gastrointestinal disorders include, for example, gastrointestinal disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, and gastroesophageal reflux disease. The aforementioned proliferative disorders include, for example, tumors such as cancer. The aforementioned cardiovascular diseases include, for example, myocardial infarction, thrombosis, atherosclerosis, heart failure, and hypertension. The aforementioned neurodegenerative diseases include, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, ischemic brain injury, and traumatic brain injury. The aforementioned inflammations include, for example, arthritis, rheumatoid arthritis, ankylosing spondylitis and associated neuropathic pain, and gout. The aforementioned pain-related disorders include, for example, hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, inflammatory pain, postoperative pain, visceral pain, toothache, periodontitis, premenstrual syndrome, endometrial pain, fibrosis-related pain, central pain, burning pain, and migraines. The aforementioned pain-related disorders include, for example, pain due to neuritis, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, pain due to cancer, and pain due to traumatic nerve injury.

[0071] The present invention further provides the use of the above-mentioned solid dispersion or pharmaceutical composition in the manufacture of a pharmaceutical for treating a disease mediated by P2X4.

[0072] The diseases mediated by P2X4 include respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative disorders, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related disorders, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue developmental disorders, or systemic disorders. The aforementioned respiratory diseases include, for example, respiratory disorders, and include idiopathic pulmonary fibrosis, respiratory failure, chronic obstructive pulmonary disease, asthma, bronchospasm, cough (e.g., acute cough, chronic cough), refractory chronic cough, and idiopathic chronic cough. The aforementioned urinary tract diseases include, for example, urinary incontinence, overactive bladder, voiding dysfunction, benign prostatic hyperplasia, cystitis (e.g., interstitial cystitis), bladder pain syndrome, and prostatitis. The aforementioned gynecological disorders include, for example, primary and secondary dysmenorrhea, dyspareunia, and adenomyosis. The aforementioned ophthalmic diseases include, for example, dry eye syndrome, neuropathic pain in the eye, and post-traumatic eye conditions. The aforementioned gastrointestinal disorders include, for example, gastrointestinal disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, and gastroesophageal reflux disease. The aforementioned proliferative disorders are tumors and cancers. The aforementioned cardiovascular diseases include, for example, myocardial infarction, thrombosis, atherosclerosis, heart failure, and hypertension. The aforementioned neurodegenerative diseases include, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, ischemic brain injury, and traumatic brain injury. The aforementioned inflammations include, for example, arthritis, rheumatoid arthritis, ankylosing spondylitis and associated neuropathic pain, and gout. The aforementioned pain-related disorders include, for example, hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, inflammatory pain, postoperative pain, visceral pain, toothache, periodontitis, premenstrual syndrome, endometrial pain, fibrosis-related pain, central pain, burning pain, and migraines. The aforementioned pain-related disorders include, for example, pain due to neuritis, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, pain due to cancer, and pain due to traumatic nerve injury.

[0073] The present invention further provides a method for treating respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative disorders, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related disorders, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue developmental disorders, or systemic disorders, comprising administering the above-mentioned solid dispersion or pharmaceutical composition to an individual in need thereof, the specific scope of these diseases being as described above.

[0074] Beneficial effects The present invention provides a solid dispersion containing active ingredients (compounds 1 to 48), the obtained solid dispersion having improved solubility and elution effect of the active ingredients, good stability, and no significant increase in impurities under 25°C / 60%RH (open) and 40°C / 75%RH (open) conditions. Furthermore, the manufacturing method is simple and can be carried out by spray drying, solvent method, or hot melt extrusion, and the residual solvent content of the obtained product is satisfactory.

[0075] Furthermore, the resulting solid dispersion effectively improves the pharmacokinetic effects of the active ingredient.

[0076] The present invention further provides a pharmaceutical composition comprising the solid dispersion, wherein the pharmaceutical composition exhibits good disintegration effects and disintegration times are all within the limits of the pharmacopoeia. Therefore, the pharmaceutical composition of the present invention provides convenience for the subsequent development of dosage forms of the active ingredient.

[0077] In this application, "multiple types" means two types or more than two types. [Modes for carrying out the invention]

[0078] The present invention will be further described below with reference to examples, but this does not limit the present invention to the scope of the above examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or according to the product description.

