TW202525285A - Solid dispersion of p2x3 receptor antagonist and preperation method thereof - Google Patents

Abstract

The present invention provides a solid dispersion comprising a P2X3 receptor antagonist compound shown in Formula I. The solid dispersion is capable of significantly improving the solubility of the compound shown in Formula I, greatly improving the dissolution and bioavailability of the drug, and ensuring the therapeutic effect of the drug. At the same time, the solid dispersion of the present invention is stable, and during storage, there is no crystalline transformation and no significant growth of the related substances, which improves the safety of the clinical application of the drug.

Description

Solid dispersion of P2X3 receptor antagonist and preparation method thereof

The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a solid dispersion of a P2X3 receptor antagonist and a preparation method thereof.

P2X3 is a subunit of ATP-gated ion channels and belongs to the purinergic P2X family. It is expressed in the airways and central nervous system terminals. Numerous clinical studies have demonstrated that P2X3 receptor antagonists can significantly improve cough frequency, urge, and severity in patients with refractory chronic cough. The most common adverse reaction is decreased taste perception. The incidence of taste impairment can be reduced by lowering the drug dose and choosing a more selective P2X3 receptor antagonist. Currently, multiple P2X3 clinical trials are underway, and P2X3 receptor antagonists are expected to become one of the most promising treatments for refractory chronic cough.

Gefapixant, the first selective P2X3 receptor antagonist targeting the same target, was approved for marketing in Japan in January 2022, with plans to submit an NDA to the FDA and EMA in 2023. Its clinical adverse reactions include taste loss or impairment, dry mouth, and nausea. These taste disturbances may be related to Gefapixant's effects on P2X2/3 receptors. The development of highly selective P2X3 receptor antagonists is needed to reduce the adverse effects of taste loss or impairment. Several P2X3 selective antagonists are currently in clinical development: Bellus' Camlipixant (Phase III), Bayer's Eliapixant (Phase IIb), Shionogi's Sivopixant (Phase III planned), and four domestically in Phase I-II stages, demonstrating favorable safety profiles. Compared to the marketed Gefapixant, the P2X3-specific antagonist compound represented by Formula I of the present invention can significantly reduce the occurrence of taste loss and is intended for the treatment of refractory chronic cough.

However, during research, the inventors discovered that the compound represented by Formula I has very poor solubility. Its saturation solubility in media with a pH range of 1.0 to 6.8 is less than 0.02 mg/ml, and its solubility in media with pH values of 1.2, 4.5, 6.8, and water is less than 10%. Furthermore, the drug substance has poor thermodynamic stability, prone to crystallization during storage, and exhibits poor stability. Therefore, there is a need to provide a new formulation to address the poor solubility and stability of the compound represented by Formula I.

This application requires the applicant to:

The priority benefit of the prior patent application No. 202311872796.5, filed with the National Intellectual Property Administration of China on December 29, 2023, entitled “Solid dispersion of a P2X3 receptor antagonist and its preparation process”;

The priority benefit of the prior patent application filed with the National Intellectual Property Administration of China on December 23, 2024, with patent application number 202411907674.X, entitled “Solid dispersion of a P2X3 receptor antagonist and its preparation process”;

The entire content of the prior application is incorporated into the present invention by reference.

To address the above-mentioned technical issues, the present invention provides a solid dispersion of a P2X3 receptor antagonist (a compound represented by Formula I). The solid dispersion can improve the solubility of the compound represented by Formula I, significantly enhancing the drug's dissolution rate and bioavailability. Furthermore, the solid dispersion is highly stable and does not undergo crystal transformation during storage.

The present invention provides a solid dispersion (SD) of a P2X3 receptor antagonist, wherein the solid dispersion comprises: a P2X3 receptor antagonist and a pharmaceutically acceptable carrier;

Wherein, the P2X3 receptor antagonist is selected from the compound represented by the following formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: wherein ^R1 is independently selected from halogen, _C3 - _C6 cycloalkyl, C1- _{C4 alkyl} which is unsubstituted or substituted by 1-5 identical or different halogens; X is halogen; m is selected from an integer of 1, 2 or 3; L is -( _CH2 ) _n- , wherein n is selected from an integer of 0, 1 or 2; ^R2 is independently selected from hydrogen, _C1 - _C6 alkyl which is unsubstituted or substituted ^{by Ra} , _C3 - _C7 cycloalkyl which is unsubstituted or substituted by ^Ra, 5-8 membered aryl which is unsubstituted or substituted by ^Ra , 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the _C1 - _C6 alkyl which is substituted by ^Ra , the _C3 -C7 cycloalkyl which is substituted by Ra ^, wherein the _5-7 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted with one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C _{1 -C 4 alkyl), -C(O)-(C 1} -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, or deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted ^{by Ra} , the ^4-7 membered heterocycloalkyl substituted by Ra, or the _6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted by Ra, or the _{6-12 membered} heterobicycloalkyl substituted by Ra, wherein the _{5-8 membered} aryl substituted by _Ra , the 5-10 membered heteroaryl substituted by Ra, the _{4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered} heterobicycloalkyl substituted by Ra, wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted by Ra, In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R3 is independently selected from hydrogen, _C1 - _C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; A is independently unsubstituted or substituted by R a 5- to 10-membered heteroaryl group substituted with ^Re , wherein the 5- to 10-membered heteroaryl group substituted with ^Re is substituted with one or more substituents, ^and each ^Re is independently selected from the following substituents: halogen, _C1 - _C3 alkyl which is unsubstituted or substituted with 1-5 identical or different halogens, and -O-( _C1 - _C3 alkyl) which is unsubstituted or substituted with 1-5 identical or different halogens; when there are multiple substituents, the substituents may be the same or different.

In an embodiment of the present invention, the solid dispersion is an amorphous solid dispersion.

In an embodiment of the present invention, the P2X3 receptor antagonist exists in an amorphous form.

In an embodiment of the present invention, the pharmaceutically acceptable carrier is a pharmaceutically acceptable polymer carrier.

In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following: 1) Cellulose derivative carriers; for example, hydroxypropylmethylcellulose E5 (HPMC-E5), hydroxypropylmethylcellulose acetate succinate LF (HPMC-AS-LF), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose phthalate (HPMCP), etc.; 2) Polyacrylic resin carriers; for example, Eudragit L100-55 (Eudragit-L100-55), Eudragit S100, Eudragit L100; 3) Vinyl polymer carriers, for example, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), copovidone VA64, copovidone S630, etc.

In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following:

Hydroxypropyl methylcellulose (HPMC), copolyvidone (PVP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polymethacrylate (Eudragit), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus); preferably, any one or more selected from the following: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polymethacrylate (Eudragit).

In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following: hydroxypropyl methylcellulose E5 (HPMC-E5), copolyvidone VA64 (PVP VA64), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), Eudragit L100-55 (Eudragit-L100-55), and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus); preferably, it is selected from any one or more of the following: hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55 (Eudragit-L100-55).

