WO2024255861A1 - 一种p2x4抑制剂固体分散体及其制备方法和应用 - Google Patents

一种p2x4抑制剂固体分散体及其制备方法和应用 Download PDF

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Publication number
WO2024255861A1
WO2024255861A1 PCT/CN2024/099304 CN2024099304W WO2024255861A1 WO 2024255861 A1 WO2024255861 A1 WO 2024255861A1 CN 2024099304 W CN2024099304 W CN 2024099304W WO 2024255861 A1 WO2024255861 A1 WO 2024255861A1
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Prior art keywords
solvent
solid dispersion
pain
diseases
content
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English (en)
French (fr)
Inventor
洪华云
王亚丽
娄军
张轶涵
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Wuhan Createrna Science and Technology Co Ltd
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Wuhan Createrna Science and Technology Co Ltd
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Priority to EP24822808.2A priority Critical patent/EP4729053A1/en
Priority to CN202480031564.3A priority patent/CN121175035A/zh
Priority to AU2024303437A priority patent/AU2024303437A1/en
Publication of WO2024255861A1 publication Critical patent/WO2024255861A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • Patent application number 2023107248878 filed with the State Intellectual Property Office of China on June 16, 2023, with the invention name “A solid dispersion of a P2X4 inhibitor, a method for preparing the same, and use thereof”
  • Patent application number 2024105673321 filed with the State Intellectual Property Office of China on May 9, 2024, with the invention name “A solid dispersion of a P2X4 inhibitor, a method for preparing the same, and use thereof”.
  • Patent application number 2024105673321 filed with the State Intellectual Property Office of China on May 9, 2024, with the invention name “A solid dispersion of a P2X4 inhibitor, a method for preparing the same, and use thereof”.
  • the present invention belongs to the field of medical technology, and specifically relates to a P2X4 inhibitor solid dispersion and a preparation method and application thereof.
  • Purinergic receptors are widely present in almost all mammalian cell membranes and are involved 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. So far, 7 subtypes of P2X receptors (P2X1 ⁇ 7) have been disclosed.
  • the P2X4 receptor is the only subtype of the P2X family whose crystal structure has been solved, and its resolution is as high as And the study found that P2X4 is the P2X subtype with the strongest permeability to Ca2 + .
  • P2X4 inhibitors are the research and development focus of many companies.
  • Patent document WO2016198374A1 discloses a plurality of 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, and 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.
  • pain syndromes acute and chronic
  • inflammation-induced pain neuropathic pain
  • pelvic pain pelvic pain
  • cancer-related pain endometriosis-related pain
  • endometriosis endometriosis itself
  • proliferative diseases similar to endometriosis itself can be used as a single agent or in combination with other active ingredients.
  • Patent document WO2017191000A1 discloses a plurality of P2X4 inhibitor compounds, which are used as a sole agent or in combination with other active ingredients to manufacture a pharmaceutical composition for treating or preventing a disease (especially a disease in a mammal, such as but not limited to a disease 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, pain, cancer-related pain, endometriosis-related pain, and endometriosis itself, cancer itself, multiple sclerosis itself, bone marrow or ischemic brain injury itself.
  • a disease especially a disease in a mammal, such as but not limited to a disease associated with pain
  • spondylitis syndrome acute and chronic
  • inflammatory-induced pain neuropathic pain, pelvic pain, pain, cancer-related pain, endometriosis-related pain, and endometri
  • Patent document WO2019081573A1 discloses the use of multiple P2X4 inhibitor compounds for preparing drugs for treating hemorrhagic stroke and traumatic brain injury.
  • Patent documents WO2022002859A1 and WO2022002860A1 disclose multiple phenylacetamide compounds having P2X4 receptor antagonist activity, and the use of multiple phenylacetamide compounds having P2X4 receptor antagonist activity in the preparation of drugs for treating certain eye diseases.
  • Patent document WO2021104486A1 discloses a benzene ring-containing compound and its application, wherein multiple benzene ring-containing compounds as P2X4 inhibitors are disclosed, and these compounds are further disclosed for treating P2X4-mediated related diseases, and compounds 1 to 48 are disclosed.
  • Such compounds have high inhibitory activity against P2X4, good selectivity, low toxicity, and good metabolic stability.
  • Such compounds have poor dissolution effects, so it is necessary to develop formulations for such compounds to improve the above problems.
  • the purpose of the present invention is to provide a solid dispersion of a P2X4 inhibitor in view of the deficiencies of the prior art, which 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 copolyvidone, povidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate (HPMPCP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid resin, cellulose acetate phthalate (CAP), methacrylic acid Acid-methyl methacrylate copolymer, or one or more of polyethylene oxide (PEO), preferably copovidone, hydroxypropyl methylcellulose acetate succinate or povidone, and most preferably copovidone.
  • HPMPCP hydroxypropyl methylcellulose acetate succinate
  • HPMPCP hydroxypropyl methylcellulose phthalate
  • Soluplus polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer
  • Soluplus
  • copolyvidone in the carrier, copolyvidone is PVP-VA64, which is also called 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).
  • copolyvidones 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.
  • the solid dispersion further comprises a surfactant.
  • the surfactant is selected from sodium dodecyl sulfate (abbreviated as SLS or SDS), sodium hexadecyl sulfate, sodium octadecyl sulfate, Tween (such as Tween 80, 60, 40 and 20), hydrogenated castor oil (such as Cremophor EL), glyceryl monostearate, vitamin E polyethylene glycol succinate (VE-TPGS), polyoxyethylene castor oil derivatives (such as Cremophor RH40), poloxamer (such as poloxamer F68, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, etc.), or polyethylene glycol-15 hydroxystearate (Solutol HS15), and a mixture obtained by mixing one or more of them in any proportion, preferably a mixture obtained by mixing one or more of sodium dodecyl sulfate, Tween (such
  • the active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof.
  • compounds 1 to 48 may refer to the compounds disclosed in patent document WO2021104486A1, the entire text of which is incorporated herein by reference.
  • 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.
  • 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.
  • 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.
  • the solid dispersion comprises: Compound 1 and copovidone
  • compound 1, copolyvidone and VE-TPGS Alternatively, compound 1, copolyvidone and VE-TPGS;
  • compound 1 povidone and Cremophor RH40;
  • compound 1 povidone and SLS
  • compound 1 povidone and VE-TPGS.
  • the solid dispersion comprises: Compound 1, copolyvidone and Cremophor RH40;
  • compound 1, copolyvidone and VE-TPGS Alternatively, compound 1, copolyvidone and VE-TPGS;
  • compound 1 povidone and Cremophor RH40;
  • compound 1 povidone and SLS
  • compound 1 povidone and VE-TPGS.
  • the solid dispersion comprises: Compound 1, copolyvidone and Cremophor RH40;
  • the solid dispersion comprises: Compound 1, copovidone and SLS;
  • VE-TPGS vitamin E polyethylene glycol succinate
  • the solid dispersion comprises: Compound 1, PVP-VA64 and SLS;
  • compound 1, PVP-VA64 and vitamin E polyethylene glycol succinate VE-TPGS.
  • 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 part 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).
  • the carrier is selected from any one of copovidone, povidone or hydroxypropyl methylcellulose acetate succinate
  • 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).
  • 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).
  • VE-TPGS vitamin E polyethylene glycol succinate
  • 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, and comprises the following steps:
  • Spray drying method the raw material is added to the solvent S1 to prepare a solution, and then spray drying is performed; in the formulation including a surfactant, the active ingredient, the carrier and the surfactant are added to the solvent S1 to prepare a solution, and then spray drying is performed;
  • Solvent method Add the raw material into solvent S2 and stir evenly until the raw material is completely dissolved to obtain a solution, then remove the solvent from the obtained 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, and an alcohol solvent.
  • the "raw materials" in the above-mentioned method for preparing solid dispersion include active ingredients and carriers; when the solid dispersion also includes a surfactant, the raw materials include active ingredients, carriers and surfactants.
  • the raw materials in the above-mentioned solid dispersion preparation method may include active ingredient compound 1 and a carrier, or may include active ingredient compound 1, a carrier and optionally a surfactant, depending on different solid dispersion preparation requirements;
  • the “optional” includes not selecting, or selecting one, two or more of them.
  • the ketone solvent may be one or more of acetone, butanone and methyl isobutyl ketone, preferably acetone.
  • the halogenated alkane solvent is dichloromethane.
  • the alcohol solvent is methanol, ethanol or propanol.
  • 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.
  • 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.
  • 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.
  • the solvent S1 is a mixed solvent consisting of acetone, ethanol and water.
  • 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.
  • the volume ratio of the solvent S2 to another solvent is (1-10):1, for example (5-9):1.
  • the concentration of the active ingredient in the obtained solution is 5-50 mg/mL, such as 15-25 mg/mL.
  • the mass fraction of the active ingredient in the obtained solution is 5%-50%, such as 10%-40%.
  • 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 oils in any proportion.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the solid dispersion as described above and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is prepared into tablets, powders, granules, capsules, pellets or micropills through a common preparation process, preferably tablets.
  • the administration routes of the pharmaceutical composition of the present invention include oral, rectal, vaginal and sublingual administration.
  • the auxiliary material includes one or more of a filler, a lubricant and a disintegrant.
  • the filler is selected from lactose, dextrin, mannitol, microcrystalline cellulose, starch, pregelatinized starch, cellulose lactose, calcium hydrogen phosphate, and a mixture of one or more of them in any proportion, preferably a mixture of one or more of microcrystalline cellulose, mannitol, and starch in any proportion.
  • 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, one or more of which are mixed in any proportion; preferably, one or more of magnesium stearate, colloidal silicon dioxide, hydrophobic silicon dioxide are mixed in any proportion;
  • the disintegrant is selected from the group consisting 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, and the mixture obtained by mixing one or more of them in any proportion; preferably, the mixture obtained by mixing one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose in any proportion.
  • 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%;
  • 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%
  • 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%.
  • the pharmaceutical composition further comprises a disintegration aid.
  • 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 a mixture thereof obtained by mixing one or more of them in any proportion; preferably, a mixture thereof obtained by mixing one or more of sodium chloride, sodium carbonate, and sodium bicarbonate in any proportion.
  • the contents of the components in the pharmaceutical composition are, by weight percentage, 30%-50% solid dispersion, 20%-50% filler, 1%-15% disintegrant, 1%-15% lubricant and 0.1%-10% disintegrant.
  • 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%
  • the disintegrant content is 1%-10%
  • 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%
  • the disintegrant content is 5%-10%.
  • the pharmaceutical composition is a solid preparation, such as a tablet.
  • the present invention also provides a method for preparing the above-mentioned pharmaceutical composition, comprising the following steps: mixing the solid dispersion and pharmaceutically acceptable excipients.
  • the auxiliary materials may be sieved before mixing.
  • the pharmaceutical composition is prepared by a dry granulation process, and the preparation method is: weigh the materials of the formula, wherein the solid dispersion is not sieved, and other auxiliary materials are sieved for standby use, the added filler, disintegrant, glidant and solid dispersion are premixed and then milled and sieved, and dry granulated after adding a lubricant, and then the added filler, disintegrant, expander, and lubricant are added and then mixed.
  • the active ingredient is packaged according to the dosage requirements, and then tablets of pharmaceutical specifications are obtained by tableting.
  • 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.
  • the present invention also provides use of the solid dispersion or pharmaceutical composition described above in preparing a P2X4 receptor antagonist.
  • the P2X4 receptor antagonist is used to treat the following diseases: respiratory diseases, endocrine diseases, Urinary system diseases, gynecological diseases, ophthalmic diseases, gastrointestinal diseases, proliferative diseases, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, inflammation, pain-related diseases, pruritus (such as 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;
  • 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 include, for example, gastrointestinal dysfunction, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn’s disease, gastroesophageal reflux disease, etc.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • Crohn’s disease gastroesophageal reflux disease
  • 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.
  • the present invention also provides use of the solid dispersion or pharmaceutical composition described above in preparing a drug for treating a P2X4-mediated disease.
  • 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 developmental 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;
  • 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 include, for example, gastrointestinal dysfunction, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn’s disease, gastroesophageal reflux disease, etc.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • Crohn’s disease gastroesophageal reflux disease
  • the proliferative disease is, for example, a tumor or 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.
  • 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 range of these diseases is as described above.
  • the present invention provides a solid dispersion containing active ingredients (compounds 1 to 48), the obtained solid dispersion can improve the solubility and dissolution effect of the active ingredients, and has good stability, and the impurities have no obvious growth under the conditions of 25°C/60%RH (open) and 40°C/75%RH (open).
  • the preparation method is simple, and can be prepared by spray drying, solvent method, or hot melt extrusion method, and the obtained product has a qualified solvent residue.
  • the obtained solid dispersion effectively improves the pharmacokinetic effect of the active ingredient.
  • the present invention further provides a pharmaceutical composition containing the solid dispersion, wherein the disintegration effect of the pharmaceutical composition is The disintegration time is within the limits of the pharmacopoeia. Therefore, the pharmaceutical composition of the present invention provides convenience for the development of subsequent dosage forms of the active ingredient.
  • everal types means containing 2 or more types.
  • 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 coconut sulfate, sodium lauryl sulfate
  • Soluplus polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer
  • HPMC E3 hydroxypropyl methylcellulose E3
  • TFA trifluoroacetic acid
  • Avg.Dis average value
  • RSD relative standard deviation
  • FA fatty acid.
  • the 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: 5 ⁇ 50X.
  • the solid samples were characterized using a Bruker D8 advance X-ray diffractometer.
  • Light pipe Phototube voltage: 40 kV, phototube current: 40 mA, scanning range: 3 to 40 degrees, sample plate conversion: 15 rpm, scanning rate: 10 degrees/min.
  • Instrument model TAQ5000 Thermogravimetric Analyzer; Place the sample (2-10 mg) on an aluminum foil pan and run as follows: Place the sample in a 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 25mL/min N2 conditions.
  • DSC Differential thermal analysis
  • Instrument model TAQ 2000 Differential Scanning Calorimeter. Details of the DSC method used in the experiment are as follows: Take a sample ( ⁇ 4 mg) The sample was placed in a DSC aluminum pan and covered with a perforated lid for testing. The sample was heated from room temperature to 250°C at a rate of 2°C/min under 50mL/min N2 conditions.
  • the solid dispersions corresponding to Compound 1 were prepared by spray drying using the carrier polymers and solvents shown in Table 3 below.
  • Example 6 Stability test of the solid dispersion of compound 1 obtained by spray drying
  • Example 3 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.
  • Preparation Examples 1-5 and Comparative Examples 1-7 were all prepared by dry granulation process, and the specific operations were as follows: accurately weighing the materials in the formulation, wherein the solid dispersion of Compound 1 was not sieved, and other auxiliary materials were sieved and set aside, the added filler, disintegrant, glidant and solid dispersion of Compound 1 were premixed and then ground and sieved, dry granulation was performed after adding lubricant, and the added filler, disintegrant, expander and lubricant were added and then mixed, and after the total mixing, they were packaged according to the required amount of active ingredients, and then tablets of pharmaceutical specifications were obtained by tableting.
  • 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.
  • the disintegration time of the tablets in Preparation Example 3 with 10% sodium chloride was shortened to 1.5 minutes
  • the disintegration time of the tablets in Preparation Examples 1-5 was significantly improved and shortened to the limits of the pharmacopoeia.
  • the disintegration phenomenon of the tablets in Comparative Examples 1-7 was dissolution, while the disintegration phenomenon of the tablets in Preparation Examples 1-5 was water absorption, swelling and disintegration into lumps or particles.
  • the dissolution test method is shown in Tables 11 and 12 below, and the analysis and test data results are shown in Tables 13 and 14.
  • 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 disintegrated into particles in a short time in the dissolution cup without the appearance of lumps.
  • the SD rats were divided into 2 groups, 3 male rats in each group, SPF grade, weight range 160-320g [Source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd., Certificate No.: 1103242011040898].
  • Dispensing According to the drug concentration and dosage requirements in Table 15 below, the API is accurately weighed, and the required volume of 5% solutol is added, vortexed for 2 minutes, ultrasonicated for 10 minutes, and stirred for 1 hour before administration;
  • the SD rats were divided into 6 groups, with 3 male rats in each group, SPF grade, and body weight range of 160-320 g [Source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd., Certificate No.: 110011210113195883 (male)].
  • Preparation 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 (i.g.). The experiment can be scaled up according to the animal body weight and the dosage concentration.
  • Sample pretreatment process Take 40 ⁇ L of sample, add 160 ⁇ L of acetonitrile containing 0.1% FA and 200 ng/mL mixed standard solution to precipitate protein, vortex to mix evenly, and centrifuge the sample at 13000 pm in a centrifuge at 4°C for 10 minutes.
  • the mass spectrometer used an electrospray ion source (ESI) positive ion mode to monitor Tolbutamide, and its parent ion ⁇ daughter ion mass-to-charge ratio (m/z) was 415.1 ⁇ 263.1 and 271.1 ⁇ 155, respectively.
  • ESI electrospray ion source