[0079] The manufacturing method and use of the present invention will be described in more detail below with specific examples. The following examples are merely illustrative and interpretive of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies realized based on the foregoing aspects of the present invention are included within the scope of protection of the present invention.

[0080] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be manufactured by known methods. [Examples]

[0081] Related reagents and their origins:

[0082] [Table 1-1]

[0083] The English abbreviations in the following examples have the following meanings.

[0084] Cremofor EL: Polyoxyethylene castor oil, Poloxamer 407: Poloxamer 407, Poloxamer 188: Poloxamer 188, Tween 80: Tween 80; HPC-SSL: Hydroxypropyl cellulose, Eudragit L100: Polyacrylic acid resin L100, SLS: Sodium lauryl sulfate, sodium coco sulfate, sodium dodecyl sulfate, Soluplus: Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, HPMC E3: Hypromellose E3, TFA: Trifluoroacetic acid, Avg. Dis: Mean value, RSD: Relative standard deviation, FA: Fatty acid.

[0085] Experimental method: HPLC method (content and related substances)

[0086] [Table 1-2]

[0087] UPLC method (two-step elution)

[0088] [Table 1-3]

[0089] Polarizing microscope (PLM) Details of the polarized light microscopy method used in the test: Instrument model: Nikon LV100POL polarized light microscope, Detection method: Sample placed on a glass slide, dispersed in silicone oil, and then observed, Eyepiece: 50x, Objective lens: 5-50x.

[0090] Powder X-ray diffraction (XRPD) Instrument model used: A Bruker D8 advance powder X-ray diffractometer was used to evaluate the properties of the solid sample.

[0091] The sample will be analyzed by XRPD under the following conditions.

[0092] X-ray tube: Cu:K-Alpha (λ = 1.54179 Å), tube voltage: 40 kV, tube current: 40 mA, scan range: 3 - 40 deg., sample pan rotation: 15 rpm, scan speed: 10 deg. / min.

[0093] Thermogravimetric analysis (TGA) Instrument model: TAQ5000 thermogravimetric analyzer. Put the sample (2 - 10 mg) into an aluminum pan and perform the test in the following method. Put the sample into the TGA aluminum pan for testing and heat the sample from room temperature to 300 °C (or until a 20% weight loss is observed) at a heating rate of 10 °C / min under a N2 atmosphere of 25 mL / min for analysis.

[0094] Differential scanning calorimetry (DSC) Instrument model: TAQ2000 differential scanning calorimeter. Details of the DSC method used in the experiment: Put the sample (~4 mg) into a DSC aluminum pan with a perforated lid and heat the sample from room temperature to 250 °C at a heating rate of 2 °C / min under a N2 atmosphere of 50 mL / min for analysis.

[0095] Example 1: Method for preparing Compound 1 Compound 1 was prepared by referring to Example 1 of Published Patent WO2021104486A1.

[0096]

Chemical formula

[0097] Example 2: Solubilization test of surfactant for Compound 1 Weighed 50 mg of Compound 1 into 5 mL of FaSSIF medium containing 5 mg of different surfactants (target concentration of API (Compound 1): 10 mg / mL). Shake it at 500 rpm / 37 °C for 0.5 h, 1 h, 2 h and 4 h, take 0.5 mL of the suspension sample respectively, centrifuge it at 14000 rpm for 5 minutes, take the supernatant, dilute it and then analyze it by HPLC. The test results are as shown in Table 1.

[0098] Table 1: Solubility results of Compound 1 in FaSSIF containing 10% by weight of surfactant

[0099] [Table 1-4]

[0100] The results showed that the surfactants SLS, Cremofor EL, Cremofor RH40, VE-TPGS, Tween 80, Poloxamer 407, and Solutol HS15 could all significantly improve the solubility of compound 1.

[0101] Example 3: Preparation of a solid dispersion (SDD) of compound 1 by solvent method According to the carrier polymer, solvent composition, and material ratio shown in Table 2 below, 9 mg of compound 1 and 21 mg of carrier polymer (in a mass ratio of 3:7) were weighed out, transferred to 40 mL glass vials, and 1 mL of the corresponding solvent was added to each to prepare a sample solution with a 30% drug load. All sample solutions were transferred to an 80°C oven and allowed to stand until the solvent had completely evaporated. The appearance of the resulting solids was observed and recorded.

