Solid dispersion of p2x4 inhibitor, and preparation method therefor and use thereof

Abstract

A solid dispersion of a P2X4 inhibitor, comprising an active ingredient and a carrier. The obtained solid dispersion can improve the solubility and dissolution effect of the active ingredient, has a good stability, and has no obvious increase in impurities under 25°C / 60％ RH (open) and 40°C / 75％ RH (open) conditions. The method for preparing the solid dispersion is simple. The solid dispersion can be prepared using a spray drying method, a solvent method, or a hot-melt extrusion method, and the solvent residue content in the obtained product is qualified. Furthermore, the obtained solid dispersion effectively improves the pharmacokinetic effect of the active ingredient. A pharmaceutical composition containing the solid dispersion. The pharmaceutical composition has a good disintegration effect, and the disintegration time is within pharmacopoeial limits. Therefore, the pharmaceutical composition provides convenience for the development of subsequent dosage forms of the active ingredient.

Description

A P2X4 inhibitor solid dispersion and its preparation method and application

[0001] This application claims priority to the following prior applications: Patent Application No. 2023107248878, filed with the State Intellectual Property Office of China on June 16, 2023, entitled “A Solid Dispersion of a P2X4 Inhibitor, Its Preparation Method, and Application”; and Patent Application No. 2024105673321, filed with the State Intellectual Property Office of China on May 9, 2024, entitled “A Solid Dispersion of a P2X4 Inhibitor, Its Preparation Method, and Application”. The entire contents of these two prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medical technology, and specifically relates to a P2X4 inhibitor solid dispersion, a preparation method and an application thereof. Background Art

[0003] Purinergic receptors are widely present in almost all mammalian cell membranes and participate in the regulation of multiple biological signaling pathways. Purinergic receptors can be divided into adenosine and ATP receptors. ATP receptors are roughly divided into the P2X family of ion channel receptors and the P2Y family of G protein conjugated receptors. P2X receptors are widely distributed in various tissues throughout the body, including the brain, lungs, neurons, glial cells, heart, blood vessels, etc. To date, 7 subtypes of P2X receptors (P2X1 to 7) have been disclosed. Among them, the P2X4 receptor is the only subtype of the P2X family whose crystal structure has been solved, and its resolution is as high as 1000 nm. And the study found that P2X4 is Ca 2+ The most permeable P2X isoform.

[0004] Currently, P2X4 inhibitors are the research and development focus of many companies.

[0005] Patent document WO2016198374A1 discloses multiple P2X4 inhibitor compounds, which are antagonists or negative allosteric modulators of P2X4. Such compounds are used to treat or prevent pain-related diseases, or to treat or prevent pain syndromes (acute and chronic), inflammation-induced pain, neuropathic pain, pelvic pain, cancer-related pain, endometriosis-related pain, as well as endometriosis itself, cancer itself, and proliferative diseases similar to endometriosis itself, and can be used as a single agent or in combination with other active ingredients.

[0006] Patent document WO2017191000A1 discloses a plurality of P2X4 inhibitor compounds, which are used as sole agents or in combination with other active ingredients to manufacture pharmaceutical compositions for treating or preventing diseases (especially diseases in mammals, such as but not limited to diseases associated with pain) or for treating or preventing pain or neuronal damage and inflammation in the brain or bone marrow or arthritis or spondylitis syndrome (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-related pain, endometriosis-related pain, as well as endometriosis itself, cancer itself, multiple sclerosis itself, bone marrow or ischemic brain injury itself.

[0007] Patent document WO2019081573A1 discloses the use of multiple P2X4 inhibitor compounds for preparing drugs for treating hemorrhagic stroke and traumatic brain injury.

[0008] Patent documents WO2022002859A1 and WO2022002860A1 disclose multiple phenylacetamide compounds with P2X4 receptor antagonist activity, as well as the use of multiple phenylacetamide compounds with P2X4 receptor antagonist activity in the preparation of drugs for treating certain eye diseases.

[0009] Patent document WO2021104486A1 discloses a benzene ring-containing compound and its application. It discloses multiple benzene ring-containing compounds as P2X4 inhibitors and further discloses that these compounds are used to treat P2X4-mediated related diseases. Compounds 1 to 48 are disclosed. These compounds have high inhibitory activity against P2X4, good selectivity, low toxicity, and good metabolic stability. However, these compounds have poor dissolution effects, so it is necessary to develop formulations for these compounds to improve the above-mentioned problems.

[0010] Summary of the Invention

[0011] The present invention aims to address the deficiencies of the prior art and to provide a solid dispersion of a P2X4 inhibitor, comprising: an active ingredient and a carrier; the active ingredient is selected from at least one of the following compounds 1 to 48 or pharmaceutically acceptable salts thereof:

[0012] The carrier is selected from one or more of copovidone, povidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate (HPMPCP), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid resin, cellulose acetate phthalate (CAP), methacrylic acid-methyl methacrylate copolymer, or polyethylene oxide (PEO), preferably copovidone, hydroxypropyl methylcellulose acetate succinate or povidone, and most preferably copovidone.

[0013] According to an embodiment of the present invention, in the carrier, the copolyvidone is PVP-VA64, which is also known as polyvinyl pyrrolidone / vinyl acetate copolymer. Polyvinyl pyrrolidone / vinyl acetate copolymer is a series of linear copolymers of N-vinyl pyrrolidone (NVP) and vinyl acetate (VA). Commonly used copolyvidones on the market include: PVP-VA64, Kollidon VA64, Plasdone S-630, etc.; the povidone is PVP-K30, wherein povidone is a series of water-soluble homopolymers of N-vinyl pyrrolidone (NVP), and commonly used povidones include PVP-K30, PVP-K90, etc.; the hydroxypropyl methylcellulose is HPMC E3; the polyacrylic acid resin is Eudragit L100.

[0014] According to an embodiment of the present invention, the solid dispersion further comprises a surfactant.