In an embodiment of the present invention, the mass ratio of the P2X3 receptor antagonist to the pharmaceutically acceptable carrier is 1:0.1-10, preferably 1:0.5-5, for example 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5.

In an embodiment of the present invention, the solid dispersion comprises the following components: 10-60 wt% of a P2X3 receptor antagonist 40-90 wt% of a pharmaceutically acceptable carrier.

In an embodiment of the present invention, the solid dispersion comprises the following components: 20-55 wt% of a P2X3 receptor antagonist 45-80 wt% of a pharmaceutically acceptable carrier.

In an embodiment of the present invention, the solid dispersion comprises the following components: 25-50 wt% (e.g., 25 wt%, 33 wt%, 33.3 wt%, 50 wt%) of a P2X3 receptor antagonist 50-75 wt% (e.g., 50 wt%, 67 wt%, 66.7 wt%, 75 wt%) of a pharmaceutically acceptable carrier.

In an embodiment of the present invention, the solid dispersion comprises the following components: A P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises no less than 66.7 wt%;

In an embodiment of the present invention, the solid dispersion comprises the following components: A P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises no less than 75 wt%;

In an embodiment of the present invention, the solid dispersion comprises the following components: P2X3 receptor antagonist: 25 wt%, 33.3 wt%, and 50 wt% Pharmaceutically acceptable carrier: 50 wt%, 66.7 wt%, and 75 wt%.

The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55.

In an embodiment of the present invention, the solid dispersion comprises the following components: P2X3 receptor antagonist 25 wt% Pharmaceutically acceptable carrier 75 wt%

The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55.

In this embodiment of the present invention, the solid dispersion comprises the following components: P2X3 receptor antagonist 33.3 wt% Pharmaceutically acceptable carrier 66.7 wt%

The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55.

In an embodiment of the present invention, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hydroxypropyl methylcellulose acetate succinate LF, wherein the proportion of hydroxypropyl methylcellulose acetate succinate LF is not less than 75%.

In an embodiment of the present invention, the solid dispersion comprises the following components: P2X3 receptor antagonist 25 wt% Hydroxypropylmethylcellulose acetate succinate LF 75 wt%

In an embodiment of the present invention, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hydroxypropylmethylcellulose acetate succinate LF, wherein the proportion of hydroxypropylmethylcellulose acetate succinate LF is not less than 66.7 wt%.

In this embodiment of the present invention, the solid dispersion comprises the following components: P2X3 receptor antagonist 33.3 wt% Hydroxypropylmethylcellulose acetate succinate LF 66.7 wt%

In an embodiment of the present invention, the solid dispersion optionally further comprises a solvent.

In an embodiment of the present invention, the solvent is a volatile solvent. The solvent evaporates during the process of preparing the solid dispersion.

In an embodiment of the present invention, the solvent is selected from any one or more of the following: dichloromethane, ethanol, acetone, methanol; preferably acetone, dichloromethane-methanol mixed solvent.

In an embodiment of the present invention, the solid dispersion optionally further comprises any one or more of the following: a sweetener, a flavoring, a coloring agent, a surfactant, a filler, a lubricant, a disintegrant, a disintegration promoter, a recrystallization inhibitor, a defoaming agent, an antioxidant, and a pH regulator.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein ^R1 is independently selected from halogen, _C3 - _C6 cycloalkyl, C1- _C4 alkyl which is unsubstituted or substituted by 1-5 identical or _different halogens; X is halogen; m is selected from an integer of 1, 2 or 3; L is -( _CH2 ) _n- , wherein n is selected from an integer of 0, 1 or 2; ^R2 is independently selected from hydrogen, _C1 - _C6 alkyl which is unsubstituted or substituted ^{by Ra} , _C3 - _C7 cycloalkyl which is unsubstituted or substituted by ^Ra, 5-8 membered aryl which is unsubstituted or substituted by ^Ra , 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the _C1 - _C6 alkyl which is substituted by ^Ra , the _C3 -C7 cycloalkyl which is substituted by Ra ^, wherein the _5-7 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered heterobicycloalkyl substituted by Ra, the substitutions independently refer to substitutions by one or more of the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR ^b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), or deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted ^{by Ra} , the ^{4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered heterobicycloalkyl substituted by Ra, the substitutions independently refer to substitutions by one or more of the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R c , -COOR 4} _{, oxo} (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), or deuterated C ₁ -C ₆ alkyl, unsubstituted or substituted by 1 to 5 identical or different halogens. In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R3 is independently selected from hydrogen, _C1 - _C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; A is independently unsubstituted or substituted by R a 5- to 10-membered heteroaryl group substituted with ^Re , wherein the 5- to 10-membered heteroaryl group substituted with ^Re is substituted with one or more substituents, ^and each ^Re is independently selected from the following substituents: halogen, _C1 - _C3 alkyl which is unsubstituted or substituted with 1-5 identical or different halogens, and -O-( _C1 - _C3 alkyl) which is unsubstituted or substituted with 1-5 identical or different halogens; when there are multiple substituents, the substituents may be the same or different.

In a preferred embodiment of the present invention, when R ¹ is a halogen, the halogen is F, Cl, Br, or I, preferably Cl.

In a preferred embodiment of the present invention, when R ¹ is an unsubstituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl or ethyl.

In a preferred embodiment of the present invention, when R ¹ is a C ₁ -C ₄ alkyl group substituted with 1 to 5 identical or different halogens, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl.

In a preferred embodiment of the present invention, when R ¹ is a C ₁ -C ₄ alkyl group substituted with 1 to 5 identical or different halogens, the halogens are F, Cl, Br, I, preferably Cl or F.

In a preferred embodiment of the present invention, when X is a halogen, the halogen is one of F and Cl.

In a preferred embodiment of the present invention, m is selected from integers 1, 2 or 3, preferably 1.

In a preferred embodiment of the present invention, when L is -(CH ₂ ) _n -, n is an integer of 0, 1 or 2, preferably n is 0 or 1.

In a preferred embodiment of the present invention, when R ² is a C ₁ -C ₆ alkyl group which is unsubstituted or substituted by ^Ra , the C ₁ -C ₆ alkyl group is a C ₁ -C ₄ alkyl group, preferably a sec-butyl group.

In a preferred embodiment of the present invention, when R ² is unsubstituted or ^substituted C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a preferred embodiment of the present invention, when R ² is unsubstituted or ^substituted C ₃ -C ₇ cycloalkyl, the C ₃ -C ₇ alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

In a preferred embodiment of the present invention, when R ² is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the 4-7 membered heterocycloalkyl group is a 4-membered, 5-membered or 6-membered heterocycloalkyl group.

In a preferred embodiment of the present invention, when R ² is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted ^{by Ra} , the heteroatom in the 4-7 membered heterocycloalkyl group is one or more of N, S, O, and P, preferably one or more of N or O.

In a preferred embodiment of the present invention, when R ² is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the number of heteroatoms in the 4-7 membered heterocycloalkyl group is 1 to 3, preferably 1 or 2.

In a preferred embodiment of the present invention, when R ² is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted with ^Ra , the number of ^Ra is 1 to 3, preferably 1.