[0102] Table 2: Preparation of solid dispersion of compound 1 by solvent method

[0103] [Table 2]

[0104] Example 4: Preparation of a solid dispersion of compound 1 by spray drying method A solid dispersion corresponding to compound 1 was prepared by spray drying with the carrier polymer and solvent shown in Table 3 below.

[0105] Compound 1 and the corresponding carrier polymer were added to the corresponding solvent at a 30% drug load, stirred at 700 rpm until compound 1 and the corresponding carrier polymer were completely dissolved, and then spray-dried. All spray-dried samples were vacuum-dried at 50°C for 20-24 hours and characterized by polarized light microscopy (PLM), powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), dynamic vapor adsorption (DVS), and thermogravimetric analysis (TGA), respectively. The formulations and spray-drying parameters for each solid dispersion are shown in Table 3, and the characterization results for PLM, XRPD, DVS, DSC, and TGA are shown in Table 4.

[0106] Table 3: Material ratios and manufacturing parameters for producing solid dispersions by spray drying.

[0107] [Table 3-1]

[0108] [Table 3-2]

[0109] [Table 4]

[0110] Characterization results showed that all manufactured samples were amorphous and that the solvent residue levels complied with pharmacopoeia requirements.

[0111] Example 5: Dynamic solubility experiment of solid dispersions 20 mg each of the solid dispersions of formulations 1-9 obtained in Example 4 was taken, and 3 mL of SGF (API target concentration: 2 mg / mL) was added to each. The mixture was stirred for 0.25 hours and 0.5 hours under conditions of 37°C / 500 rpm, and then samples were taken. Next, 3 mL of 2×FaSSIF was added to adjust the pH of the solution to approximately 6.5. Stirring was continued for 0.25 h, 0.5 h, 1 h, and 1.5 h, and samples were taken at each stage. The collected samples were detected by UPLC, and the pH of the final solution was measured. The test results are shown in Table 5.

[0112] [Table 5]

[0113] The results showed that the solid dispersions using PVP-K30, PVP-VA64, and HPMCASMG as carriers all exhibited significantly improved elution compared to APIs. Furthermore, the elution data for the solid dispersions of formulations 5 and 6 using PVP-VA64 as a carrier indicated that the solubility changes of the solid dispersions of formulations 5 and 6 were stable over time and within an appropriate range.

[0114] Example 6: Stability test of a solid dispersion of compound 1 produced by spray drying. The stability of the solid dispersion products produced in Example 3 and Example 4 was detected under conditions of 25°C / 60%RH (open) and 40°C / 75%RH (open). Samples were taken after 2 weeks and 4 weeks, respectively, and the appearance, purity, and impurities of the samples were detected. The results are shown in Tables 6 and 7.

[0115] [Table 6-1]

[0116] [Table 6-2]

[0117] [Table 6-3]

[0118] [Table 7]

[0119] The results showed that all samples exhibited good chemical stability under 25°C / 60% RH (open) and 40°C / 75% RH (open) conditions, with no significant increase in impurities.

[0120] The physical stability results showed that the appearance of the samples from formulations 1-6 and 8 did not change significantly, except for some partial solidification.

[0121] The solid dispersions of formulations 4, 5, 6, and 8 maintained good physical stability and were all amorphous even after being left for 4 weeks under conditions of 25°C / 60% RH (open) and 40°C / 75% RH (open).

[0122] Example 7: Experiment to produce a solid dispersion of a scale-up sample A spray-dried solution with a concentration of 15 mg / mL (calculated based on API) was prepared using acetone:ethanol:water = 4:3.5:2.5 (v:v:v) as the solvent, and scale-up sample preparation was carried out according to the proposed process parameters (see Table 8).

[0123] Referring to the formulation list, 50 g of compound 1 was weighed and added to acetone. After stirring until completely dissolved, ethanol and water were added and mixed uniformly. Then, the formulation amounts of PVP VA64 and SLS were added to the solvent. All solids were stirred under 700 rpm until completely dissolved, then spray-dried. The resulting spray-dried sample was vacuum-dried at 50°C for 20-24 hours to obtain the product.