[0015] According to an embodiment of the present invention, the surfactant is selected from sodium lauryl sulfate (abbreviated as SLS or SDS), sodium cetyl sulfate, sodium octadecyl sulfate, Tween (for example, Tween 80, 60, 40 and 20), hydrogenated castor oil (for example, Cremophor EL), glyceryl monostearate, vitamin E polyethylene glycol succinate (VE-TPGS), polyoxyethylene castor oil derivatives (such as Cremophor RH40), poloxamer (for example, poloxamer F68, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, etc.), or polyethylene glycol-15 hydroxystearate (Solutol HS15), a mixture of one or more of them mixed in any proportion, preferably a mixture of one or more of sodium lauryl sulfate, vitamin E polyethylene glycol succinate, and Cremophor RH40 mixed in any proportion.

[0016] In a preferred embodiment, the active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof.

[0017] According to an embodiment of the present invention, compounds 1 to 48 can refer to the compounds disclosed in patent document WO2021104486A1, the entire text of which is incorporated herein by reference.

[0018] According to an embodiment of the present invention, the mass ratio of the active ingredient to the carrier is 1:(1-7), preferably 1:(2-5), more preferably 3:(6-7), and most preferably 3:7.

[0019] According to some embodiments of the present invention, the mass ratio of the active ingredient to the carrier is 1:(1-7), preferably 1:(2-5), more preferably 3:(6-9), and most preferably 1:2.8.

[0020] According to an embodiment of the present invention, the solid dispersion comprises: an active ingredient, a carrier and a surfactant; the mass ratio of the active ingredient, the carrier and the surfactant is 1:(1-7):(0.1-1), preferably 1:(2-5):(0.1-1), for example, 3:6.5:0.5.

[0021] In some embodiments of the present invention, the solid dispersion comprises: Compound 1 and copovidone;

[0022] Alternatively, compound 1 and povidone;

[0023] Alternatively, Compound 1 and hydroxypropylmethylcellulose acetate succinate;

[0024] Alternatively, compound 1, copovidone and Cremophor RH40;

[0025] Alternatively, compound 1, copolyvidone and SLS,

[0026] Alternatively, compound 1, copolyvidone and VE-TPGS;

[0027] Alternatively, compound 1, povidone and Cremophor RH40;

[0028] Alternatively, compound 1, povidone and SLS;

[0029] Alternatively, compound 1, povidone and VE-TPGS.

[0030] In some embodiments of the present invention, the solid dispersion comprises: Compound 1, copovidone and Cremophor RH40;

[0031] Alternatively, compound 1, copolyvidone and SLS,

[0032] Alternatively, compound 1, copolyvidone and VE-TPGS;

[0033] Alternatively, compound 1, povidone and Cremophor RH40;

[0034] Alternatively, compound 1, povidone and SLS;

[0035] Alternatively, compound 1, povidone and VE-TPGS.

[0036] In some embodiments of the present invention, the solid dispersion comprises: Compound 1, copovidone and Cremophor RH40;

[0037] Alternatively, compound 1, copolyvidone and SLS,

[0038] Alternatively, Compound 1, copovidone and VE-TPGS.

[0039] In some embodiments of the present invention, the solid dispersion comprises: Compound 1, copovidone and SLS;

[0040] Alternatively, Compound 1, copovidone and vitamin E polyethylene glycol succinate (VE-TPGS).

[0041] In some specific embodiments of the present invention, the solid dispersion comprises: Compound 1, PVP-VA64 and SLS;

[0042] Alternatively, compound 1, PVP-VA64 and vitamin E polyethylene glycol succinate (VE-TPGS).

[0043] In some specific embodiments of the present invention, the solid dispersion comprises the following components in parts by weight: 1 part by weight of compound 1, 1-7 parts by weight of a carrier and 0.1-1 parts by weight of a surfactant, wherein the carrier is selected from any one of copovidone, povidone or hydroxypropyl methylcellulose acetate succinate, and the surfactant is selected from any one of sodium lauryl sulfate, vitamin E polyethylene glycol succinate (VE-TPGS), and polyoxyethylene castor oil derivatives (such as Cremophor RH40).

[0044] In some specific embodiments of the present invention, the solid dispersion comprises the following components in parts by weight: 1 part by weight of Compound 1, 1-7 parts by weight of PVP-VA64 and 0.1-1 parts by weight of SLS; or, 1 part by weight of Compound 1, 1-7 parts by weight of PVP-VA64 and 0.1-1 parts by weight of vitamin E polyethylene glycol succinate (VE-TPGS).

[0045] The present invention also provides a method for preparing the solid dispersion as described above, which is prepared by a spray drying method, a solvent method, or a hot melt extrusion method, comprising the following steps:

[0046] Spray drying method: the raw material is added to solvent S1 to prepare a solution, which is then spray-dried. In a formulation including a surfactant, the active ingredient, carrier, and surfactant are added to solvent S1 to prepare a solution, which is then spray-dried.

[0047] Solvent method: Add the raw materials into solvent S2 and stir evenly until the raw materials are completely dissolved to obtain a solution, then remove the solvent from the obtained solution, dry and grind it to obtain a solid dispersion;

[0048] Hot melt extrusion method: After mixing the raw materials, optionally add an appropriate amount of lubricant and perform hot melt extrusion;

[0049] The solvent S1 is a ketone solvent, or a mixed solvent consisting of a ketone solvent and the following solvents: a halogenated alkane solvent, water, or an alcohol solvent;

[0050] The solvent S2 is a ketone solvent, or a mixed solvent consisting of a ketone solvent and the following solvents: a halogenated alkane solvent, and an alcohol solvent.

[0051] The “raw materials” mentioned in the above-mentioned method for preparing solid dispersion include active ingredients and carriers; when the solid dispersion further includes a surfactant, the raw materials include active ingredients, carriers and surfactants.

[0052] According to an embodiment of the present invention, the raw materials in the above-mentioned solid dispersion preparation method 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 different solid dispersion preparation requirements;

[0053] The term "optionally" includes not selecting, or selecting one, two or more of the options.