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Abstract

一种P2X4抑制剂的固体分散体，其包括活性成分和载体。所得固体分散体可改善活性成分的溶解度和溶出效果，并具有较好的稳定性，在25℃/60％RH(敞口)和40℃/75％RH(敞口)条件下杂质无明显增长。所述固体分散体的制备方法简单，可采用喷雾干燥法，溶剂法，或热熔挤出法制备，所得产物溶剂残留量合格。进一步地，所得固体分散体有效地提高了活性成分的药代动力学效果。一种含所述固体分散体的药物组合物，所述药物组合物的崩解效果好，崩解时间均在药典限度范围内。因此，所述药物组合物为所述活性成分后续剂型的开发，提供了便利。

Description

一种P2X4抑制剂固体分散体及其制备方法和应用
本申请要求以下在先申请的优先权：2023年06月16日向中国国家知识产权局提交的专利申请号为2023107248878，发明名称为“一种P2X4抑制剂固体分散体及其制备方法和应用”的在先申请；2024年05月09日向中国国家知识产权局提交的专利申请号为2024105673321，发明名称为“一种P2X4抑制剂固体分散体及其制备方法和应用”的在先申请。这两件先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药技术领域，具体涉及一种P2X4抑制剂固体分散体及其制备方法和应用。
背景技术
嘌呤受体广泛地存在于几乎所有哺乳动物细胞膜，参与多项生物信号通路的调控。嘌呤受体可分为腺苷和ATP类受体，ATP受体大致分为离子通道型受体的P2X家族和G蛋白质共轭型受体的P2Y家族，P2X受体广泛分布于全身的各组织，包括脑、肺、神经元、神经胶质细胞、心脏、血管等。迄今为止，P2X受体已公开7种亚型(P2X1～7)。其中，P2X4受体是目前P2X家族唯一解出晶体结构的亚型，且其分辨率高达并且研究发现，P2X4是对Ca2+通透性最强的P2X亚型。
目前，P2X4的抑制剂是众多企业的研发重点。
专利文献WO2016198374A1公开了多个P2X4抑制剂化合物，所述的化合物是P2X4的拮抗剂或负向别构调节剂。这类化合物用于治疗或预防与疼痛相关的疾病，或用于治疗或预防疼痛综合征(急性和慢性)、炎症诱发的疼痛、神经性疼痛、骨盆疼痛、癌症相关的疼痛、子宫内膜异位相关的疼痛以及子宫内膜异位本身、癌症本身和类似于子宫内膜异位的增殖疾病本身，可以作为单一药剂，或与其它活性组分联用。
专利文献WO2017191000A1公开了多个P2X4抑制剂化合物，此类化合物作为唯一药剂或与其它活性成分组合用于制造药物组合物，所述药物组合物用于治疗或预防疾病(尤其哺乳动物中的疾病，诸如但不限于与疼痛相关的疾病)或用于治疗或预防脑或骨髓中的疼痛或神经元损害和炎症或关节炎或脊柱炎综合征(急性和慢性)、炎性诱导的疼痛、神经性疼痛、骨盆 疼痛、癌症相关疼痛、子宫内膜异位症相关疼痛以及子宫内膜异位症本身、癌症本身、多发性硬化本身、骨髓或缺血性脑损伤本身。
专利文献WO2019081573A1公开了多个P2X4抑制剂化合物用于制备治疗出血性中风、创伤性脑损伤的药物的用途。
专利文献WO2022002859A1、WO2022002860A1公开了多个具有P2X4受体拮抗活性的苯乙酰胺类化合物，以及多个具有P2X4受体拮抗活性的苯乙酰胺类化合物在制备治疗某些眼部疾病的药物中的用途。
专利文献WO2021104486A1公开了一种含苯环的化合物及其应用，其中公开了多个含苯环的作为P2X4抑制剂的化合物，进一步公开了这些化合物用于治疗P2X4介导的相关疾病，并且公开了化合物1至化合物48，该类化合物对P2X4具有较高的抑制活性，且具有很好的选择性，毒性较低，代谢稳定性好。但该类化合物溶出效果差，因此有必要对该类化合物进行制剂开发，以改善上述问题。
发明内容
本发明的目的是针对现有技术的不足，提供一种P2X4抑制剂的固体分散体，其包括：活性成分和载体；所述活性成分选自如下化合物1至化合物48或其药学上可接受的盐中的至少一种：