[0124] [Table 8]

[0125] Example 8: Manufacturing of solid dosage form and disintegration experiment Manufacturing Examples 1-5 and Comparative Examples 1-7 in Table 9 below were all manufactured using a dry granulation process, and the specific procedure is as follows: The materials were accurately weighed according to the formulation. Here, the solid dispersion of compound 1 was not sieved, while the other excipients were sieved for later use. After pre-mixing the internally added fillers, disintegrants, and flow promoters with the solid dispersion, grinding and sieving were performed. After adding a lubricant, dry granulation was carried out. After adding the externally added fillers, disintegrants, leavening agents, and lubricants, final mixing was performed. After final mixing, the required amount of active ingredient was packaged, and then the mixture was compressed to obtain tablets conforming to the formulation specifications.

[0126] The resulting tablets were subjected to a disintegration test according to the disintegration time test of the Chinese Pharmacopoeia 2020 edition, and the disintegration times of each production example and comparative example are shown in Tables 9 and 10 below.

[0127] [Table 9]

[0128] [Table 10-1]

[0129] [Table 10-2]

[0130] Note: In Tables 9 and 10, " / " indicates that this component is not included.

[0131] The following was found from the decay time results: The disintegration times of the tablets in Comparative Example 7 and Comparative Examples 1, 3-6, which did not contain inorganic salts, all exceeded the pharmacopoeia specifications. The disintegration time of the tablet in Production Example 1, to which 1% sodium chloride was added, was shortened to approximately 6 minutes; the disintegration time of the tablet in Production Example 2, to which 5% sodium chloride was added, was shortened to approximately 2 minutes; the disintegration time of the tablet in Production Example 3, to which 10% sodium chloride was added, was shortened to 1.5 minutes; the disintegration time of the tablet in Production Example 4, to which 5% sodium chloride was added internally and 5% sodium chloride was added externally to the granules, was shortened to 1.5 minutes; the disintegration time of the tablet in Production Example 5, to which 5% sodium bicarbonate was added, was shortened to approximately 5 minutes; and the disintegration times of the tablets in Production Examples 1-5 were significantly improved, all shortened to within the pharmacopoeia specifications. Furthermore, while the tablets in Comparative Examples 1-7 disintegrated by erosion, the tablets in Production Examples 1-5 disintegrated by water absorption and swelling, breaking down into lumps and granules.

[0132] The results above show that the addition of inorganic salts effectively inhibits the gelation of PVP-VA64, thereby promoting the rapid disintegration of the tablets. Sodium chloride showed the most significant disintegration-promoting effect, reducing the disintegration time to 6 minutes with a dosage of only 1%, and further reducing it to within 2 minutes with additions of 5% and 10% outside the granules. Sodium bicarbonate also showed excellent disintegration-promoting effect, reducing the disintegration time to 5 minutes with an addition of 5% outside the granules.

[0133] Example 9: Dissolution experiment of solid formulation Based on the pH values ​​of commonly used elution media and the solubility test results of the solid dispersions mentioned above, a pH 1.2 hydrochloric acid medium and a pH 1.2 hydrochloric acid + 0.3% SLS medium were selected to detect the elution results. The elution detection methods are shown in Tables 11 and 12 below, and the detection data analysis results are shown in Tables 13 and 14.

[0134] [Table 11]

[0135] [Table 12]

[0136] [Table 13]

[0137] [Table 14]

[0138] The elution results revealed the following: In a hydrochloric acid solution with a pH of 1.2, the elution rates of production examples 3-5 were faster than those of comparative examples 2, 4, and 7.

[0139] In a pH=1.2 hydrochloric acid solution + 0.3% SLS medium, the final dissolution rates for Comparative Example 7 and Production Examples 1-5 all reached approximately 100%. Production Examples 3-5 showed faster dissolution rates compared to Comparative Example 7 and Production Examples 1-2, with Production Example 5 reaching an 86% dissolution rate in 30 minutes, demonstrating the most significant advantage. In summary, from the disintegration time, it can be seen that the tablets of Production Examples 1-5 all effectively shortened their disintegration time to within the pharmacopoeia limits. From the dissolution data and dissolution phenomena, it can be seen that Production Examples 1 and 5 showed faster dissolution rates and higher dissolution rates than Production Examples 2, 3, and 4, and rapidly disintegrated into granules in the dissolution container without forming clumps.

[0140] Example 10: Pharmacokinetic experiment Experiment Preparation 1 SPF-grade SD rats were divided into two groups of male rats, with three rats in each group, and their weight range was 160-320g [Source: Beijing Vital River Laboratory Animal Technology Co., Ltd., Certificate Number: 1103242011040898].