In a preferred embodiment of the present invention, ^Ra is a hydroxyl group.

In a preferred embodiment of the present invention, when ^Ra is a halogen, the halogen is F, Cl, Br, or I, preferably F or Cl.

In a preferred embodiment of the present invention, when ^Ra is a _C1 - _C6 alkyl group, the _C1 - _C6 alkyl group is a _C1 - _C3 alkyl group, preferably a methyl group.

In a preferred embodiment of the present invention, when ^Ra is a deuterated C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ deuterated alkyl group, preferably .

In a preferred embodiment of the present invention, when ^Ra is -( _C1 - _C6 alkylene)-OH, the _C1 - _C6 alkylene is _C1 - _C4 alkylene, preferably methylene, ethylene, n-propylene or isopropylene, more preferably methylene.

In a preferred embodiment of the present invention, R ³ is hydrogen.

In a preferred embodiment of the present invention, when R ³ is an unsubstituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl.

In a preferred embodiment of the present invention, when A is a 5- to 10-membered heteroaryl group substituted by ^Re , the 5- to 10-membered heteroaryl group is a 6-membered heteroaryl group, preferably pyrimidine or oxazine.

In a preferred embodiment of the present invention, when A is a 5- to 10-membered heteroaryl group substituted by ^Re , the ^Re substitution is monosubstituted.

In a preferred embodiment of the present invention, when A is a 5- to 10-membered heteroaryl group substituted by ^Re , ^Re is a C ₁ -C ₃ alkyl group substituted by 1-5 identical or different halogens, preferably a trifluoromethyl group.

In a preferred embodiment of the present invention, when A is a 5- to 10-membered heteroaryl group substituted by ^Re , ^Re is an unsubstituted C ₁ -C ₃ alkyl group, preferably a methyl group.

In a preferred embodiment of the present invention, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 or .

In a preferred embodiment of the present invention, -LR ² is or .

In a preferred embodiment of the present invention, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In a preferred embodiment of the present invention, R ¹ is methyl, ethyl or Cl.

In a preferred embodiment of the present invention, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In a preferred embodiment of the present invention, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In a preferred embodiment of the present invention, R ³ is methyl or hydrogen.

In a preferred embodiment of the present invention, A is selected from 、 or .

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra , 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the R wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted by one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, and deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted ^{by Ra} , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 6-12 membered heterobicycloalkyl substituted by Ra is independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 5-10 membered heteroaryl substituted by Ra is one or more In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra , 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the R wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted by one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, and deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted ^{by Ra} , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 6-12 membered heterobicycloalkyl substituted by Ra is independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 5-10 membered heteroaryl substituted by Ra is one or more In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra , 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the R wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted by one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, and deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted ^{by Ra} , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 6-12 membered heterobicycloalkyl substituted by Ra is independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 5-10 membered heteroaryl substituted by Ra is one or more In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted ^or substituted by Ra; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the R wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted by one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, and deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted ^{by Ra} , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 6-12 membered heterobicycloalkyl substituted by Ra is independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 5-10 membered heteroaryl substituted by Ra is one or more In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is independently selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the R wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted by one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, and deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted ^{by Ra} , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 6-12 membered heterobicycloalkyl substituted by Ra is independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 5-10 membered heteroaryl substituted by Ra is one or more In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is independently selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the R wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted by one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, and deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted ^{by Ra} , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 6-12 membered heterobicycloalkyl substituted by Ra is independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 5-10 membered heteroaryl substituted by Ra is one or more In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is independently selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the R wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein ^Ra is substituted by one or more substituents, and each ^Ra is independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, and deuterated C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-7 membered heterocycloalkyl substituted ^{by Ra} , or the 6-12 membered heterobicycloalkyl substituted by Ra, wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 6-12 membered heterobicycloalkyl substituted by Ra is independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra is one or more substituents, and the 5-10 membered heteroaryl substituted by Ra is one or more In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl.

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any one of the following compounds: .

In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any one of the following compounds: .

In an embodiment of the present invention, the P2X3 receptor antagonist is selected from a compound represented by formula A, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: Formula A (i.e. compound I-27).

The present invention also provides a method for preparing the above-mentioned solid dispersion, which comprises the following steps: (1) adding each component to a solvent and stirring to dissolve; (2) drying the dissolved solution to obtain the solid dispersion.

In the embodiment of the present invention, step (1) specifically comprises: first adding a pharmaceutically acceptable carrier to a solvent and stirring to dissolve; then adding a P2X3 receptor antagonist and continuing to stir to dissolve.

In an embodiment of the present invention, the drying method of step (2) is selected from spray drying.

In the embodiment of the present invention, step (2) specifically comprises: filtering the dissolved solution into a transfer tank, and then drying the filtered solution to obtain a solid dispersion;

Preferably, the liquid is filtered through a precision filter of a certain pore size into a transfer tank.

In the embodiment of the present invention, after the drying treatment in step (2), the dried solid dispersion is optionally further subjected to pressure reduction drying.

In the embodiment of the present invention, in step (1), the stirring time is not less than 60 minutes (for example, not less than 120 minutes); preferably 60 to 120 minutes, 120 to 180 minutes.

In the embodiment of the present invention, in step (2), the pore size of the precision pressure filter is 1 μm-22 μm, preferably 5 μm.

In an embodiment of the present invention, in step (2), the feed frequency of the spray drying is 5 Hz-50 Hz, preferably 10 Hz-20 Hz;

and/or, atomization pressure is 0.1 Mpa -1.0 Mpa, preferably 0.1 Mpa -0.2 Mpa;

And/or, the inlet air temperature is 60℃-120℃, preferably 85℃-110℃;

And/or, the air outlet temperature is 40℃-70℃, preferably 50℃-55℃.

The present invention also provides a pharmaceutical composition comprising the above-mentioned solid dispersion and a pharmaceutically acceptable carrier, diluent or excipient.

In an embodiment of the present invention, the dosage form of the pharmaceutical composition is selected from a solid preparation, a liquid preparation; for example, powder, granules, pills, tablets, sachets, capsules, dragees, chewable tablets, blister tablets, dispersible tablets, troches, melts, solutions, suspensions or emulsions.

According to specific embodiments of the present invention, the pharmaceutical composition is mixed with a pharmaceutically acceptable carrier, diluent, or excipient to prepare a pharmaceutical formulation suitable for oral or parenteral administration. Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.

The present invention also provides a pharmaceutical preparation comprising the solid dispersion and a pharmaceutically acceptable carrier, diluent or excipient.

In an embodiment of the present invention, the pharmaceutical preparation is selected from a solid preparation or a liquid preparation, such as a powder, granules, pills, tablets, sachets, capsules, dragees, chewable tablets, blister tablets, dispersible tablets, troches, melts, solutions, suspensions, or emulsions. The pharmaceutical preparation can be prepared according to methods known in the art of manufacturing pharmaceutical preparations.