所述载体选自共聚维酮、聚维酮、醋酸羟丙基甲基纤维素琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯(HPMPCP)、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)、羟丙基纤维素、羟丙基甲基纤维素、聚丙烯酸树脂、醋酸邻苯二甲酸纤维素(CAP)、甲基丙烯 酸-甲基丙烯酸甲酯共聚物、或聚环氧乙烷(PEO)中的一种或若干种，优选为共聚维酮、醋酸羟丙基甲基纤维素琥珀酸酯或聚维酮，最优选为共聚维酮。
根据本发明的实施方案，所述载体中，共聚维酮为PVP-VA64，共聚维酮又称为聚乙烯吡咯烷酮/乙酸乙烯酯共聚物，聚乙烯吡咯烷酮/醋酸乙烯酯共聚物，是一系列N-乙烯基吡咯烷酮(NVP)与醋酸乙烯酯(VA)的线性共聚物，市售常用的共聚维酮包括：PVP-VA64、Kollidon VA64，Plasdone S-630等；所述聚维酮为PVP-K30，其中聚维酮为一系列水溶性N-乙烯基吡咯烷酮(NVP)的均聚物，常用的聚维酮有PVP-K30、PVP-K90等；所述羟丙基甲基纤维素为HPMC E3；所述聚丙烯酸树脂为Eudragit L100。
根据本发明的实施方案，所述固体分散体还包括表面活性剂。
根据本发明的实施方案，所述表面活性剂选自十二烷基硫酸钠(简称SLS或SDS)、十六烷基硫酸钠、十八烷基硫酸钠、吐温(例如Tween 80、60、40和20)、氢化蓖麻油(例如Cremophor EL)、单硬脂酸甘油酯、维生素E聚乙二醇琥珀酸酯(VE-TPGS)、聚氧乙烯蓖麻油衍生物(如Cremophor RH40)、泊洛沙姆(例如泊洛沙姆F68，泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、泊洛沙姆407等)，或聚乙二醇-15羟基硬脂酸酯(Solutol HS15)中的一种或若干种以任意比例混合所得的混合物，优选十二烷基硫酸钠、维生素E聚乙二醇琥珀酸酯、Cremophor RH40中的一种或若干种以任意比例混合所得的混合物。
在一个优选的实施方案中，所述活性成分为化合物1或其药学上可接受的盐。
根据本发明的实施方案，化合物1至化合物48可参考专利文献WO2021104486A1中公开的化合物，其全文引入本发明中作为参考。
根据本发明的实施方案，所述活性成分与载体的质量比为1：(1-7)，优选为1：(2-5)，更优选为3:(6-7)，最优选为3:7。
根据本发明的一些实施方案，所述活性成分与载体的质量比为1：(1-7)，优选为1：(2-5)，更优选为3:(6-9)，最优选为1:2.8。
根据本发明的实施方案，所述固体分散体包括：活性成分，载体和表面活性剂；所述活性成分，载体与表面活性剂的质量比为1:(1-7):(0.1-1)，优选为1:(2-5):(0.1-1)，例如为3:6.5:0.5。
在本发明的一些实施方案中，所述固体分散体包括：化合物1和共聚维酮；
或者，化合物1和聚维酮；
或者，化合物1和醋酸羟丙基甲基纤维素琥珀酸酯；
或者，化合物1，共聚维酮及Cremophor RH40；
或者，化合物1，共聚维酮和SLS，
或者，化合物1，共聚维酮和VE-TPGS；
或者，化合物1，聚维酮和Cremophor RH40；
或者，化合物1，聚维酮和SLS；
或者，化合物1，聚维酮和VE-TPGS。
在本发明的一些实施方案中，所述固体分散体包括：化合物1，共聚维酮及Cremophor RH40；
或者，化合物1，共聚维酮和SLS，
或者，化合物1，共聚维酮和VE-TPGS；
或者，化合物1，聚维酮和Cremophor RH40；
或者，化合物1，聚维酮和SLS；
或者，化合物1，聚维酮和VE-TPGS。
在本发明的一些实施方案中，所述固体分散体包括：化合物1，共聚维酮及Cremophor RH40；
或者，化合物1，共聚维酮和SLS，
或者，化合物1，共聚维酮和VE-TPGS。
在本发明的一些实施方案中，所述固体分散体包括：化合物1，共聚维酮及SLS；
或者，化合物1，共聚维酮及维生素E聚乙二醇琥珀酸酯(VE-TPGS)。
在本发明的一些具体的实施方案中，所述固体分散体包括：化合物1，PVP-VA64及SLS；
或者，化合物1，PVP-VA64及维生素E聚乙二醇琥珀酸酯(VE-TPGS)。
在本发明的一些具体的实施方案中，所述固体分散体包括如下重量份的组分：1重量份化合物1，1-7重量份载体及0.1-1重量份表面活性剂，所述载体选自共聚维酮，聚维酮或醋酸羟丙基甲基纤维素琥珀酸酯中的任意一种，所述表面活性剂选自十二烷基硫酸钠，维生素E聚乙二醇琥珀酸酯(VE-TPGS)，聚氧乙烯蓖麻油衍生物(如Cremophor RH40)中的任意一种。
在本发明的一些具体的实施方案中，所述固体分散体包括如下重量份的组分：1重量份化合物1，1-7重量份PVP-VA64及0.1-1重量份SLS；或者，1重量份化合物1，1-7重量份PVP-VA64及0.1-1重量份维生素E聚乙二醇琥珀酸酯(VE-TPGS)。
本发明还提供如上所述固体分散体的制备方法，其采用喷雾干燥法，或溶剂法，或热熔挤出法制备，包括如下步骤：
喷雾干燥法：将原料加入溶剂S1中制备溶液，然后进行喷雾干燥；在包括表面活性剂的组方中，将活性成分、载体和表面活性剂加入溶剂S1中制备溶液，然后进行喷雾干燥；
溶剂法：将原料加入溶剂S2中搅拌均匀至原料完全溶解得到溶液，再将所得溶液中溶剂除去，并干燥、粉碎得到固体分散体；
热熔挤出法：将原料混合后，任选地再加入适量润滑剂进行热熔挤出；
所述溶剂S1为酮类溶剂，或酮类溶剂与如下溶剂构成的混合溶剂：卤代烷烃类溶剂，水，醇类溶剂；
所述溶剂S2为酮类溶剂，或酮类溶剂与如下溶剂构成的混合溶剂：卤代烷烃类溶剂，醇类溶剂。
上述固体分散体制备方法中所述“原料”包括活性成分和载体；当所述固体分散体中还包括表面活性剂时，所述原料包括活性成分、载体和表面活性剂。
根据本发明的实施方案，上述固体分散体制备方法中的原料根据不同的固体分散体制备需求，可以包括活性成分化合物1和载体、也可以包括活性成分化合物1、载体及任选地表面活性剂；
所述“任选”包括不选择，或者选择其中的一种、两者或者多种。
根据本发明的实施方案，所述酮类溶剂可以为丙酮、丁酮和甲基异丁基酮中的一种或多种，优选为丙酮。
根据本发明的实施方案，所述卤代烷烃类溶剂为二氯甲烷。
根据本发明的实施方案，所述醇类溶剂为甲醇，乙醇或者丙醇。
根据本发明的实施方案，所述溶剂S1酮类溶剂与如下溶剂构成的双组分混合溶剂：卤代烷烃类溶剂，水，醇类溶剂，所述酮类溶剂与另一溶剂的体积比为(1-10):1，例如(1-5):1。
根据本发明的实施方案，所述溶剂S1为丙酮与如下溶剂构成的双组分混合溶剂：二氯甲烷、乙醇、水，所述丙酮与另一溶剂的体积比为(1-5):1。
根据本发明的实施方案，所述溶剂S1为丙酮与二氯甲烷的双组分混合溶剂，且丙酮与二氯甲烷的体积比为6:4；或者，所述溶剂S1为丙酮与水的双组分溶剂，且丙酮与水的体积比为7:3；或者，所述溶剂S1为丙酮与乙醇的双组分溶剂，且丙酮与乙醇的体积比为1:1。
根据本发明的实施方案，所述溶剂S1为丙酮、乙醇、水组成的混合溶剂。
根据本发明具体的实施方案，所述溶剂S1为丙酮、乙醇、水组成的混合溶剂，其中丙酮、乙醇、水的体积比为1:(0.8-1)：(0.2-0.7)，优选为8:7:5，2:2:1,5:4:1,4:3:3，最优选为8:7:5。
根据本发明的实施方案，所述溶剂S2为双组分的混合溶剂时，其与另一溶剂的体积比为(1-10):1，例如(5-9):1。
根据本发明的实施方案，采用喷雾干燥法时，所得溶液中活性成分的浓度为5-50mg/mL，例如15-25mg/mL。
根据本发明的实施方案，采用溶剂法时，所得溶液中活性成分的质量分数为5％-50％，例如10％-40％。
根据本发明的实施方案，所述热熔挤出法制备固体分散体的方案中，所述润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、胶态二氧化硅、水合二氧化硅、疏水性二氧化硅、十八烷基富马酸钠、聚乙二醇、硬脂酰富马酸钠、单硬脂酸甘油酯、氢化植物油中的一种或若干种以任意比例混合所得混合物。
本发明还提供一种药物组合物，其包含如上所述固体分散体以及药学上可接受的辅料。
根据本发明的实施方案，所述药物组合物经过通用的制备工艺被制成片剂、散剂、颗粒剂、胶囊剂、滴丸剂或微丸剂，优选为片剂。
本发明的药物组合物的给药途径包括：口服、直肠、阴道、舌下。
根据本发明的实施方案，所述辅料包括填充剂、润滑剂和崩解剂中的一种或若干种。