[0141] Preparation: Following the drug concentration and dosage requirements in Table 15 below, the API was accurately weighed, 5% of the required volume of Solutol was added, vortexed for 2 minutes, sonicated for 10 minutes, stirred for 1 hour, and then administered.

[0142] [Table 15-1]

[0143] Experiment Preparation 2 SPF-grade SD rats were divided into six groups of male rats, with three rats in each group, and their weight range was 160-320g [Source: Beijing Vital River Laboratory Animal Technology Co., Ltd., Certificate Number: 110011210113195883 (males)].

[0144] Preparation: Accurately weigh 80 mg of the corresponding sample from the table below, disperse it in the required volume of pure water, vortex for 5 minutes, and then administer intragastricly (ig). The dosage was increased proportionally based on the body weight and concentration of the experimental animals.

[0145] Sample collection and preparation After administering the drug to SD rats in groups 1 and 2, approximately 0.2–0.3 mL of blood sample was collected from the orbital venous plexus at 0.167, 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 post-administration time points into anticoagulation EP tubes (containing 4 μL of EDTA-K2, 375 mg / mL). The tubes were gently inverted three times, stored in an icebox (not exceeding 30 minutes), centrifuged at 3500 × g for 10 minutes at 4°C, the supernatant was transferred to a labeled EP tube, plasma hemolysis was observed and recorded, and then biological analysis was performed.

[0146] Analysis of the sample: Sample preparation process: 40 μL of the sample was mixed with 160 μL of acetonitrile containing 0.1% FA and a mixed internal standard of 200 ng / mL. The protein was precipitated, and the mixture was homogenized by vortexing. The sample was then centrifuged at 13000 rpm at 4°C for 10 minutes.

[0147] Transfer 110 μL of the supernatant to another 96-piece deep well plate, add 110 μL of a methanol: water (1:3, v: v) solution containing 0.1% FA thereto, shake for 10 minutes to mix, and then analyze using an LC-MS / MS system, which was gradient eluted with an XBridge BEH C18 (2.1×50 mm, 2.5 μm) column on a Sciex Exion LC AD high performance liquid chromatography system and analyzed with an AB Sciex Qtrap 4500 mass spectrometer. The mass spectrometer monitored tolbutamide using an electrospray ionization (ESI) source in positive ion mode, and the parent ion→daughter ion mass charge ratios (m / z) were 415.1→263.1 and 271.1→155, respectively.

[0148] Data analysis The data were analyzed using WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) in a non-compartmental model to obtain PK parameters (parameters such as C max , T max , T 1 / 2 , AUC last etc.).

[0149]

Table 15-2

[0150]

Table 16

[0151] The results showed that after producing Compound 1 as a solid dispersion, the obtained solid dispersion had significantly improved C max , T max , T 1 / 2 , AUC last values compared with the API, and it was found that the in vivo absorption and bioavailability of the API were effectively improved.

[0152] Embodiments of the present disclosure have been described above. However, the present invention is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention are within the scope of protection of the present invention.

Claims

1. A solid dispersion of a P2X4 inhibitor, The product comprises an active ingredient and a carrier, wherein the active ingredient is selected from at least one of the following compounds 1 to 48, or pharmaceutically acceptable salts thereof. 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 The carrier is characterized by being selected from one or more of the following: copovidone, povidone, hypromellose acetate succinate, hypromellose phthalate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl cellulose, hypromellose, polyacrylic acid resin, cellulose acetate phthalate, methacrylic acid-methyl methacrylate copolymer, or polyethylene oxide, and is a solid dispersion of a P2X4 inhibitor.

2. The solid dispersion further comprises a surfactant, Preferably, the surfactant is selected from a mixture obtained by mixing one or more of the following in any proportion: sodium lauryl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, tween, hydrogenated castor oil, glycerol monostearate, vitamin E polyethylene glycol succinate, polyoxyethylene castor oil derivative, poloxamer, or sorbitol HS15. A solid dispersion of a P2X4 inhibitor according to claim 1, wherein the surfactant is selected from a mixture obtained by mixing one or more of sodium lauryl sulfate, vitamin E polyethylene glycol succinate, and Cremophor RH40 in any proportion.