The pharmaceutical formulation can be administered by any route, for example, by infusion or bolus injection, or by absorption through epithelial or mucosal membranes (e.g., oral mucosa or rectum). Administration can be systemic or local. Examples of oral formulations include solid or liquid dosage forms, specifically tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, and the like. The formulation can be prepared by methods known in the art and include carriers, diluents, or excipients conventionally used in the field of pharmaceutical formulations.

The present invention also provides the use of the above-mentioned solid dispersion, pharmaceutical composition, and pharmaceutical preparation in the preparation of drugs for treating and/or preventing P2X3-related diseases.

In an embodiment of the present invention, the P2X3-related disease is pain, respiratory disease or urogenital disease.

In an embodiment of the present invention, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine, or visceral pain; and/or the genitourinary system disease is decreased bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, or cystitis; and/or the respiratory system disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, obstructive apnea, chronic cough, refractory chronic cough, and acute cough.

The present invention also provides a method for treating and/or preventing a P2X3-related disease, comprising administering an effective amount of the above-mentioned solid dispersion, pharmaceutical composition, or pharmaceutical preparation to a patient suffering from a P2X3-related disease.

In an embodiment of the present invention, the P2X3-related disease is pain, respiratory disease or urogenital disease.

In an embodiment of the present invention, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine, or visceral pain; and/or the genitourinary system disease is decreased bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, or cystitis; and/or the respiratory system disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, obstructive apnea, chronic cough, refractory chronic cough, and acute cough.

Terms and Definitions

Unless otherwise specified, the terms and definitions used in this application, including the specification and scope of the invention, are as follows.

It will be understood by those skilled in the art that, according to the common practice in the art, in the structural formula of the present invention, Used to depict chemical bonds, which are the points of attachment of a moiety or substituent to a core or backbone structure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable non-toxic acid or base salt, including salts of inorganic acids and bases, and organic acids and bases.

The term "solvate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the compound is a hydrate.

The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvent degradation. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional manipulations or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amine group within a compound of the present invention is attached to any moiety. When a prodrug of a compound of the present invention is administered to a mammal, the prodrug is cleaved to form free hydroxyl and free amine groups, respectively.

The term "stereoisomers" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, mirror isomers, non-mirror isomers, and conformational isomers.

Depending on the choice of starting materials and methods, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as a mixture of isomers, such as a racemic and amorphous isomers, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes D and L or (+) and (–) are used to designate the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers may also be referred to as mirror image isomers, and mixtures of such isomers are often referred to as mixtures of mirror image isomers. A 50:50 mixture of mirror image isomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When compounds described herein contain olefinic double bonds, such double bonds include both E and Z geometric isomers unless otherwise specified. If the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis- or trans- configuration.

When bonds to chiral carbon atoms are depicted as straight lines in the formulae of the present invention, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the resulting mirror-pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and mirror-pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is represented by a wedge-shaped bond and a dashed bond.

Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using known techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or non-mirrorally pure forms), 2-phenylglycinol, norphedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Racemic mixtures can also be resolved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzylphenylglycine). High performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be employed. The specific method, elution conditions, and chromatographic column selection can be determined by one of ordinary skill in the art based on the compound's structure and experimental results. Furthermore, any mirror image or non-mirror image of the compounds described in the present invention can be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.

The term "tautomer" refers to functional group isomers that arise from the rapid shift of an atom between two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually produce a mixture whose physical and chemical properties are consistent with those of the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), or C-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

With respect to drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in a composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by one skilled in the art through routine experimentation.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

The term "substituted" means that any one or more hydrogen atoms on a particular atom may be replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that the group may or may not be substituted. Unless otherwise specified, the type and number of substituents may be any chemically feasible basis.

The term "C ₁ -C ₆ alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. Such alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or isomers thereof. In particular, the group has 1, 2, 3 or 4 carbon atoms ("C ₁ -C ₄ alkyl"), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The term "C ₁ -C ₃ alkoxy" is to be understood as -O-(C ₁ -C ₃ alkyl), wherein "C ₁ -C ₃ alkyl" has the above definition.

The term "deuterated C ₁ -C ₆ alkyl" is understood to mean a C ₁ -C ₆ alkyl group in which one or more hydrogen atoms are replaced by deuterium, wherein "C ₁ -C ₆ alkyl" has the above definition.

The term " _C3 - _C7 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 7 carbon atoms, including fused or bridged polycyclic ring systems. Similarly, " _C3 - _C6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms as defined above. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "alkylene" is understood to mean a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains 1-10 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; and in yet other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include, but are not limited to, methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), n-propylene _{( -CH2CH2CH2- )} , isopropylene (-CH( _CH3 ) _CH2- ), and _the like.

The term "heterocycloalkyl" is understood to mean a saturated monovalent monocyclic hydrocarbon ring having the specified number of ring atoms, wherein one, two, or three ring atoms of the hydrocarbon ring are replaced by one, two, or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O) ₂ , or N. "4- to 7-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic "heterocycloalkyl" ring as defined above containing 4, 5, 6, or 7 ring atoms. Similarly, "4- to 6-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic "heterocycloalkyl" ring as defined above containing 4, 5, or 6 ring atoms.

The term "6- to 12-membered heterobicycloalkyl" is understood to mean a saturated monovalent bicyclic alkyl group wherein the two rings share one or two common ring atoms, wherein the bicyclic alkyl group contains 5, 6, 7, 8, 9 or 10 carbon atoms and one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O) ₂ or N, provided that the total number of ring atoms is not greater than 12.

The term "5-8 membered aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 5-8 carbon atoms, particularly a ring having 6 carbon atoms (" _C6 aryl"), such as phenyl. When the 5-8 membered aryl group is substituted, it may be mono- or polysubstituted. Furthermore, the position of substitution is not limited, and for example, substitution may be ortho-, para-, or meta-positioned.

The term "5- to 10-membered heteroaryl" is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5 to 10 ring atoms, in particular 5 or 6 carbon atoms, and containing 1 to 5 heteroatoms independently selected from N, O and S. Preferably, the monovalent monocyclic, bicyclic or tricyclic aromatic ring radical contains 1 to 3 heteroatoms independently selected from N, O and S, and, in each case, may additionally be benzofused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; or pyridinyl, oxazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, oxazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

Furthermore, it should be noted that, unless expressly stated otherwise, the term "independently" used in this invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by the same symbols in different groups do not affect each other, or that specific options expressed by the same symbols in the same group do not affect each other.

Beneficial effects

The present invention provides a solid dispersion comprising a P2X3 receptor antagonist compound represented by Formula I. This solid dispersion significantly improves the solubility of the compound represented by Formula I, significantly enhancing its dissolution rate and bioavailability, thereby ensuring its therapeutic efficacy. Furthermore, the solid dispersion exhibits excellent stability and does not undergo crystal transformation during storage, thereby enhancing the safety of the drug in clinical applications.

The present invention conducted extensive solid dispersion screening for the compound of Formula A, including various solid dispersion carriers and drug-carrier ratios, to obtain a solid dispersion with a relatively high drug-carrier ratio and excellent drug stability. In dogs, the compound exhibited good exposure at a dose of 20 mg/kg, maintained supersaturated concentrations for relatively long periods, and maintained stable and sustained in vivo absorption after 4 hours.