根据本发明的实施方案，所述填充剂选自乳糖、糊精、甘露醇、微晶纤维素、淀粉、预胶化淀粉、纤维素乳糖、磷酸氢钙、甘露醇-淀粉复合物中的一种或若干种以任意比例混合所得的混合物，优选微晶纤维素、甘露醇、淀粉中的一种或若干种以任意比例混合所得的混合物。
根据本发明的实施方案，所述润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、胶态二氧化硅、水合二氧化硅、疏水性二氧化硅、十八烷基富马酸钠、聚乙二醇、硬脂酰富马酸钠、单硬脂酸甘油酯、氢化植物油中的一种或若干种以任意比例混合所得混合物；优选硬脂酸镁、胶态二氧化硅、疏水性二氧化硅中的一种或若干种以任意比例混合所得混合物；
根据本发明的实施方案，所述崩解剂选自干淀粉、交联羧甲基纤维素钠、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、甲基纤维素、低取代羟丙基纤维素、交联聚维酮、壳聚糖、微晶纤维素中的一种或若干种以任意比例混合所得混合物；优选交联羧甲基纤维素钠、羧甲基纤维素钠、羧甲基纤维素钙的一种或若干种以任意比例混合所得混合物。
根据本发明的实施方案，按重量百分比计，所述药物组合物中，固体分散体含量为30％-50％，填充剂含量为20％-50％，崩解剂含量为1％-15％，润滑剂含量为1-15％；
优选，按重量百分比计，所述固体分散体含量为35％-45％，填充剂含量为35％-45％，崩解剂含量为1％-10％，润滑剂含量为1％-10％；
更优选，按重量百分比计，所述固体分散体含量为40％-45％，填充剂含量为40％-45％，崩解剂含量为5％-10％，润滑剂含量为1％-5％。
根据本发明的实施方案，所述药物组合物还包括助崩剂。
根据本发明的实施方案，所述助崩剂选自氯化钠、碳酸钠、碳酸钙、碳酸钾、碳酸钙镁、碳酸锌、碳酸镁、碳酸铵、甘氨酸碳酸钠、倍半碳酸钠、碳酸氢钠、碳酸氢钙、碳酸氢钾、碳酸氢铵中的一种或若干种以任意比例混合所得混合物；优选为氯化钠、碳酸钠、碳酸氢钠中的一种或若干种以任意比例混合所得混合物。
根据本发明的实施方案，当还包括助崩解剂时，按重量百分比计，所述药物组合物中各组分的含量为：固体分散体含量为30％-50％，填充剂含量为20％-50％，崩解剂含量为1％-15％，润滑剂含量为1％-15％，助崩剂含量为0.1％-10％。
优选，按重量百分比计，所述固体分散体含量为35％-45％，填充剂含量为35％-45％，崩解剂含量为1％-10％，润滑剂含量为1％-10％，助崩剂含量为1％-10％；
更优选，按重量百分比计，所述固体分散体含量为40％-45％，填充剂含量为40％-45％，崩解剂含量为5％-10％，润滑剂含量为1％-5％，助崩剂含量为5％-10％。
根据本发明的实施方案，所述药物组合物为固体制剂，例如片剂。
本发明还提供如上所述药物组合物的制备方法，包括如下步骤：将固体分散体以及药学上可接受的辅料进行混合。
根据本发明的实施方案，可以在混合前将辅料进行过筛。
根据本发明的实施方案，所述药物组合物采用干法制粒工艺制备，制备方法为：称量组方量的物料，其中固体分散体不过筛，其他辅料过筛后备用，将内加的填充剂、崩解剂、助流剂和固体分散体预混后碾磨过筛，加入润滑剂后进行干法制粒，再加入外加的填充剂、崩解剂、膨胀剂、润滑剂后进行总混。优选地，总混后根据活性成分用量需求分包装，然后通过压片获得药用规格片剂。
本发明所采用的活性成分具有抑制、拮抗、负变构调节P2X4受体的作用，因此，向哺乳动物(包括人类)施用一定量的本发明的固体分散体或者药物组合物，具有抑制、拮抗、负变构调节P2X4受体的作用，可有效治疗相关病症。
本发明还提供如上所述固体分散体或药物组合物在制备P2X4受体拮抗剂中的用途。
根据本发明的实施方案，所述P2X4受体拮抗剂用于治疗如下疾病：呼吸系统疾病、泌 尿道系统疾病、妇科疾病、眼科疾病、胃肠道疾病、增生性疾病、心脑血管疾病、神经退行性变性疾病、炎症、疼痛相关疾病，瘙痒(例如慢性瘙痒)、脑卒中、缺血性脑损伤、外伤性脑损伤，肌肉骨骼和结缔组织发育障碍、或系统性障碍疾病；
所述呼吸系统疾病例如为呼吸障碍，包括特发性肺纤维化、呼吸衰竭、慢性阻塞性肺病、哮喘、支气管痉挛、咳嗽(例如急性咳嗽、慢性咳嗽)，难治性慢性咳嗽、特发性慢性咳嗽；
所述泌尿道系统疾病例如为尿失禁、膀胱过度活动症、排尿困难、前列腺增生、膀胱炎(例如间质性膀胱炎)、膀胱疼痛综合征、前列腺炎；
所述妇科疾病例如为子宫内膜异位症，原发性和继发性痛经，性交疼痛，子宫腺肌症；
所述眼科疾病例如为干眼症、眼部神经性疼痛、眼部外伤和术后眼部疼痛等；
所述胃肠道疾病例如为胃肠功能紊乱、肠道易激综合征(IBS)、炎性肠病(IBD)、克罗恩氏病(Crohn’s disease)、胃食管逆流等；
所述增生性疾病例如为肿瘤，例如癌症；
所述心血管疾病例如为心肌梗死、血栓症、动脉粥样硬化、心衰、高血压；
所述神经退行性或变性疾病例如为帕金森病、阿尔茨海默病、亨廷顿病、肌萎缩侧索硬化症、脑卒中、缺血性脑损伤、外伤性脑损伤；
所述炎症例如关节炎、类风湿性关节炎、强直性脊柱炎和相关神经痛、痛风；
所述疼痛相关疾病例如为痛觉过敏、触摸痛、急性和慢性炎性和神经性疼痛、炎性疼痛、手术性疼痛、内脏疼痛、牙痛、牙周炎、经前疼痛、子宫内膜异位症相关疼痛、与纤维化疾病相关的疼痛、中枢性疼痛、烧伤的疼痛、偏头痛；
所述疼痛相关疾病例如为由于神经炎导致的疼痛，由于中毒导致的疼痛、由于缺血性损伤导致的疼痛、由于间质性膀胱炎导致的疼痛、由于癌症导致的疼痛，由于创伤性神经损伤导致的疼痛。
本发明还提供如上所述固体分散体或药物组合物在制备用于治疗P2X4介导的疾病的药物中的用途。
所述P2X4介导的疾病包括呼吸系统疾病、泌尿道系统疾病、妇科疾病、眼科疾病、胃肠道疾病、增生性疾病、心脑血管疾病、神经退行性变性疾病、炎症、疼痛相关疾病，瘙痒(例如慢性瘙痒)、脑卒中、缺血性脑损伤、外伤性脑损伤，肌肉骨骼和结缔组织发育障碍、或系统性障碍疾病；
所述呼吸系统疾病例如为呼吸障碍，包括特发性肺纤维化、呼吸衰竭、慢性阻塞性肺病、哮喘、支气管痉挛、咳嗽(例如急性咳嗽、慢性咳嗽)，难治性慢性咳嗽、特发性慢性咳嗽；
所述泌尿道系统疾病例如为尿失禁、膀胱过度活动症、排尿困难、前列腺增生、膀胱炎(例如间质性膀胱炎)、膀胱疼痛综合征、前列腺炎；
所述妇科疾病例如为子宫内膜异位症，原发性和继发性痛经，性交疼痛，子宫腺肌症；
所述眼科疾病例如为干眼症、眼部神经性疼痛、眼部外伤和术后眼部疼痛等；
所述胃肠道疾病例如为胃肠功能紊乱、肠道易激综合征(IBS)、炎性肠病(IBD)、克罗恩氏病(Crohn’s disease)、胃食管逆流等；
所述增生性疾病例如为肿瘤，癌症；
所述心血管疾病例如为心肌梗死、血栓症、动脉粥样硬化、心衰、高血压；
所述神经退行性或变性疾病例如为帕金森病、阿尔茨海默病、亨廷顿病、肌萎缩侧索硬化症、脑卒中、缺血性脑损伤、外伤性脑损伤；
所述炎症例如关节炎、类风湿性关节炎、强直性脊柱炎和相关神经痛、痛风；
所述疼痛相关疾病例如为痛觉过敏、触摸痛、急性和慢性炎性和神经性疼痛、炎性疼痛、手术性疼痛、内脏疼痛、牙痛、牙周炎、经前疼痛、子宫内膜异位症相关疼痛、与纤维化疾病相关的疼痛、中枢性疼痛、烧伤的疼痛、偏头痛；
所述疼痛相关疾病例如为由于神经炎导致的疼痛，由于中毒导致的疼痛、由于缺血性损伤导致的疼痛、由于间质性膀胱炎导致的疼痛、由于癌症导致的疼痛，由于创伤性神经损伤导致的疼痛。
本发明还提供一种治疗呼吸系统疾病、泌尿道系统疾病、妇科疾病、眼科疾病、胃肠道疾病、增生性疾病、心脑血管疾病、神经退行性变性疾病、炎症、疼痛相关疾病，瘙痒(例如慢性瘙痒)、脑卒中、缺血性脑损伤、外伤性脑损伤，肌肉骨骼和结缔组织发育障碍、或系统性障碍疾病的方法，包括将如上所述固体分散体或药物组合物施用于有此需要的个体，这些疾病的具体范围如上所述。
有益效果
本发明提供了一种含活性成分(化合物1至化合物48)的固体分散体，所得固体分散体可改善活性成分的溶解度和溶出效果，并具有较好的稳定性，在25℃/60％RH(敞口)和40℃/75％RH(敞口)条件下杂质无明显增长。且其制备方法简单，可采用喷雾干燥法，或溶剂法，或热熔挤出法制备，所得产物溶剂残留量合格。
进一步地，所得固体分散体有效地提高了活性成分的药代动力学效果。
本发明进一步提供了一种含所述固体分散体的药物组合物，所述药物组合物的崩解效果 好，崩解时间均在药典限度范围内。因此，本发明的药物组合物为所述活性成分后续剂型的开发，提供了便利。
本申请中“若干种”表示含有2种或2种以上。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下文将结合具体实施例对本发明制备方法和应用做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
相关试剂及其来源：