3. The mass ratio of the active ingredient to the carrier is 1:(1 to 7), preferably 1:(2 to 5). Preferably, the mass ratio of the active ingredient, carrier and surfactant is 1:(1-7):(0.1-1), and more preferably, 1:(2-5):(0.1-1), characterized in that it is a solid dispersion of the P2X4 inhibitor according to claim 2.

4. The solid dispersion comprises compound 1, copovidone, and cremophor RH40. Alternatively, comprising compound 1, copovidone and SLS, Alternatively, the compound comprises compound 1, copovidone, and vitamin E polyethylene glycol succinate (VE-TPGS), Preferably, the solid dispersion comprises compound 1, PVP-VA64, and SLS. Alternatively, the compound comprises compound 1, PVP-VA64 and vitamin E polyethylene glycol succinate (VE-TPGS), Preferably, the solid dispersion contains, by weight, 1 part by weight of compound 1, 1 to 7 parts by weight of PVP-VA64 and 0.1 to 1 part by weight of SLS, or 1 part by weight of compound 1, 1 to 7 parts by weight of PVP-VA64 and 0.1 to 1 part by weight of vitamin E polyethylene glycol succinate (VE-TPGS), as a component, the solid dispersion of a P2X4 inhibitor according to any one of claims 1 to 3.

5. A method for producing a solid dispersion according to any one of claims 1 to 4, characterized by being produced using a spray drying method, a solvent method, or a hot melt extrusion method, and comprising the following steps: Spray drying method: A step in which raw materials are added to solvent S1 to produce a solution, and then spray-dried to obtain a solid dispersion. Solvent method: The raw materials are added to solvent S2 to produce a solution, the solvent is removed from the resulting solution, dried, and pulverized to obtain a solid dispersion. Hot melt extrusion method: After mixing the raw materials, an appropriate amount of lubricant is optionally added and the mixture is extruded using the hot melt method. The solvent S1 is a ketone-based solvent, or a mixed solvent consisting of a ketone-based solvent and a halogenated alkane-based solvent, water, or an alcohol-based solvent. The solvent S2 is a ketone-based solvent, or a mixed solvent consisting of a ketone-based solvent and a halogenated alkane-based solvent or an alcohol-based solvent. Preferably, the solvent S1 is a two-component mixed solvent consisting of a ketone solvent, a halogenated alkane solvent, water, and an alcohol solvent, and the volume ratio of the ketone solvent to the other solvents is (1 to 10):

1. More preferably, the solvent S1 is a two-component mixed solvent consisting of acetone and a solvent dichloromethane, ethanol, and water, and the volume ratio of acetone to the other solvents is (1 to 5):

1.

6. The solvent S1 is a mixed solvent consisting of acetone, ethanol, and water. Preferably, the volume ratio of acetone, ethanol, and water in solvent S1 is 1:(0.8-1):(0.2-0.7), Preferably, when the solvent S2 is a two-component mixed solvent, the volume ratio of the ketone to the other solvent is (1 to 10):1, as described in claim 5.

7. A pharmaceutical composition comprising a solid dispersion according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition according to claim 7, characterized in that the pharmaceutically acceptable excipient comprises one or more of fillers, lubricants, and disintegrants.

9. The filler is a mixture obtained by mixing one or more selected from lactose, dextrin, mannitol, microcrystalline cellulose, starch, pregelatinized starch, cellulose lactose, calcium hydrogen phosphate, and mannitol-starch complex in any proportion. Preferably, the lubricant is a mixture obtained by mixing one or more selected from talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, hydrated silicon dioxide, hydrophobic silicon dioxide, sodium stearyl fumarate, polyethylene glycol, sodium stearyl fumarate, glycerol monostearate, and hydrogenated vegetable oil in any proportion. Preferably, the disintegrant is selected from a mixture obtained by mixing one or more of the following in any proportion: dried starch, croscarmellose sodium, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, methylcellulose, low-substituted hydroxypropylcellulose, crospovidone, chitosan, and microcrystalline cellulose. Preferably, in the pharmaceutical composition, the content of the solid dispersion is 30% to 50% by weight, the content of the filler is 20% to 50%, the content of the disintegrant is 1% to 15%, and the content of the lubricant is 1% to 15%. Preferably, in the pharmaceutical composition, the content of the solid dispersion is 35% to 45% by weight, the content of the filler is 35% to 45%, the content of the disintegrant is 1% to 10%, and the content of the lubricant is 1% to 10%. The pharmaceutical composition according to claim 8, more preferably characterized in that, by weight percentage, the solid dispersion content is 40% to 45%, the filler content is 40% to 45%, the disintegrant content is 5% to 10%, and the lubricant content is 1% to 5%.