[0054] According to an embodiment of the present invention, the ketone solvent may be one or more of acetone, butanone and methyl isobutyl ketone, preferably acetone.

[0055] According to an embodiment of the present invention, the halogenated alkane solvent is dichloromethane.

[0056] According to an embodiment of the present invention, the alcohol solvent is methanol, ethanol or propanol.

[0057] According to an embodiment of the present invention, the solvent S1 is a two-component mixed solvent consisting of a ketone solvent and the following solvents: a halogenated alkane solvent, water, and an alcohol solvent, and the volume ratio of the ketone solvent to the other solvent is (1-10):1, for example (1-5):1.

[0058] According to an embodiment of the present invention, the solvent S1 is a two-component mixed solvent consisting of acetone and the following solvents: dichloromethane, ethanol, and water, and the volume ratio of the acetone to the other solvent is (1-5):1.

[0059] According to an embodiment of the present invention, the solvent S1 is a two-component mixed solvent of acetone and dichloromethane, and the volume ratio of acetone to dichloromethane is 6:4; or, the solvent S1 is a two-component solvent of acetone and water, and the volume ratio of acetone to water is 7:3; or, the solvent S1 is a two-component solvent of acetone and ethanol, and the volume ratio of acetone to ethanol is 1:1.

[0060] According to an embodiment of the present invention, the solvent S1 is a mixed solvent consisting of acetone, ethanol and water.

[0061] According to a specific embodiment of the present invention, the solvent S1 is a mixed solvent consisting of acetone, ethanol and water, wherein 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.

[0062] According to an embodiment of the present invention, when the solvent S2 is a two-component mixed solvent, the volume ratio of the solvent S2 to the other solvent is (1-10):1, for example (5-9):1.

[0063] According to an embodiment of the present invention, when the spray drying method is adopted, the concentration of the active ingredient in the obtained solution is 5-50 mg / mL, such as 15-25 mg / mL.

[0064] According to an embodiment of the present invention, when the solvent method is adopted, the mass fraction of the active ingredient in the obtained solution is 5%-50%, for example, 10%-40%.

[0065] According to an embodiment of the present invention, in the scheme of preparing the solid dispersion by hot melt extrusion, the lubricant is selected from one or more of talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, hydrated silicon dioxide, hydrophobic silicon dioxide, sodium octadecyl fumarate, polyethylene glycol, sodium stearyl fumarate, glyceryl monostearate, and hydrogenated vegetable oil, and the mixture is mixed in any proportion.

[0066] The present invention also provides a pharmaceutical composition comprising the solid dispersion and pharmaceutically acceptable excipients.

[0067] According to an embodiment of the present invention, the pharmaceutical composition is prepared into tablets, powders, granules, capsules, pellets or micropills through a common preparation process, preferably tablets.

[0068] The administration routes of the pharmaceutical composition of the present invention include oral, rectal, vaginal and sublingual administration.

[0069] According to an embodiment of the present invention, the excipients include one or more of a filler, a lubricant and a disintegrant.

[0070] According to an embodiment of the present invention, the filler is selected from one or more of lactose, dextrin, mannitol, microcrystalline cellulose, starch, pregelatinized starch, cellulose lactose, calcium hydrogen phosphate, and a mannitol-starch complex, and preferably a mixture of one or more of microcrystalline cellulose, mannitol, and starch in any proportion.

[0071] According to an embodiment of the present invention, the lubricant is selected from talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, hydrated silicon dioxide, hydrophobic silicon dioxide, sodium octadecyl fumarate, polyethylene glycol, sodium stearyl fumarate, glyceryl monostearate, hydrogenated vegetable oil, and a mixture thereof in any proportion; preferably, the lubricant is selected from magnesium stearate, colloidal silicon dioxide, and a mixture thereof in any proportion;

[0072] According to an embodiment of the present invention, the disintegrant is selected from the group consisting of dry starch, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, methyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, chitosan, and microcrystalline cellulose, and the mixture is obtained by mixing one or more of them in any proportion; preferably, the mixture is obtained by mixing one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, and carboxymethyl cellulose calcium in any proportion.

[0073] According to an embodiment of the present invention, in the pharmaceutical composition, by weight percentage, the solid dispersion content is 30%-50%, the filler content is 20%-50%, the disintegrant content is 1%-15%, and the lubricant content is 1-15%;

[0074] Preferably, by weight percentage, the solid dispersion content is 35%-45%, the filler content is 35%-45%, the disintegrant content is 1%-10%, and the lubricant content is 1%-10%;

[0075] More preferably, by weight percentage, the solid dispersion content is 40%-45%, the filler content is 40%-45%, the disintegrant content is 5%-10%, and the lubricant content is 1%-5%.

[0076] According to an embodiment of the present invention, the pharmaceutical composition further comprises a disintegration aid.

[0077] According to an embodiment of the present invention, the disintegration aid is selected from the group consisting of 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, and the mixture obtained by mixing them in any proportion; preferably, the mixture obtained by mixing one or more of sodium chloride, sodium carbonate, and sodium bicarbonate in any proportion.

[0078] According to an embodiment of the present invention, when a disintegrant is also included, the content of each component in the pharmaceutical composition is, by weight percentage, 30%-50% of the solid dispersion, 20%-50% of the filler, 1%-15% of the disintegrant, 1%-15% of the lubricant, and 0.1%-10% of the disintegrant.

[0079] Preferably, by weight percentage, the solid dispersion content is 35%-45%, the filler content is 35%-45%, the disintegrant content is 1%-10%, the lubricant content is 1%-10%, and the disintegrant content is 1%-10%;

[0080] More preferably, by weight percentage, the solid dispersion content is 40%-45%, the filler content is 40%-45%, the disintegrant content is 5%-10%, the lubricant content is 1%-5%, and the disintegrant content is 5%-10%.