如下实施例中部分英文简写具有如下含义：
Cremophor EL：聚氧乙烯蓖麻油；Poloxamer 407：泊洛沙姆407；Poloxamer 188：泊洛沙姆188；Tween 80：吐温80；HPC-SSL：羟丙基纤维素；Eudragit L100：聚丙烯酸树脂L100；SLS：十二烷基硫酸钠、椰油醇硫酸钠、月桂醇硫酸钠；Soluplus：聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物；HPMC E3：羟丙基甲基纤维素E3；TFA：三氟乙酸；Avg.Dis：平均值；RSD：相对标准偏差；FA：脂肪酸。
实验方法
HPLC方法(含量和有关物质)
UPLC方法(两步溶出)
偏光显微镜(PLM)
测试中使用的偏振光显微镜方法的细节如下所述：仪器型号：尼康LV100POL偏光显微镜；测试方法：样品置于载玻片上，硅油分散后观察；目镜：50X；物镜：5～50X。
X-射线粉末衍射(XRPD)
使用仪器型号为：布鲁克D8 advance X-射线衍射仪对固体样品进行表征。
样品在XRPD上按以下方法运行：
光管：光管电压：40kV，光管电流:40mA，扫描范围：3至40deg.，样品盘转换：15rpm，扫描速率:10deg./min。
热重分析(TGA)
仪器型号：TAQ5000热重分析仪；将样品(2～10mg)放在铝箔锅上，按下列方法运行：将样品置于TGA铝箔锅内进行测试，在25mL/minN2条件下，以10℃/min的升温速率，加热样品从室温到300℃(或失重20％)。
差热分析(DSC)
仪器型号：TAQ 2000差示扫描量热仪。实验中所使用的DSC法的细节如下：取样品(～4mg) 置于DSC铝锅内进行测试，加上扎孔盖后进行测试，在50mL/min N2条件下，以2℃/min的速率升温，加热样品从室温至250℃。
实施例1：化合物1的制备方法
参照已公开的专利WO2021104486A1实施例1制备得到化合物1。
实施例2表面活性剂对化合物1的增溶实验
分别称取50mg化合物1至含有5mg不同表面活性剂的5mL的FaSSIF介质中(API(化合物1)目标浓度10mg/mL)。500rpm/37℃条件下振摇0.5h、1h、2h和4h，并分别取0.5mL混悬样品，14000rpm离心5min，取上清液稀释后进行HPLC分析，测试结果见表1。
表1化合物1在含10％重量比表面活性剂的FaSSIF中的溶解度结果
上表中“-”表示未使用表面活性剂。
结果显示，表面活性剂SLS、Cremophor EL、Cremophor RH40、VE-TPGS、Tween 80、Poloxamer 407和Solutol HS15均可显著改善化合物1的溶解度。
实施例3溶剂法制备化合物1的固体分散体(SDD)
根据如下表2所示的载体聚合物、溶剂成分及物料配比，分别对应称取9mg化合物1和21mg载体聚合物(质量比3:7)并转移至40mL玻璃瓶中，分别加入1mL对应的溶剂制备得到载药量为30％的样品溶液。将所有样品溶液转移至80℃烘箱中放置直至溶剂挥发完全，观察记录所得固体的外观。
表2溶剂法制备化合物1固体分散体
实施例4采用喷雾干燥法制备化合物1的固体分散体
分别以如下表3中所示载体聚合物和溶剂进行喷雾干燥法制备化合物1对应的固体分散体。
以30％的载药量处方比向对应的溶剂中加入化合物1和对应载体聚合物，700rpm搅拌直至化合物1和载体聚合物完全溶解后进行喷雾干燥。所有喷雾干燥所得样品在50℃条件下真空干燥20～24h并分别用偏光显微镜图像(PLM)、X-射线粉末衍射图(XRPD)、差示扫描热量分析(DSC)、动态水分吸附分析(DVS)和热重分析(TGA)来进行表征。各固体分散体的配制处方及喷雾干燥参数见表3，PLM、XRPD、DVS、DSC、TGA的表征结果见表4。
表3喷雾干燥法制备固体分散体的物料配比及制备参数