10. The aforementioned pharmaceutical composition further comprises a disintegration accelerator. Preferably, the disintegration accelerator is selected from a mixture obtained by mixing one or more of the following in any proportion: sodium chloride, sodium carbonate, calcium carbonate, potassium carbonate, calcium magnesium carbonate, zinc carbonate, magnesium carbonate, ammonium carbonate, sodium glycine carbonate, sodium sesquicarbonate, sodium bicarbonate, calcium bicarbonate, potassium bicarbonate, or ammonium bicarbonate. Preferably, in the pharmaceutical composition, by weight percentage, the solid dispersion content is 30% to 50%, the filler content is 20% to 50%, the disintegrant content is 1% to 15%, the lubricant content is 1% to 15%, and the disintegration accelerator content is 0.1% to 10%. Preferably, the solid dispersion content is 35% to 45% by weight, the filler content is 35% to 45%, the disintegrant content is 1% to 10%, the lubricant content is 1% to 10%, and the disintegration accelerator content is 1% to 10%. The pharmaceutical composition according to claim 9, more preferably characterized in that, by weight percentage, the solid dispersion content is 40% to 45%, the filler content is 40% to 45%, the disintegrant content is 5% to 10%, the lubricant content is 1% to 5%, and the disintegration accelerator content is 5% to 10%.

11. A method for producing a pharmaceutical composition according to any one of claims 7 to 9, characterized by comprising the step of mixing a solid dispersion according to any one of claims 7 to 9 with a pharmaceutically acceptable excipient.

12. The aforementioned pharmaceutical composition is manufactured by a dry granulation process, Preferably, the dry granulation method is characterized by weighing the materials in the amounts to be blended, where the solid dispersion is not sieved, other excipients are sieved for later use, the internally added filler, disintegrant, flow promoter and solid dispersion are pre-mixed, then crushing and sieving are performed, a lubricant is added and dry granulation is performed, then the externally added filler, disintegrant, leavening agent and lubricant are added, and finally mixing and tableting is performed, as described in claim 11.

13. Use of a solid dispersion according to any one of claims 1 to 4, or a pharmaceutical composition according to any one of claims 7 to 10, in the manufacture of a P2X4 receptor antagonist.

14. The P2X4 receptor antagonist is used to treat respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative disorders, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related disorders, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue developmental disorders, or systemic disorders. The aforementioned respiratory diseases include respiratory disorders such as idiopathic pulmonary fibrosis, respiratory failure, chronic obstructive pulmonary disease, asthma, bronchospasm, cough (e.g., acute cough, chronic cough), refractory chronic cough, and idiopathic chronic cough. The aforementioned urinary tract diseases include, for example, urinary incontinence, overactive bladder, voiding dysfunction, benign prostatic hyperplasia, cystitis (e.g., interstitial cystitis), bladder pain syndrome, and prostatitis. The aforementioned gynecological diseases include, for example, endometriosis, primary and secondary dysmenorrhea, dyspareunia, and adenomyosis. The aforementioned ophthalmic diseases include, for example, dry eye syndrome, neuropathic pain of the eye, eye trauma, and postoperative eye pain. The aforementioned gastrointestinal disorders include, for example, gastrointestinal disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, and gastroesophageal reflux disease. The aforementioned proliferative disorders include, for example, tumors such as cancer. The aforementioned cardiovascular diseases include, for example, myocardial infarction, thrombosis, atherosclerosis, heart failure, and hypertension. The aforementioned neurodegenerative diseases include, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, ischemic brain injury, and traumatic brain injury. The aforementioned inflammations include, for example, arthritis, rheumatoid arthritis, ankylosing spondylitis and associated neuropathic pain, and gout. The aforementioned pain-related disorders include, for example, hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, inflammatory pain, postoperative pain, visceral pain, toothache, periodontitis, premenstrual syndrome, endometrial pain, fibrosis-related pain, central pain, burning pain, and migraines. The use according to claim 13, characterized in that the pain-related disease is, for example, pain due to neuritis, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, pain due to cancer, or pain due to traumatic nerve injury.

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