[0081] According to an embodiment of the present invention, the pharmaceutical composition is a solid preparation, such as a tablet.

[0082] The present invention also provides a method for preparing the pharmaceutical composition, comprising the following steps: mixing the solid dispersion and pharmaceutically acceptable excipients.

[0083] According to an embodiment of the present invention, the auxiliary materials may be sieved before mixing.

[0084] According to an embodiment of the present invention, the pharmaceutical composition is prepared using a dry granulation process. The preparation method comprises: weighing the ingredients in the formula, wherein the solid dispersion is not sieved, and the other excipients are sieved and set aside; premixing the added filler, disintegrant, glidant, and solid dispersion, and then grinding and sieving them; adding a lubricant and dry granulating them; and then adding the external filler, disintegrant, expander, and lubricant and mixing them together. Preferably, after mixing together, the ingredients are packaged according to the required amount of active ingredient, and then tablets of pharmaceutical specifications are obtained by tableting.

[0085] The active ingredients used in the present invention have the effects of inhibiting, antagonizing, and negatively allosterically regulating P2X4 receptors. Therefore, administering a certain amount of the solid dispersion or pharmaceutical composition of the present invention to mammals (including humans) has the effects of inhibiting, antagonizing, and negatively allosterically regulating P2X4 receptors, and can effectively treat related diseases.

[0086] The present invention also provides use of the solid dispersion or pharmaceutical composition described above in preparing a P2X4 receptor antagonist.

[0087] According to an embodiment of the present invention, the P2X4 receptor antagonist is used to treat the following diseases: respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative diseases, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related diseases, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue development disorders, or systemic disorders;

[0088] The respiratory system diseases include, for example, respiratory disorders, including 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;

[0089] The urinary tract diseases are, for example, urinary incontinence, overactive bladder, dysuria, prostatic hyperplasia, cystitis (e.g., interstitial cystitis), painful bladder syndrome, and prostatitis;

[0090] The gynecological diseases include endometriosis, primary and secondary dysmenorrhea, dyspareunia, and adenomyosis;

[0091] The ophthalmic diseases include, for example, dry eye, ocular neuropathic pain, ocular trauma, and postoperative ocular pain;

[0092] The gastrointestinal diseases include, for example, gastrointestinal dysfunction, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, gastroesophageal reflux disease, etc.

[0093] The proliferative disease is, for example, a tumor, such as cancer;

[0094] The cardiovascular diseases include myocardial infarction, thrombosis, atherosclerosis, heart failure, and hypertension;

[0095] The neurodegenerative or degenerative diseases are, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, ischemic brain injury, traumatic brain injury;

[0096] The inflammatory diseases such as arthritis, rheumatoid arthritis, ankylosing spondylitis and related neuralgia, gout;

[0097] The pain-related diseases are, for example, hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, inflammatory pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, pain associated with endometriosis, pain associated with fibrotic diseases, central pain, pain from burns, and migraine;

[0098] The pain-related diseases 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.

[0099] The present invention also provides use of the solid dispersion or pharmaceutical composition described above in preparing a medicament for treating a P2X4-mediated disease.

[0100] The P2X4-mediated diseases include respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative diseases, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related diseases, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue development disorders, or systemic disorders;

[0101] The respiratory system diseases include, for example, respiratory disorders, including 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;

[0102] The urinary tract diseases are, for example, urinary incontinence, overactive bladder, dysuria, prostatic hyperplasia, cystitis (e.g., interstitial cystitis), painful bladder syndrome, and prostatitis;

[0103] The gynecological diseases are, for example, endometriosis, primary and secondary dysmenorrhea, dyspareunia, and adenomyosis;

[0104] The ophthalmic diseases include, for example, dry eye, ocular neuropathic pain, ocular trauma, and postoperative ocular pain;

[0105] The gastrointestinal diseases include, for example, gastrointestinal dysfunction, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, gastroesophageal reflux disease, etc.

[0106] The proliferative disease is, for example, a tumor or cancer;

[0107] The cardiovascular diseases include myocardial infarction, thrombosis, atherosclerosis, heart failure, and hypertension;

[0108] The neurodegenerative or degenerative diseases are, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, ischemic brain injury, traumatic brain injury;

[0109] The inflammatory diseases such as arthritis, rheumatoid arthritis, ankylosing spondylitis and related neuralgia, gout;

[0110] The pain-related diseases are, for example, hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, inflammatory pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, pain associated with endometriosis, pain associated with fibrotic diseases, central pain, pain from burns, and migraine;

[0111] The pain-related diseases 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.

[0112] The present invention also provides a method for treating respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative diseases, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related diseases, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue developmental disorders, or systemic disorders, comprising administering the solid dispersion or pharmaceutical composition as described above to an individual in need thereof, and the specific scope of these diseases is as described above. Beneficial effects

[0113] The present invention provides a solid dispersion containing active ingredients (Compounds 1 to 48). The resulting solid dispersion improves the solubility and dissolution of the active ingredients and exhibits good stability, with no significant growth of impurities at 25°C / 60% RH (open) and 40°C / 75% RH (open). The preparation method is simple and can be prepared by spray drying, solvent processing, or hot melt extrusion. The resulting product has a qualified residual solvent content.

[0114] Furthermore, the obtained solid dispersion effectively improves the pharmacokinetic effect of the active ingredient.

[0115] The present invention further provides a pharmaceutical composition containing the solid dispersion, wherein the pharmaceutical composition has good disintegration effect and the disintegration time is within the pharmacopoeial limit. Therefore, the pharmaceutical composition of the present invention facilitates the development of subsequent dosage forms of the active ingredient.

[0116] In this application, "several types" means containing two or more types. DETAILED DESCRIPTION

[0117] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0118] The preparation method and application of the present invention will be further described in detail below with reference to specific examples. The following examples are merely illustrative and explain the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection intended by the present invention.