上表中“-”表示未使用表面活性剂。
表4喷雾干燥法制备所得固体分散体的表征结果汇总
表征结果显示，所制备的样品均为无定形态，且溶剂残留符合药典的规定。
实施例5固体分散体的动态溶解度实验
取实施例4所得处方1-9的固体分散体产品各20mg，向其中分别加入3mL SGF(API目标浓度为2mg/mL)，在37℃/500rpm条件下，搅拌0.25h和0.5h后并分别取样，然后加入3mL2×FaSSIF使溶液pH约为6.5。继续搅拌0.25h、0.5h、1h和1.5h并分别取样。对所取样品进行UPLC测试，并测试最终溶液的pH，测试结果见表5。
表5固体分散体的两步溶出结果
注：2×FaSSIF表示两倍浓度的FaSSIF；
结果显示，与API相比，以PVP-K30、PVP-VA64和HPMCASMG为载体的固体分散体的溶出均有明显提高；且使用PVP-VA64作为载体的处方5和6的固体分散体所测溶出数据显示，随时间延长，处方5和6的固体分散体的溶解度变化稳定，且处于较合适的范围内。
实施例6：喷雾干燥法所得化合物1的固体分散体的稳定性实验
在25℃/60％RH(敞口)和40℃/75％RH(敞口)条件下分别测试根据实施例3、实施例4所制备的固体分散体产品的稳定性；分别在2周和4周取出样品，对样品的检测包括外观，纯度和杂质，结果见表6-7。
表6喷雾干燥法所得化合物1固体分散体的2和4周稳定性考察结果

表7喷雾干燥法化合物1固体分散体物理稳定性考察结果

结果显示，所有样品在25℃/60％RH(敞口)和40℃/75％RH(敞口)条件下化学稳定性良好，没有明显杂质增加。
物理稳定性结果显示，处方1-6、处方8的样品外观除部分结块外均无明显变化。
处方4、处方5、处方6、处方8的固体分散体在25℃/60％RH(敞口)和40℃/75％RH(敞口)条件下放置4周物理稳定性良好，均为无定形。
实施例7：放大样品的固体分散体制备实验
以丙酮:乙醇:水＝4:3.5:2.5(v:v:v)为溶剂配制浓度为15mg/mL(以API计)的喷雾干燥溶液，参考拟定工艺参数(见表8)进行放大样品制备。
参考处方列表称取50g化合物1加入丙酮中，搅拌至完全溶解后加入乙醇和水混合均匀，再将处方量的PVP VA64和SLS加入溶剂中。待所有固体在700rpm条件下搅拌至完全溶解后，进行喷雾干燥，所得喷雾干燥样品在50℃条件下真空干燥20～24h后得产品。
表8放大样品物料配比及制备参数表
实施例8:固体制剂的制备和崩解实验
如下表9中制备例1-5和对比例1-7均采用干法制粒工艺制备，具体操作为：准确称量组方量的物料，其中化合物1的固体分散体不过筛，其他辅料过筛后备用，将内加的填充剂、崩解剂、助流剂和化合物1的固体分散体预混后碾磨过筛，加入润滑剂后进行干法制粒，加入外加的填充剂、崩解剂、膨胀剂、润滑剂后进行总混，总混后根据活性成分用量需求分包装，然后通过压片获得药用规格片剂。
将所得片剂按照中国药典2020版中的崩解时限检查法进行崩解实验，各制备例和对比例的崩解时间见下表9和表10。
表9固体制剂的制备例物料配比及崩解实验结果表
表10固体制剂的对比例物料配比及崩解实验结果表