Pharmacokinetic tests in rats, mice, and dogs in the present invention showed that compounds I-27, I-28, I-29, and I-30 have comparable pharmacokinetic properties.

The following text further illustrates the technical solutions of the present invention in conjunction with specific embodiments. It should be understood that the following embodiments are intended only to illustrate 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-mentioned content of the present invention are included within the scope of protection intended by the present invention.

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

The compounds of the present invention and their preparation are described in WO2022068930A1 and WO2023185931A1.

"Pharmaceutically acceptable" means an excipient that is suitable for use in contact with human and animal tissues within the scope of sound medical judgment, does not cause excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a reasonable benefit/risk ratio.

Abbreviation list

Table 1-1 Abbreviations and their full names in this invention Abbreviation Full name API Active ingredient (compound of formula A, i.e. compound of formula I-27) SD solid dispersion SDD Spray drying solid dispersion HPMC-E5 Hydroxypropyl Methylcellulose E5 HPMC-AS-LF Hydroxypropyl methylcellulose acetate succinate LF Eudragit-L100-55 Eudragit L100-55 Soluplus Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer PVP VA64 Copolyvinylpyrrolidone VA64 DCM dichloromethane SGF Simulated gastric juice FaSSIF Simulated fasting bowel fluid HPLC High-performance chromatography MeOH Methanol XRD X-ray powder diffraction analyzer RH Relative humidity XRPD X-ray powder diffraction TGA Thermogravimetric analysis DSC Differential Scanning Calorimetry DVS Dynamic vapor adsorption

Instruments and testing methods

Laboratory equipment

The main instrument models and manufacturers used in this invention are shown in Table 2-1:

Table 2-1 Main instruments used in the experiment Name Model Manufacturer electronic balance XS5205DU Mettler Toledo X-ray diffractometer Aeris Research Malvern Panalytial Differential scanning calorimeter DSC250 TA Thermogravimetric analyzer TGA550 TA Dynamic Water Vapor Adsorption Analyzer Intrinsic Plus SMS Polarizing microscope Axio Observer Vett. A1 ZEISS HPLC 1260 Infinity II Aiglient Spray Dry ADL311S (GAS410 organic solvent recovery) Yamato Vacuum drying oven PZG-6050D Shanghai Senxin Laboratory Instruments 96-channel pipette Liquidator 96 Mettler Toledo Constant temperature rocking bed ZQTY-70N Shanghai Zhichu

2. X-ray powder diffraction (XRPD)

The relevant parameters of the X-ray powder diffraction (XRPD) instrument are shown in Table 2-2:

Table 2-2 XRPD instrument parameters Instruments Malvern Panalytical Aeris X-ray wavelength Cu, Kα:1.5419Å X-ray pipeline setup 40 kV, 15 mA Scan Mode 1D Scanning range (2θ) 3.5 ^o -40 ^o Scanning step length (2θ) 0.0027166 ^o Scan rate (2θ) 10 ^o /min

3. Thermogravimetric analysis (TGA)

The relevant parameters of the TGA instrument are shown in Table 2-3:

Table 2-3 TGA instrument related parameters Laboratory equipment TA, TGA500 How to use Linear temperature rise Temperature range 25-300.00 ℃ Heating rate 10 ℃ /min Blowing gas _N2 (＞99.999%) Sample plate type Aluminum sample tray, open without lid

4. Differential Scanning Calorimetry (DSC)

The relevant parameters of the DSC instrument are shown in Table 2-4:

Table 2-4 DSC instrument related parameters Laboratory equipment TA, DSC250 How to use Linear temperature rise Temperature range RT -300.00 ℃ Heating rate 10 ℃ /min Blowing gas _N2 (＞99.999%) Sample plate type Aluminum sample tray with lid and perforated top cover

5. Dynamic Vapor Sorption (DVS)

The DVS test records the dynamic water absorption curve at 25°C, relative humidity 0-90%RH, and dm/dt = 0.002%/min. The relevant parameters of the test instrument are shown in Table 2-5:

Table 2-5 DVS instrument test method Laboratory equipment DVS, Intrinsic Plus Humidity range 50%RH-0%RH-90%RH-0%RH-50%RH Humidity gradient 10% RH per step Test temperature 25 ℃ Step switching method dm/dt: 0.002% Number of loops 1 Gas flow rate _N2 200 mL/min

6. High Performance Liquid Chromatography (HPLC) Analysis Method

The HPLC test method and related parameters are shown in Table 2-6:

Table 2-6 HPLC analysis method (physiological media-related dissolution test) Column Thermo Acclaim™ 120 C18 4.6 Í 100 mm 5 μm Column temperature 35 ℃ Wavelength 210 nm flow rate 1 mL/min Injection volume 10 µL mobile phase Mobile phase A: 0.1% perchloric acid solution Mobile phase B: acetonitrile Elution gradient Isocratic elution, mobile phase A - mobile phase B (40:60, v%:v%) solvent 50% acetonitrile solution Control solution 0.05 mg/mL (light-shielded)

Reagents, auxiliary materials and their manufacturers

Table 3-1 Reagents, auxiliary materials and their manufacturers used in this invention Reagents / auxiliaries Model and manufacturer HPMC-E5 METHOCEL™, Colorcon HPMC-AS-LF AQOAT ^® , Shin-Etsu Eudragit-L100-55 Eudragit ^® , EVONIK Soluplus Soluplus ^® , BASF PVP VA64 Kollidon ^® , BASF FaSSIF biorelevant FaSSGF biorelevant

API Preparation

Compound API of Formula A (I-27) was prepared according to the methods described in WO2022068930A1 and WO2023185931A1. The product was characterized by XRPD (Figure 1), DSC (Figure 2), and TGA (Figure 2), confirming that it was the free base form A of WO2023185931A1.

Embodiment 1 Screening of solid dispersion excipients

1 , Research on Screening of Amorphous Solid Dispersion Carriers

Table 4-1 Screening research of amorphous solid dispersion carriers Inspection content carrier 96-well plate: row arrangement Prescription F1~F20 1 2 3 4 5 6 7 8 9 10 11 12 API : Carrier API 1:1 1:2 1:3 SDD does not add sedimentation inhibitor HPMC-AS-LF A F1 F1 F1 F1 F2 F2 F2 F2 F3 F3 F3 F16 Eudragit L100-55 B F4 F4 F4 F4 F5 F5 F5 F5 F6 F6 F6 F17 HPMC-E5 C F7 F7 F7 F7 F8 F8 F8 F8 F9 F9 F9 F18 PVP VA64 D F10 F10 F10 F10 F11 F11 F11 F11 F12 F12 F12 F19 Soluplus E F13 F13 F13 F13 F14 F14 F14 F14 F15 F15 F15 F20

The compound represented by Formula A has a high solubility in a dichloromethane/methanol system (volume ratio of 1:1). This solvent system was selected to prepare thin films of amorphous solid dispersions. The experimental steps are as follows:

1) Prepare amorphous solid dispersion films in 96-well plates using the mass ratios listed in Table 4-1. Prepare 10 identical 96-well plates, with each well containing 400 μg of the API (generally 10 times the maximum saturated solubility in physiological solution).