[0119] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0120] Related reagents and their sources:

[0121] Some of the English abbreviations in the following examples have the following meanings:

[0122] Cremophor 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 cocoyl sulfate, sodium lauryl sulfate; Soluplus: polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; HPMC E3: hydroxypropyl methylcellulose E3; TFA: trifluoroacetic acid; Avg.Dis: mean value; RSD: relative standard deviation; FA: fatty acid.

[0123] Experimental methods

[0124] HPLC method (content and related substances)

[0125] UPLC method (two-step dissolution)

[0126] Polarized Light Microscopy (PLM)

[0127] Details of the polarized light microscopy method used in the test are as follows: Instrument model: Nikon LV100POL polarizing microscope; Test method: The sample is placed on a glass slide and observed after silicone oil is dispersed; Eyepiece: 50X; Objective lens: 5-50X.

[0128] X-ray powder diffraction (XRPD)

[0129] The solid samples were characterized using a Bruker D8 advance X-ray diffractometer.

[0130] The samples were run on XRPD using the following method:

[0131] Fluorescent tube: Light tube voltage: 40 kV, light tube current: 40 mA, scanning range: 3 to 40 degrees, sample plate switching: 15 rpm, scanning rate: 10 degrees / min.

[0132] Thermogravimetric analysis (TGA)

[0133] Instrument model: TAQ5000 Thermogravimetric Analyzer; Place the sample (2-10 mg) in an aluminum foil pan and operate as follows: Place the sample in the TGA aluminum foil pan for testing and heat the sample from room temperature to 300°C (or 20% weight loss) at a heating rate of 10°C / min under 25 mL / min N2 conditions.

[0134] Differential thermal analysis (DSC)

[0135] Instrument model: TAQ 2000 Differential Scanning Calorimeter. Details of the DSC method used in the experiment are as follows: A sample (~4 mg) was placed in an aluminum DSC pan with a perforated lid and tested. The sample was heated from room temperature to 250°C at a rate of 2°C / min under 50 mL / min N₂.

[0136] Example 1: Preparation of Compound 1

[0137] Compound 1 was prepared with reference to Example 1 of the published patent WO2021104486A1.

[0138] Example 2 Solubilization experiment of compound 1 by surfactant

[0139] 50 mg of compound 1 was weighed into 5 mL of FaSSIF medium containing 5 mg of different surfactants (target API (compound 1) concentration: 10 mg / mL). The mixture was shaken at 500 rpm / 37°C for 0.5 h, 1 h, 2 h, and 4 h. 0.5 mL of the suspension was collected and centrifuged at 14,000 rpm for 5 min. The supernatant was diluted and analyzed by HPLC. The test results are shown in Table 1.

[0140] Table 1 Solubility results of compound 1 in FaSSIF containing 10% by weight of surfactant

[0141] In the above table, “-” means no surfactant was used.

[0142] The results showed that surfactants SLS, Cremophor EL, Cremophor RH40, VE-TPGS, Tween 80, Poloxamer 407 and Solutol HS15 could significantly improve the solubility of compound 1.

[0143] Example 3 Preparation of Solid Dispersion (SDD) of Compound 1 by Solvent Method

[0144] Based on the carrier polymer, solvent composition, and material ratios shown in Table 2 below, 9 mg of compound 1 and 21 mg of carrier polymer (mass ratio 3:7) were weighed and transferred to 40 mL glass vials. 1 mL of the corresponding solvent was added to prepare sample solutions with a drug loading of 30%. All sample solutions were transferred to an 80°C oven until the solvent evaporated completely. The appearance of the resulting solids was observed and recorded.

[0145] Table 2 Preparation of solid dispersion of compound 1 by solvent method

[0146] Example 4 Preparation of a solid dispersion of compound 1 by spray drying

[0147] The solid dispersions corresponding to Compound 1 were prepared by spray drying using the carrier polymers and solvents shown in Table 3 below.

[0148] Compound 1 and the corresponding carrier polymer were added to the corresponding solvent at a drug loading ratio of 30%, stirred at 700 rpm until compound 1 and the 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 polarizing microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic water sorption analysis (DVS), and thermogravimetric analysis (TGA). The formulations and spray-drying parameters of each solid dispersion are shown in Table 3, and the characterization results of PLM, XRPD, DVS, DSC, and TGA are shown in Table 4.

[0149] Table 3 Material ratio and preparation parameters of solid dispersion prepared by spray drying method

[0150] In the above table, “-” means no surfactant was used.

[0151] Table 4 Summary of characterization results of solid dispersions prepared by spray drying

[0152] The characterization results showed that the prepared samples were all amorphous and the solvent residues were in compliance with the requirements of the pharmacopoeia.

[0153] Example 5 Dynamic Solubility Experiment of Solid Dispersion

[0154] 20 mg of each solid dispersion product of Formulations 1-9 obtained in Example 4 was added to 3 mL of SGF (target API concentration: 2 mg / mL). The mixture was stirred at 37°C / 500 rpm for 0.25 h and 0.5 h, and samples were taken. 3 mL of 2×FaSSIF was then added to bring the solution pH to approximately 6.5. Stirring was continued for 0.25 h, 0.5 h, 1 h, and 1.5 h, and samples were taken. The samples were analyzed by UPLC, and the pH of the final solution was measured. The test results are shown in Table 5.

[0155] Table 5 Two-step dissolution results of solid dispersions

[0156] Note: 2×FaSSIF means twice the concentration of FaSSIF;

[0157] The results showed that compared with the API, the dissolution of solid dispersions using PVP-K30, PVP-VA64 and HPMCASMG as carriers was significantly improved; and the dissolution data of solid dispersions of formulations 5 and 6 using PVP-VA64 as a carrier showed that the solubility changes of the solid dispersions of formulations 5 and 6 were stable over time and were within a relatively appropriate range.