注：表9和10中“/”代表不含有该组分。
崩解时间结果显示：
未加无机盐的对比例7及对比例1、3-6的片剂崩解时间均超过药典限度范围。加入1％氯化钠的制备例1片剂崩解时间缩短至6min左右，加入5％氯化钠的制备例2片剂崩解时间 缩短至2min左右，加入10％氯化钠的制备例3片剂崩解时间缩短至1.5min，内加5％氯化钠，外加5％氯化钠的制备例4片剂崩解时间缩短至1.5min，加入5％碳酸氢钠的制备例5片剂崩解时间缩短至5min左右，制备例1-5片剂崩解时间得到明显改善，均缩短至药典限度范围内。且对比例1-7片剂崩解现象为溶蚀，而制备例1-5片剂崩解现象为吸水溶胀崩散成团块或颗粒。
上述表明，无机盐的加入可以有效抑制PVP-VA64的凝胶化，从而促进片剂快速崩解。其中，氯化钠的促崩解效果最好，仅需1％处方量崩解时间即可缩短至6min，外加5％和10％的量则将崩解时间缩短至2min内。碳酸氢钠促崩解效果也较好，外加5％即可缩短至5min。
实施例9固体制剂的溶出实验
根据溶出常用介质pH值以及上述固体分散体的溶解度考察结果，选择pH值＝1.2盐酸介质及pH值＝1.2盐酸溶液+0.3％ SLS测定溶出结果。溶出检测方法见下表11和12，分析检测数据结果参见表13和14。
表11固体制剂溶出方法
表12固体制剂溶出方法液相参数

表13对比例2、4、7和制备例1-5固体制剂在pH值＝1.2盐酸溶液介质中的溶出数据
表14对比例7和制备例1-5固体制剂在pH值＝1.2盐酸+0.3％SLS溶液介质中的溶出数据

溶出结果显示：
在pH值＝1.2盐酸溶液中，制备例3-5的溶出速率与对比例2、4和7相比更快。
在pH值＝1.2盐酸溶液+0.3％SLS介质中，对比例7、制备例1-5的最终溶出度均可达100％左右。制备例3-5显示出比对比例7和制备例1-2更快的溶出速率，其中制备例5在30min时的溶出度即可达到86％，优势最为明显。综上，从崩解时间来看，制备例1-5片剂均可有效缩短崩解时间，达到药典标准。从溶出数据及溶出现象来看，制备例1、制备例5表现出较制备例2、3、4更快的溶出速率和更高的溶出度，且在溶出杯中短时间即可崩散成颗粒，没有团块出现。
实施例10药代动力学实验
实验准备1
对SD大鼠进行分组，共2组雄鼠，每组3只，SPF级，体重范围160-320g[来源：北京维通利华实验动物技术有限公司，合格证号：1103242011040898]。
配药：根据下表15的药物浓度和给药剂量需求，API精确称量后，加入所需体积的5％solutol，涡旋混匀2min后，超声10min，搅拌1h后给药；
表15API药代动力学实验配药和给药方案
实验准备2
对SD大鼠进行分组，共6组雄鼠，每组3只，SPF级，体重范围160-320g[来源：北京维通利华实验动物技术有限公司，合格证号：110011210113195883(雄性)]。
配药：分别精确称量80mg下表中对应样品后，加入所需体积的纯水分散，涡旋5min后灌胃给药(i.g.)，实验根据动物体重和给药浓度等比例放大。
样品的采集和制备
实验准备1和实验准备2各个分组中的SD大鼠给药后，分别在给药后0.167、0.5、1、2、3、4、6、8、10和24h的时间点从眼眶静脉丛收集血液，每个时间点采集约0.2-0.3mL血液于抗凝EP管中(内含4μL EDTA-K2，375mg/mL)，缓慢上下倒置3次，置于冰盒内保存(不超过30分钟)，在4℃下使用3500×g离心10分钟，移取上清液至标记的EP管中，观察血浆溶血情况并记录，后进行生物分析检测。
样品分析
样品前处理过程：取40μL样品，加入160μL含0.1％ FA和200ng/mL混标溶液的乙腈沉淀蛋白，涡旋混合均匀，样品于4℃的离心机中13000pm离心10分钟。
取上清液110μL于另一96深孔板中，加入110μL的含0.1％FA的甲醇：水(1：3，v：v)溶液，振荡混合10分钟后用LC-MS/MS系统进行分析，该系统运用Sciex Exion LC AD高效液相色谱系统以及XBridge BEH C18(2.1×50mm,2.5μm)色谱柱进行梯度洗脱，AB Sciex Qtrap 4500质谱进行分析。质谱使用电喷雾离子源(ESI)正离子模式监测Tolbutamide，其母离子→子离子质荷比(m/z)分别为415.1→263.1和271.1→155。
数据分析
数据将使用WinNonlin(version 5.2.1Pharsight,Mountain View,CA)通过非房室模型进行分析，得到PK参数(Cmax，Tmax，T1/2，AUClast等参数)。
表15部分固体分散体的药代动力学数据
表16 API的药代动力学数据

结果表明，将化合物1制成固体分散体后，所得固体分散体的Cmax，Tmax，T1/2，AUClast数值相对于API均有明显的改善，有效提高了API的体内吸收效果和生物利用度。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (14)