2) Using the rapid solvent evaporation method, a total of 10 96-well plates were prepared (8 for physiologically relevant dissolution, 1 for physical stability assessment, and 1 for excipient control). Details are shown in Table 4-1.

3) Perform physiologically relevant dissolution experiments in eight 96-well plates containing amorphous solid dispersion films. Sampling (96 channels), filtration (96 channels), and dilution (96 channels) were performed at the following time points: 5 and 10 minutes for simulated gastric fluid (SGF); 15 minutes for concentrated simulated fasting intestinal fluid (FaSSIF), with medium exchange; and sampling at 20, 30, 45, 60, 90, and 120 minutes.

4) Analyze the dissolved samples by HPLC to recreate a 96-channel physiologically relevant dissolution experiment.

5) Physical stability evaluation plates and blank supplement plates were imaged using high-throughput orthogonal polarization imaging at T0 and 7 days (40°C-75% RH) to assess the physical stability of the prescription.

6) Compare the differences among different formulations and prepare solid dispersions (SDDs) by spray drying the carrier with better dynamic dissolution and sedimentation inhibitor.

2 , dissolution of amorphous films with different carrier types and ratios

Amorphous solid dispersion films containing different types and proportions of API carriers were prepared and subjected to dynamic solubility tests in physiologically relevant media. The dynamic solubility results were compared with those of amorphous API films, and dynamic dissolution curves were prepared. The experimental results are shown in Tables 4-4 to 4-8 and Figures 3 to 7.

The test method is as follows:

Table 4-2 Dynamic Solubility Test Methods for Physiologically Relevant Media dissolution apparatus Fucose Dissolution method Paddle method Speed 75 rpm medium SGF medium 15 minutes, SGF+FaSSIF medium 105 minutes Medium volume 300 mL, 300 mL + 600 mL Medium temperature 37℃ ± 0.5℃ Sampling time 5min, 10min, 20min, 30min, 45min, 60min, 90min, 120min

born Configuration of related media:

The preparation method for SGF and concentrated FaSSIF solutions is shown in the table below. The pH of the concentrated FaSSIF solution is pre-adjusted with a 1.0 mol/L aqueous NaOH solution. After mixing SGF and concentrated FaSSIF at a 1:2 volume ratio, the pH is 6.5.

Table 4-3 Preparation methods of SGF and concentrated FaSSIF solutions Material Name Sample weight (g/200ml) SGF Concentrated FaSSIF Sodium chloride 0.4 1.6558 Sodium hydroxide / 0.126 Sodium dihydrogen phosphate / 1.0314 FaSSIF or FaSSGF 0.012 0.666 pH 1.6 Qs* * Adjust according to the pH of the mixed solution.

Table 4-4 Dynamic dissolution results of API and HPMC-AS-LF amorphous films at different ratios

In Table 4-4, AS LF-1:1 means API:HPMC-AS-LF=1:1, AS LF-1:2 means API:HPMC-AS-LF=1:2, and AS LF-1:3 means API:HPMC-AS-LF=1:3.

Table 4-5 Dynamic dissolution results of API and Eudragit L100-55 amorphous film at different ratios

In Table 4-5, L100-55-1:1 means API: Eudragit-L100-55=1:1, L100-55-1:2 means API: Eudragit-L100-55=1:2, and L100-55-1:3 means API: Eudragit-L100-55=1:3.

Table 4-6 Dynamic dissolution results of API and HPMC-E5 amorphous films at different ratios

In Table 4-6, E5-1:1 means API: HPMC E5=1:1, E5-1:2 means API: HPMC E5=1:2, and E5-1:3 means API: HPMC E5=1:3.

Table 4-7 Dynamic dissolution results of API and PVP VA64 amorphous films with different ratios

In Table 4-7, VA64-1:1 indicates API: PVP VA64 = 1:1, VA64-1:2 indicates API: PVP VA64 = 1:2, and VA64-1:3 indicates API: PVP VA64 = 1:3.

Table 4-8 Dynamic dissolution results of API and Soluplus amorphous film at different ratios

In Table 4-8, Soluplus-1:1 means API: Soluplus=1:1, Soluplus-1:2 means API: Soluplus=1:2, and Soluplus-1:3 means API: Soluplus=1:3.

3 , Summary of Experimental Research on Amorphous Solid Dispersion Screening

The experimental results above (Tables 4-4 to 4-8 and Figure 3-7) show that compared with the API control group, the dissolution of SDD prepared with the addition of carriers (HPMC-E5, HPMC-AS-LF, Eudragit L100-55, PVP VA64, and Soluplus) was improved to varying degrees. Among them, the dissolution improvement of SDD prepared with HPMC-E5, HPMC-AS-LF, and Eudragit L100-55 was the most significant.

Embodiment 2 Spray drying preparation SDD and dissolution curve investigation

Based on the above screening results, the carriers HPMC-E5, HPMC-AS-LF, and Eudragit-L100-55 were spray dried. Acetone was used as a solvent to prepare the solid dispersion. The steps are as follows: (1) The carrier was slowly added to the solvent and stirred for not less than 60 minutes until it was dissolved to a clear state. (2) The compound was slowly added to the above solution and stirred for not less than 120 minutes until it was dissolved to a clear state. (3) The above solution was filtered through a precision filter with a pore size of 5μm into a transfer tank of appropriate volume. (4) The filtered solution was spray dried. The feeding frequency is 20Hz; the atomization pressure is 0.2Mpa; the inlet air temperature is controlled at about 85-110℃, and the outlet air temperature range is 40-70℃. (5) The solid dispersion after spray drying is transferred to a vacuum box for reduced pressure drying to obtain a dry solid dispersion.

Finally, the solid dispersions obtained with different prescriptions were subjected to physiologically relevant dissolution tests.

Table 5-1 Summary of Prescription Information for F21~F28 Prescription F21 F22 F23 F24 F25 F26 F27 F28 API 50% 33.3% 25% 50% 33.3% 25% 33.3% 25% HPMC-E5 50% 66.7% 75% / / / / / HPMCAS-LF / / / 50% 66.7% 75% / / Eudragit-L100-55 / / / / / / 66.7% 75% total 100% 100% 100% 100% 100% 100% 100% 100%

The dissolution results are shown in Table 5-2 and Table 5-3.