[0158] Example 6: Stability test of the solid dispersion of compound 1 obtained by spray drying

[0159] The stability of the solid dispersion products prepared according to Example 3 and Example 4 was tested under the conditions of 25°C / 60% RH (open) and 40°C / 75% RH (open). Samples were taken out after 2 weeks and 4 weeks, respectively, and the samples were tested for appearance, purity, and impurities. The results are shown in Tables 6-7.

[0160] Table 6 2- and 4-week stability results of the solid dispersion of Compound 1 obtained by spray drying

[0161] Table 7 Physical stability test results of spray-dried solid dispersion of Compound 1

[0162] The results showed that all samples had good chemical stability under 25°C / 60% RH (open) and 40°C / 75% RH (open) conditions, with no obvious increase in impurities.

[0163] The physical stability results showed that the appearance of the samples of Prescriptions 1-6 and Prescription 8 had no obvious changes except for some agglomeration.

[0164] The solid dispersions of Prescription 4, Prescription 5, Prescription 6, and Prescription 8 showed good physical stability after being placed under 25°C / 60% RH (open) and 40°C / 75% RH (open) conditions for 4 weeks, and all were amorphous.

[0165] Example 7: Solid dispersion preparation experiment of amplified samples

[0166] A spray drying solution with a concentration of 15 mg / mL (based on API) was prepared using acetone:ethanol:water = 4:3.5:2.5 (v:v:v) as the solvent, and the scaled-up sample preparation was performed according to the proposed process parameters (see Table 8).

[0167] Refer to the recipe list and weigh 50g of compound 1 in acetone. Stir until completely dissolved, then add ethanol and water and mix thoroughly. Add the prescribed amount of PVP VA64 and SLS to the solvent. Stir at 700 rpm until all solids are completely dissolved, then spray dry. Vacuum dry the resulting spray-dried sample at 50°C for 20-24 hours to obtain the product.

[0168] Table 8 Material ratio and preparation parameters of amplified samples

[0169] Example 8: Preparation and disintegration experiment of solid preparation

[0170] Preparation Examples 1-5 and Comparative Examples 1-7 in Table 9 below were all prepared using a dry granulation process, and the specific operations were as follows: accurately weighing the materials in the formula, wherein the solid dispersion of Compound 1 was not sieved, and other excipients were sieved and set aside; the added filler, disintegrant, glidant and solid dispersion of Compound 1 were premixed and then milled and sieved; dry granulation was performed after adding a lubricant; the added filler, disintegrant, expander and lubricant were added and then mixed; after mixing, the mixture was packaged according to the required amount of active ingredient, and then tablets of pharmaceutical specifications were obtained by tableting.

[0171] The obtained tablets were subjected to a disintegration test according to the disintegration time test method in the Chinese Pharmacopoeia 2020 edition. The disintegration time of each preparation example and comparative example is shown in Tables 9 and 10 below.

[0172] Table 9: Material ratios and disintegration test results for solid preparation preparation examples

[0173] Table 10 Comparative Example Material Ratio and Disintegration Test Results of Solid Preparations Note: “ / ” in Tables 9 and 10 means that the component is not contained.

[0174] Disintegration time results showed:

[0175] The disintegration times of the tablets in Comparative Example 7, which did not contain inorganic salts, and Comparative Examples 1, 3-6 all exceeded the pharmacopoeial limits. The disintegration time of the tablet in Preparation Example 1, which added 1% sodium chloride, was shortened to approximately 6 minutes; the disintegration time of the tablet in Preparation Example 2, which added 5% sodium chloride, was shortened to approximately 2 minutes; the disintegration time of the tablet in Preparation Example 3, which added 10% sodium chloride, was shortened to 1.5 minutes; the disintegration time of the tablet in Preparation Example 4, which added 5% sodium chloride internally and 5% sodium chloride externally, was shortened to 1.5 minutes; and the disintegration time of the tablet in Preparation Example 5, which added 5% sodium bicarbonate, was shortened to approximately 5 minutes. The disintegration times of the tablets in Preparation Examples 1-5 were significantly improved, all falling within the pharmacopoeial limits. The disintegration of the tablets in Comparative Examples 1-7 was characterized by dissolution, while the disintegration of the tablets in Preparation Examples 1-5 was characterized by water absorption, swelling, and disintegration into clumps or particles.

[0176] The above results indicate that the addition of inorganic salts can effectively inhibit the gelation of PVP-VA64, thereby promoting rapid tablet disintegration. Sodium chloride has the greatest disintegration-promoting effect, shortening the disintegration time to 6 minutes at just 1% of the formulation. Adding 5% or 10% of the formulation reduces the disintegration time to under 2 minutes. Sodium bicarbonate also exhibits a significant disintegration-promoting effect, with a 5% addition reducing the time to 5 minutes.

[0177] Example 9 Dissolution test of solid preparation

[0178] Based on the pH values ​​of commonly used dissolution media and the solubility studies of the solid dispersions described above, pH 1.2 hydrochloric acid and pH 1.2 hydrochloric acid solution + 0.3% SLS were selected to determine the dissolution results. The dissolution test methods are shown in Tables 11 and 12 below, and the analytical test data results are shown in Tables 13 and 14.

[0179] Table 11 Dissolution method of solid preparation

[0180] Table 12 Liquid phase parameters of solid preparation dissolution method

[0181] Table 13 Dissolution data of solid preparations of Comparative Examples 2, 4, 7 and Preparation Examples 1-5 in hydrochloric acid solution medium with pH value = 1.2

[0182] Table 14 Dissolution data of the solid preparations of Comparative Example 7 and Preparation Examples 1-5 in pH = 1.2 hydrochloric acid + 0.3% SLS solution medium

[0183] The dissolution results showed:

[0184] In a hydrochloric acid solution with a pH value of 1.2, the dissolution rates of Preparation Examples 3-5 were faster than those of Comparative Examples 2, 4 and 7.