  1. 一种P2X4抑制剂的固体分散体，其特征在于，其包括活性成分和载体；所述活性成分选自如下化合物1至化合物48或其药学上可接受的盐中的至少一种：



    所述载体选自共聚维酮、聚维酮、醋酸羟丙基甲基纤维素琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、羟丙基纤维素、羟丙基甲基纤维素、聚丙烯酸树脂、醋酸邻苯二甲酸纤维素、甲基丙烯酸-甲基丙烯酸甲酯共聚物、或聚环氧乙烷中的一种或若干种。
  2. 根据权利要求1所述的P2X4抑制剂的固体分散体，其特征在于，所述固体分散体还包括表面活性剂；
    优选地，所述表面活性剂选自十二烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠、吐温、氢化蓖麻油、单硬脂酸甘油酯、维生素E聚乙二醇琥珀酸酯、聚氧乙烯蓖麻油衍生物、泊洛沙姆、或Solutol HS15中的一种或若干种以任意比例混合所得的混合物；
    更优选地，所述表面活性剂选自十二烷基硫酸钠、维生素E聚乙二醇琥珀酸酯、Cremophor RH40中的一种或若干种以任意比例混合所得的混合物。
  3. 根据权利要求2所述的P2X4抑制剂的固体分散体，其特征在于，所述活性成分与载体的质量比为1：(1-7)，优选为1：(2-5)；
    优选地，所述活性成分，载体与表面活性剂的质量比为1:(1-7):(0.1-1)，优选为1:(2-5):(0.1-1)。
  4. 根据权利要求1-3任一项所述的P2X4抑制剂的固体分散体，其特征在于，所述固体分散体包括：化合物1，共聚维酮及Cremophor RH40；
    或者，化合物1，共聚维酮及SLS；
    或者，化合物1，共聚维酮及维生素E聚乙二醇琥珀酸酯(VE-TPGS)；
    优选地，所述固体分散体包括：化合物1，PVP-VA64及SLS；
    或者，化合物1，PVP-VA64及维生素E聚乙二醇琥珀酸酯(VE-TPGS)；
    优选地，所述固体分散体包括如下重量份的组分：1重量份化合物1，1-7重量份PVP-VA64及0.1-1重量份SLS；或者：1重量份化合物1，1-7重量份PVP-VA64及0.1-1重量份维生素E聚乙二醇琥珀酸酯(VE-TPGS)。
  5. 权利要求1-4任一项所述固体分散体的制备方法，其采用喷雾干燥法，或溶剂法，或热熔挤出法制备，其特征在于，包括如下步骤：
    喷雾干燥法：将原料加入溶剂S1中制备溶液，然后进行喷雾干燥得固体分散体；
    溶剂法：将原料加入溶剂S2中制备溶液，再将所得溶液中溶剂除去，干燥、粉碎得固体分散体；
    热熔挤出法：将原料混合后，任选地再加入适量润滑剂进行热熔挤出；
    所述溶剂S1为酮类溶剂，或酮类溶剂与如下溶剂构成的混合溶剂：卤代烷烃类溶剂，水，醇类溶剂；
    所述溶剂S2为酮类溶剂，或酮类溶剂与如下溶剂构成的混合溶剂：卤代烷烃类溶剂，醇类溶剂；
    优选地，所述溶剂S1为酮类溶剂与如下溶剂构成的双组分混合溶剂：卤代烷烃类溶剂，水，醇类溶剂；所述酮类溶剂与另一溶剂的体积比为(1-10)：1；
    更优选地，所述溶剂S1为丙酮与如下溶剂构成的双组分混合溶剂：二氯甲烷、乙醇、水；所述丙酮与另一溶剂的体积比为(1-5):1。
  6. 根据权利要求5所述的制备方法，其特征在于，所述溶剂S1为丙酮、乙醇、水组成的混合溶剂；
    优选地，溶剂S1中丙酮、乙醇、水的体积比为1:(0.8-1)：(0.2-0.7)；
    优选地，所述溶剂S2为双组分的混合溶剂时，其与另一溶剂的体积比为(1-10):1。
  7. 药物组合物，其特征在于，其包含权利要求1-6任一项所述固体分散体以及药学上可接受的辅料。
  8. 根据权利要求7所述的药物组合物，其特征在于，所述药学上可接受的辅料包括填充剂、润滑剂和崩解剂中的一种或若干种。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述填充剂选自乳糖、糊精、甘露醇、微晶纤维素、淀粉、预胶化淀粉、纤维素乳糖、磷酸氢钙、甘露醇-淀粉复合物中的一种 或若干种以任意比例混合所得的混合物；
    优选地，所述润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、胶态二氧化硅、水合二氧化硅、疏水性二氧化硅、十八烷基富马酸钠、聚乙二醇、硬脂酰富马酸钠、单硬脂酸甘油酯、氢化植物油中的一种或若干种以任意比例混合所得混合物；
    优选地，所述崩解剂选自干淀粉、交联羧甲基纤维素钠、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、甲基纤维素、低取代羟丙基纤维素、交联聚维酮、壳聚糖、微晶纤维素中的一种或若干种以任意比例混合所得混合物；
    优选地，按重量百分比计，所述药物组合物中，固体分散体含量为30％-50％，填充剂含量为20％-50％，崩解剂含量为1％-15％，润滑剂含量为1％-15％；
    优选地，按重量百分比计，所述药物组合物中，所述固体分散体含量为35％-45％，填充剂含量为35％-45％，崩解剂含量为1％-10％，润滑剂含量为1％-10％；
    更优选地，按重量百分比计，所述固体分散体含量为40％-45％，填充剂含量为40％-45％，崩解剂含量为5％-10％，润滑剂含量为1％-5％。
  10. 根据权利要求9所述的药物组合物，其特征在于，所述药物组合物还包括助崩剂；
    优选地，所述助崩剂选自氯化钠、碳酸钠、碳酸钙、碳酸钾、碳酸钙镁、碳酸锌、碳酸镁、碳酸铵、甘氨酸碳酸钠、倍半碳酸钠、碳酸氢钠、碳酸氢钙、碳酸氢钾、或碳酸氢铵中的一种或若干种以任意比例混合所得混合物；
    优选地，按重量百分比计，所述药物组合物中各组分的含量为：固体分散体含量为30％-50％，填充剂含量为20％-50％，崩解剂含量为1％-15％，润滑剂含量为1％-15％，助崩剂含量为0.1％-10％；
    优选地，按重量百分比计，所述固体分散体含量为35％-45％，填充剂含量为35％-45％，崩解剂含量为1％-10％，润滑剂含量为1％-10％，助崩剂含量为1％-10％；
    更优选地，按重量百分比计，所述固体分散体含量为40％-45％，填充剂含量为40％-45％，崩解剂含量为5％-10％，润滑剂含量为1％-5％，助崩剂含量为5％-10％。
  11. 权利要求7-9任一项所述药物组合物的制备方法，其特征在于，包括如下步骤：将权利要求7-9任一项所述固体分散体以及药学上可接受的辅料进行混合。
  12. 根据权利要求11所述的制备方法，其特征在于，所述药物组合物采用干法制粒工艺制备；
    优选地，干法制粒的制备方法为：称量组方量的物料，其中固体分散体不过筛，其他辅料过筛后备用，将内加的填充剂、崩解剂、助流剂和固体分散体预混后碾磨过筛，加入润滑剂后进行干法制粒，再加入外加的填充剂、崩解剂、膨胀剂、润滑剂后进行总混后压片。
  13. 权利要求1-4任一项所述固体分散体或权利要求7-10任一项所述药物组合物在制备P2X4受体拮抗剂中的用途。
  14. 根据权利要求13所述的用途，其特征在于，所述P2X4受体拮抗剂用于治疗如下疾病：呼吸系统疾病、泌尿道系统疾病、妇科疾病、眼科疾病、胃肠道疾病、增生性疾病、心脑血管疾病、神经退行性变性疾病、炎症、疼痛相关疾病，瘙痒(例如慢性瘙痒)、脑卒中、缺血性脑损伤、外伤性脑损伤，肌肉骨骼和结缔组织发育障碍、或系统性障碍疾病；
    所述呼吸系统疾病例如为呼吸障碍，包括特发性肺纤维化、呼吸衰竭、慢性阻塞性肺病、哮喘、支气管痉挛、咳嗽(例如急性咳嗽、慢性咳嗽)，难治性慢性咳嗽、特发性慢性咳嗽；
    所述泌尿道系统疾病例如为尿失禁、膀胱过度活动症、排尿困难、前列腺增生、膀胱炎(例如间质性膀胱炎)、膀胱疼痛综合征、前列腺炎；
    所述妇科疾病例如为子宫内膜异位症，原发性和继发性痛经，性交疼痛，子宫腺肌症；
    所述眼科疾病例如为干眼症、眼部神经性疼痛、眼部外伤和术后眼部疼痛等；
    所述胃肠道疾病例如为胃肠功能紊乱、肠道易激综合征(IBS)、炎性肠病(IBD)、克罗恩氏病(Crohn’s disease)、胃食管逆流；
    所述增生性疾病例如为肿瘤，例如癌症；
    所述心血管疾病例如为心肌梗死、血栓症、动脉粥样硬化、心衰、高血压；
    所述神经退行性或变性疾病例如为帕金森病、阿尔茨海默病、亨廷顿病、肌萎缩侧索硬化症、脑卒中、缺血性脑损伤、外伤性脑损伤；
    所述炎症例如关节炎、类风湿性关节炎、强直性脊柱炎和相关神经痛、痛风；
    所述疼痛相关疾病例如为痛觉过敏、触摸痛、急性和慢性炎性和神经性疼痛、炎性疼痛、手术性疼痛、内脏疼痛、牙痛、牙周炎、经前疼痛、子宫内膜异位症相关疼痛、与纤维化疾病相关的疼痛、中枢性疼痛、烧伤的疼痛、偏头痛；
    所述疼痛相关疾病例如为由于神经炎导致的疼痛，由于中毒导致的疼痛、由于缺血性损伤导致的疼痛、由于间质性膀胱炎导致的疼痛、由于癌症导致的疼痛，由于创伤性神经损伤导致的疼痛。
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