Table 5-2 Dissolution curve studies of API:HPMC-E5=1:1, 1:2, 1:3 Time point Sample API:HPMC-E5=1:1 ( n=3 ) API:HPMC-E5=1:2 ( n=3 ) API:HPMC-E5=1:3 ( n=3 ) Prescription F21 F22 F23 medium Dissolution % RSD% Dissolution % RSD% Dissolution % RSD% 5min 300mL SGF 1.1 21.0 8.4 31.3 1.5 85.8 10min 3.1 41.5 8.0 18.2 3.7 34.8 15min 4.3 27.6 7.3 18.4 5.2 43.8 20min 300 mL SGF + 600 mL FaSSIF 2.9 25.9 8.4 15.5 9.4 8.0 30min 3.8 1.6 8.4 7.7 11.0 21.9 45min 4.6 16.4 9.7 7.8 12.3 20.0 60min 5.8 12.0 11.7 15.2 15.6 12.2 90 minutes 7.8 9.7 12.2 6.5 21.3 8.9 120 minutes 9.1 8.0 15.1 8.3 23.8 3.1

Table 5-3 Dissolution study of HPMC-AS-LF and Eudragit as SDD carriers Time point Sample API:HPMC-AS-LF=1:1 ( n=3 ) API:HPMC-AS-LF=1:2 ( n=3 ) API:HPMC-AS-LF=1:3 ( n=3 ) API:Eudragit L100-50=1:2 ( n=3 ) API:Eudragit L100-50=1:3 ( n=3 ) Prescription F24 F25 F26 F27 F28 medium Dissolution % RSD% Dissolution % RSD% Dissolution % RSD% Dissolution % RSD% Dissolution % RSD% 5min 300mL SGF 2.9 8.0 12.3 12.4 13.9 13.0 4.0 10.2 4.7 17.9 10min 3.4 8.5 13.9 14.5 15.7 11.8 4.1 8.4 5.8 16.2 15min 3.8 6.1 15.2 14.2 17.1 10.9 4.9 5.3 6.8 12.6 20min 300 mL SGF + 600 mL FaSSIF 6.2 0.0 32.3 23.9 45.6 10.2 19.4 4.1 32.3 7.9 30min 7.4 0.0 35.3 23.1 63.0 11.3 27.9 4.3 42.9 4.5 45min 7.8 8.9 36.3 21.4 71.0 6.3 30.5 3.2 43.1 1.6 60min 7.1 25.9 36.0 20.9 71.8 5.3 30.6 1.5 38.1 3.1 90 minutes 9.1 7.7 36.6 18.8 68.9 3.0 30.8 1.1 33.1 2.0 120 minutes 10.4 6.7 36.8 13.1 64.1 1.3 28.6 0 31.3 0.2

The dissolution test results of three different carriers SDD, HPMC-E5, HPMC-AS-LF and Eudragit, in physiologically relevant media show that:

For the same carrier type, a higher carrier ratio resulted in higher SDD dissolution rates. For example, the API:HPMC-AS-LF ratio of 1:3 (dissolution rate 64.1%) was higher than 1:2 (dissolution rate 36.8%) and higher than 1:1 (dissolution rate 10.4%). Furthermore, the API:HPMC-E5 ratio of 1:3 (dissolution rate 23.8%) was higher than 1:2 (dissolution rate 15.1%) and higher than 1:1 (dissolution rate 9.1%). Furthermore, the API:Eudragit L100-55 ratio of 1:3 (dissolution rate 31.3%) was higher than the API:Eudragit L100-55 ratio of 1:2 (dissolution rate 28.6%). This indicates that the API:HPMC AS-LF ratio of 1:3 exhibited the best dissolution rate, reaching 72% in 60 minutes, followed by the API:HPMC-AS-LF ratio of 1:2.

Embodiment 3 Physical stability research

The experimental steps for the physical stability investigation are as follows: Weigh approximately 10.0 mg of sample into a 1.5 mL liquid phase vial, place the sample under different temperature and humidity conditions, and take samples at multiple time points within 3 days, 7 days, and 18 days for XRD testing.

The results of the stability study experiments are shown in Tables 6-1, 6-2, and 6-3.

Table 6-1 Prescription API: HPMC-AS-LF (1:1) physical stability test results Prescription condition 3 days 7 days 18 days Characteristics Solid properties Characteristics Solid properties Characteristics Solid properties F24 40℃，RH 60% White powder amorphous White powder amorphous White powder amorphous 40℃，RH 75% White powder (agglomerate) amorphous White lumps Crystallization ∥ ∥ 60℃，RH 30% White powder amorphous White powder amorphous White powder Crystallization 60℃，RH 75% White powder (agglomerate) Crystallization Light yellow hard granules ∥ Light yellow hard granules ∥ 70℃，RH 60% White powder (agglomerate) Crystallization Light yellow hard granules ∥ Light yellow hard granules ∥ 75℃，RH 30% White powder Crystallization White powder ∥ White powder ∥

Table 6-2 Prescription API: HPMC-AS-LF (1:2) physical stability test results Prescription condition 3 days 7 days 18 days Characteristics Solid properties Characteristics Solid properties Characteristics Solid properties F25 40℃, RH 60% White powder amorphous White powder amorphous White powder amorphous 40℃, RH 75% White powder (agglomerate) amorphous White powder (agglomerate) amorphous White powder (agglomerate) amorphous 60℃, RH 30% White powder amorphous White powder amorphous White powder amorphous 60℃，RH 75% White powder (agglomerate) Crystallization Light yellow hard granules ∥ Light yellow hard granules ∥ 70℃，RH 60% White powder (agglomerate) Crystallization Light yellow hard granules ∥ Light yellow hard granules ∥ 75℃, RH 30% White powder amorphous White powder Crystallization White powder ∥

Table 6-3 Physical stability test results of prescription API: HPMC-AS-LF (1:3) Prescription condition 3 days 7 days 18 days Characteristics Solid properties Characteristics Solid properties Characteristics Solid properties F26 40℃，RH 60% White powder amorphous White powder amorphous White powder amorphous 40℃，RH 75% White powder amorphous White powder (agglomerate) amorphous White powder (agglomerate) amorphous 60℃，RH 30% White powder amorphous White powder amorphous White powder amorphous 60℃，RH 75% White powder (agglomerate) amorphous Light yellow hard granules amorphous Light yellow hard granules amorphous 70℃，RH 60% White powder (agglomerate) amorphous Light yellow hard granules amorphous Light yellow hard granules amorphous 75℃，RH 30% White powder amorphous White powder amorphous White powder amorphous

The stability test results above show that under harsh conditions (60°C, RH 75%, 70°C, RH 60%, 75°C, RH 30%), the solid-state properties of recipe F24 changed after 3 days, with XRD results indicating crystal transformation. At 7 days, the appearance and color of recipes F24, F25, and F26 changed, with recipe F25 (Figure 8) showing crystal transformation at 75°C, RH 30%. The solid-state properties of recipe F26 (Figure 10) showed no significant changes.

However, after 18 days at 40°C, RH 60%, 40°C, RH 75%, and 60°C, RH 30%, formulations F25 (Figures 9-1 to 9-3) and F26 (Figure 11) showed no significant changes in appearance and solid properties. XRD results showed that they were still amorphous solid dispersions. Moreover, formulation F26 (Figure 11) remained basically stable even under the extreme conditions of 60°C, RH 75% and 70°C, RH 60% for 18 days, indicating that it can be stably produced industrially. This indicates that formulations F25 and F26 have good physical stability when achieving a relatively high drug-carrier ratio.