[0185] In a pH value = 1.2 hydrochloric acid solution + 0.3% SLS medium, the final dissolution rates of Comparative Example 7 and Preparation Examples 1-5 can reach about 100%. Preparation Examples 3-5 show a faster dissolution rate than Comparative Example 7 and Preparation Examples 1-2, among which the dissolution rate of Preparation Example 5 can reach 86% at 30 minutes, which is the most obvious advantage. In summary, from the perspective of disintegration time, the tablets of Preparation Examples 1-5 can effectively shorten the disintegration time and meet the pharmacopoeia standards. From the perspective of dissolution data and dissolution phenomena, Preparation Examples 1 and Preparation Examples 5 show faster dissolution rates and higher dissolution rates than Preparation Examples 2, 3, and 4, and can be broken into particles in a short time in the dissolution cup without the appearance of lumps.

[0186] Example 10 Pharmacokinetic Experiment

[0187] Experimental Preparation 1

[0188] SD rats were divided into two groups, with 3 male rats in each group. They were SPF grade and weighed 160-320 g [Source: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., Certificate No.: 1103242011040898].

[0189] Dispensing: According to the drug concentration and dosage requirements in Table 15 below, accurately weigh the API, add the required volume of 5% solutol, vortex mix for 2 minutes, sonicate for 10 minutes, and stir for 1 hour before administration;

[0190] Table 15 API pharmacokinetic experimental dosage and administration regimen

[0191] Experimental Preparation 2

[0192] SD rats were divided into 6 groups, 3 male rats in each group, SPF grade, weight range 160-320 g [Source: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., Certificate No.: 110011210113195883 (male)].

[0193] Dispensing: Accurately weigh 80 mg of the corresponding sample in the table below, add the required volume of pure water to disperse, vortex for 5 minutes, and then administer by gavage (ig). The experiment can be scaled up according to the animal body weight and the dosage concentration.

[0194] Sample collection and preparation

[0195] After administration of the SD rats in each group of Experimental Preparation 1 and Experimental Preparation 2, blood was collected from the orbital venous plexus at 0.167, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h after administration, respectively. Approximately 0.2-0.3 mL of blood was collected at each time point in an anticoagulant EP tube (containing 4 μL EDTA-K2, 375 mg / mL), which was slowly inverted up and down 3 times and stored in an ice box (no more than 30 min). The tubes were centrifuged at 3500 × g at 4°C for 10 min, and the supernatant was transferred to a labeled EP tube. The plasma hemolysis was observed and recorded, and then bioanalysis was performed.

[0196] Sample analysis

[0197] Sample pretreatment process: 40 μL of sample was taken, and 160 μL of acetonitrile containing 0.1% FA and 200 ng / mL mixed standard solution was added to precipitate the protein. The mixture was vortexed and mixed evenly. The sample was centrifuged at 13000 pm in a centrifuge at 4°C for 10 minutes.

[0198] 110 μL of the supernatant was transferred to another 96-deep-well plate, and 110 μL of a methanol:water (1:3, v:v) solution containing 0.1% FA was added. The mixture was shaken for 10 minutes before analysis using a LC-MS / MS system utilizing a Sciex Exion LC AD high-performance liquid chromatography system and an XBridge BEH C18 (2.1×50 mm, 2.5 μm) column for gradient elution. Analysis was performed on an AB Sciex Qtrap 4500 mass spectrometer. Tolbutamide was monitored using an electrospray ionization (ESI) source in positive ion mode. The mass-to-charge ratios (m / z) for the precursor ion to product ion were 415.1 to 263.1 and 271.1 to 155, respectively.

[0199] Data Analysis

[0200] Data will be analyzed using WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) with non-compartmental modeling to obtain PK parameters (C max , T max , T 1 / 2 , AUC last and other parameters).

[0201] Table 15 Pharmacokinetic data of some solid dispersions

[0202] Table 16 Pharmacokinetic data of API

[0203] The results showed that after compound 1 was prepared into a solid dispersion, the Cmax , T max , T 1 / 2 , AUC last The values ​​are significantly improved compared with the API, effectively improving the in vivo absorption and bioavailability of the API.

[0204] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A solid dispersion of a P2X4 inhibitor, characterized in that: It comprises an active ingredient and a carrier; the active ingredient is selected from at least one of the following compounds 1 to 48 or pharmaceutically acceptable salts thereof: The carrier is selected from one or more of copovidone, povidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid resin, cellulose acetate phthalate, methacrylic acid-methyl methacrylate copolymer, or polyethylene oxide.

2. The solid dispersion of a P2X4 inhibitor according to claim 1, characterized in that: The solid dispersion further comprises a surfactant; Preferably, the surfactant is selected from one or a mixture of several of sodium lauryl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, Tween, hydrogenated castor oil, glyceryl monostearate, vitamin E polyethylene glycol succinate, polyoxyethylene castor oil derivatives, poloxamer, or Solutol HS15 in any proportion; More preferably, the surfactant is selected from one of sodium lauryl sulfate, vitamin E polyethylene glycol succinate, Cremophor RH40, or a mixture of several of them in any proportion.

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

4. The solid dispersion of a P2X4 inhibitor according to any one of claims 1 to 3, characterized in that: The solid dispersion comprises: compound 1, copolyvidone and Cremophor RH40; Alternatively, compound 1, copolyvidone and SLS; Alternatively, compound 1, copovidone and vitamin E polyethylene glycol succinate (VE-TPGS); Preferably, the solid dispersion comprises: compound 1, PVP-VA64 and SLS; Alternatively, compound 1, PVP-VA64 and vitamin E polyethylene glycol succinate (VE-TPGS); Preferably, the solid dispersion comprises the following components in parts by weight: 1 part by weight of compound 1, 1-7 parts by weight of PVP-VA64 and 0.1-1 parts by weight of SLS; or: 1 part by weight of compound 1, 1-7 parts by weight of PVP-VA64 and 0.1-1 parts by weight of vitamin E polyethylene glycol succinate (VE-TPGS).

5. The method for preparing the solid dispersion according to any one of claims 1 to 4, which is prepared by a spray drying method, a solvent method, or a hot melt extrusion method, characterized in that: The steps include: Spray drying method: the raw material is added into solvent S1 to prepare a solution, and then spray-dried to obtain a solid dispersion; Solvent method: Add the raw material into solvent S2 to prepare a solution, then remove the solvent from the solution, dry and grind to obtain a solid dispersion; Hot melt extrusion method: After mixing the raw materials, optionally add a proper amount of lubricant for hot melt extrusion; The solvent S1 is a ketone solvent, or a mixed solvent consisting of a ketone solvent and the following solvents: a halogenated alkane solvent, water, and an alcohol solvent; The solvent S2 is a ketone solvent, or a mixed solvent consisting of a ketone solvent and the following solvents: a halogenated alkane solvent, an alcohol solvent; Preferably, the solvent S1 is a two-component mixed solvent consisting of a ketone solvent and the following solvents: a halogenated alkane solvent, water, and an alcohol solvent; the volume ratio of the ketone solvent to the other solvent is (1-10): 1; More preferably, the solvent S1 is a two-component mixed solvent consisting of acetone and the following solvents: dichloromethane, ethanol, and water; the volume ratio of the acetone to the other solvent is (1-5):

1.

6. The preparation method according to claim 5, characterized in that: 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 solvent S2 to the other solvent is (1-10):

1.

7. A pharmaceutical composition, characterized in that The invention comprises the 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 excipients include one or more of a filler, a lubricant and a disintegrant.

9. The pharmaceutical composition according to claim 8, characterized in that The filler is selected from one or a mixture of lactose, dextrin, mannitol, microcrystalline cellulose, starch, pregelatinized starch, cellulose lactose, calcium hydrogen phosphate, and mannitol-starch complex in any proportion; Preferably, the lubricant is selected from talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, hydrated silicon dioxide, hydrophobic silicon dioxide, sodium octadecyl fumarate, polyethylene glycol, sodium stearyl fumarate, glyceryl monostearate, hydrogenated vegetable oil, or a mixture thereof in any proportion; Preferably, the disintegrant is selected from one or more of dry starch, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, methyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, chitosan, and microcrystalline cellulose in any proportion; Preferably, in the pharmaceutical composition, by weight percentage, the solid dispersion content is 30%-50%, the filler content is 20%-50%, the disintegrant content is 1%-15%, and the lubricant content is 1%-15%; Preferably, in the pharmaceutical composition, by weight percentage, the solid dispersion content is 35%-45%, the filler content is 35%-45%, the disintegrant content is 1%-10%, and the lubricant content is 1%-10%; More preferably, by weight percentage, the solid dispersion content is 40%-45%, the filler content is 40%-45%, the disintegrant content is 5%-10%, and the lubricant content is 1%-5%.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition further comprises a disintegration aid; Preferably, the disintegration aid is selected from one or more of 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 in any proportion; Preferably, the contents of the components in the pharmaceutical composition are as follows, by weight percentage: 30%-50% of the solid dispersion, 20%-50% of the filler, 1%-15% of the disintegrant, 1%-15% of the lubricant, and 0.1%-10% of the disintegrant. Preferably, by weight percentage, the solid dispersion content is 35%-45%, the filler content is 35%-45%, the disintegrant content is 1%-10%, the lubricant content is 1%-10%, and the disintegrant content is 1%-10%; More preferably, by weight percentage, the solid dispersion content is 40%-45%, the filler content is 40%-45%, the disintegrant content is 5%-10%, the lubricant content is 1%-5%, and the disintegrant content is 5%-10%.

11. The method for preparing the pharmaceutical composition according to any one of claims 7 to 9, characterized in that: The method comprises the following steps: mixing the solid dispersion according to any one of claims 7 to 9 and a pharmaceutically acceptable excipient.

12. The preparation method according to claim 11, characterized in that: The pharmaceutical composition is prepared by a dry granulation process; Preferably, the preparation method of dry granulation is: weigh the materials of the formula, wherein the solid dispersion is not sieved, other auxiliary materials are sieved and set aside, the internal filler, disintegrant, glidant and solid dispersion are premixed and then ground and sieved, dry granulation is performed after adding a lubricant, and then the external filler, disintegrant, expander and lubricant are added, mixed and then tableted.

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

14. The use according to claim 13, characterized in that The P2X4 receptor antagonist is used to treat the following diseases: respiratory diseases, urinary tract diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative diseases, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related diseases, pruritus (e.g., chronic pruritus), stroke, ischemic brain injury, traumatic brain injury, musculoskeletal and connective tissue development disorders, or systemic disorders; The respiratory diseases are, for example, respiratory disorders, including idiopathic pulmonary fibrosis, respiratory failure, chronic obstructive pulmonary disease, asthma, bronchospasm, cough (e.g., acute cough, chronic cough), refractory chronic cough, idiopathic chronic cough; The urinary tract diseases are, for example, urinary incontinence, overactive bladder, dysuria, prostatic hyperplasia, cystitis (e.g., interstitial cystitis), painful bladder syndrome, prostatitis; The gynecological diseases are, for example, endometriosis, primary and secondary dysmenorrhea, dyspareunia, adenomyosis; The ophthalmic diseases include, for example, dry eye, ocular neuropathic pain, ocular trauma, and postoperative ocular pain; The gastrointestinal diseases are, for example, gastrointestinal disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, gastroesophageal reflux; The proliferative disease is, for example, a tumor, such as cancer; The cardiovascular disease is, for example, myocardial infarction, thrombosis, atherosclerosis, heart failure, and hypertension; The neurodegenerative or degenerative diseases are, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, ischemic brain injury, traumatic brain injury; The inflammation such as arthritis, rheumatoid arthritis, ankylosing spondylitis and related neuralgia, gout; The pain-related diseases are, for example, hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, inflammatory pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, pain associated with endometriosis, pain associated with fibrotic diseases, central pain, pain from burns, migraine; The pain-related diseases are, 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.

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