Test Case 1 : Pharmacokinetic studies of compounds in rats, mice and dogs

For the pharmacokinetic study in rats, male Sprague-Dawley rats (180-240 g) were fasted overnight. Three rats were orally gavaged at 10 mg/kg. Blood was collected before dosing and at 15, 30, 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C. Plasma was collected and stored at -20°C. At each time point, plasma was added to 3-5 times the volume of acetonitrile containing an internal standard, vortexed for 1 minute, and centrifuged at 13000 rpm for 10 minutes at 4°C. The supernatant was then mixed with 3 times the volume of water, and an appropriate amount of the mixture was analyzed by LC-MS/MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

Mouse pharmacokinetic studies were performed using male ICR mice (20-25 g) fasted overnight. Three mice were orally gavaged at 10 mg/kg. Blood was collected before dosing and at 15, 30, 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C. Plasma was collected and stored at -80°C. At each time point, plasma was added to a 3-5-fold volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, and centrifuged at 13,000 rpm at 4°C for 10 minutes. The supernatant was then mixed with 3-fold volume of water, and an appropriate amount of the mixture was analyzed by LC-MS/MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

Canine pharmacokinetic studies were conducted using male beagle dogs weighing 8-10 kg, fasted overnight. Three beagle dogs were administered 5 mg/kg orally by gavage. Blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Three other beagle dogs were administered 1 mg/kg intravenously, and blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4:00 a.m., and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm for 4 minutes followed by 10 minutes. The supernatant was then added to 3 times the volume of water and mixed. An appropriate amount of the mixture was used for LC-MS/MS analysis. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

The results of rat tests showed that compounds I-27, I-28, I-29, and I-30 of the present invention have excellent and comparable pharmacokinetic properties.

Table 7-1 Pharmacokinetics of test compounds in mice Test compound Pharmacokinetic parameters in mice (oral gavage) Cmax (ng/mL) Tmax (hr) AUC0-t (h*ng/mL) T1/2 (hr) I-27 3377.5 0.50 14974.5 2.89 I-28 2400.2 0.50 8761.3 2.65 I-29 4098.9 1.00 14889.1 2.23 I-30 2945.5 1.00 13784.5 2.35

The results of mouse experiments showed that compounds I-27, I-28, I-29, and I-30 of the present invention have excellent and comparable pharmacokinetic properties.

Table 7-2 Pharmacokinetics of Test Compounds in Dogs Test compound Pharmacokinetic parameters in dogs (intravenous administration) Pharmacokinetic parameters in dogs (oral gavage) CL (L/h/kg) Vz (L/kg) AUC(0-t) h*ng/mL T1/2 (h) Tmax (hr) Cmax (ng/mL) AUC(0-t) (h*ng/mL) T1/2 (hr) I-29 0.45 5.00 September 2013 7.64 1.00 1156.5 8730.3 7.26 I-30 0.26 4.88 2821.7 13.01 1.00 1025.1 12600.9 13.37

The test results showed that compounds I-29 and I-30 of the present invention have low clearance rates after intravenous injection, high exposure levels after oral and intravenous administration, long half-lives, similar pharmacokinetic properties, and good drugability.

Test Case 2 : Thermodynamic solubility test

Fasting-state analogous gastric fluid FaSSGF (pH 1.6) (1 L solution contains 80 μM sodium taurocholate, 20 μM phosphatidylcholine, 0.1 g pepsin, and 34.2 mM sodium chloride), fasting-state analogous intestinal fluid FaSSIF (pH 6.5) (1 L solution contains 3 mM sodium taurocholate, 0.2 mM phosphatidylcholine, 38.4 mM sodium hydroxide, 68.62 mM sodium chloride, and 19.12 mM maleic acid), and phosphate buffered saline (PBS) (pH 7.4) (1 L solution contains 100 mM phosphate buffer, 11 g sodium bicarbonate, and 3.5 g sodium dihydrogen phosphate dihydrate) were prepared as assay buffers.

Accurately weigh the compound and prepare a 4 mg/mL working solution using assay buffers of varying pH values. Shake at 1000 rpm for 1 hour and equilibrate overnight at room temperature. Centrifuge the sample at 12000 rpm for 10 minutes to remove undissolved particles. Transfer the supernatant to a fresh centrifuge tube and analyze the compound concentration by LCMS/MS.

The experimental results show that compounds I-27, I-28, I-29, and I-30 all have good solubility.

Test Case 3 : SDD Prescription pharmacokinetic study in dogs

Canine pharmacokinetic studies were conducted using male beagle dogs weighing 9-11 kg, fasted overnight. Nine beagle dogs were randomly divided into three groups of three. Each group received a 20 mg/kg oral gavage dose of the formulations prepared according to the respective prescriptions in this application. Approximately 0.5 mL of blood was collected before dosing, 15 minutes after dosing, and at 1, 2, 4, 8, and 24 hours. The blood was transferred into an anticoagulant tube containing EDTA- _K2 . Plasma was collected by centrifugation at 1500 g for 10 minutes at 4°C. After acetonitrile protein precipitation, an appropriate amount of the mixture was analyzed by LC-MS/MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software. The results are shown in Table 7-3.

Table 7-3 Pharmacokinetic parameters in dogs (oral gavage) Test prescription Pharmacokinetic parameters in dogs (oral gavage) Tmax (hr) Cmax (ng/mL) AUC(0-t) (h*ng/mL) T1/2 (hr) API: HPMC-AS-LF 1:3 12.0 1390 20000 12.6

The results of the canine PK study showed that the SDD formulation (API:HMPC-AS-LF 1:3) delivered at a high dose resulted in good exposure, maintaining supersaturated concentrations for a relatively long period of time and maintaining stable and sustained in vivo absorption after 4 hours.

The above describes the implementation of the present invention. However, the present invention is not limited to the above implementation. 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.

without

[Figure 1] XRPD patterns of API compounds: [Figure 2] TGA & DSC patterns of API compounds. [Figure 3] Dynamic dissolution curves of API with HPMC-AS-LF amorphous films at different concentrations. [Figure 4] Dynamic dissolution curves of API with Eudragit L100-55 amorphous films at different concentrations. [Figure 5] Dynamic dissolution curves of API with HPMC-E5 amorphous films at different concentrations. [Figure 6] Dynamic dissolution curves of API with PVPVA64 amorphous films at different concentrations. [Figure 7] Dynamic dissolution curves of API with Soluplus amorphous films at different concentrations. [Figure 8] 7-day solid-state XRPD patterns of physical stability of prescription F25 under various conditions. [Figure 9-1] 18-day solid-state XRPD patterns of physical stability of prescription F25 at 40°C and 60% RH. [Figure 9-2] Solid-state XRPD pattern of the physical stability of prescription F25 at 40°C and 75% RH for 18 days. [Figure 9-3] Solid-state XRPD pattern of the physical stability of prescription F25 at 60°C and 30% RH for 18 days. [Figure 10] Solid-state XRPD pattern of the physical stability of prescription F26 under various conditions for 7 days. [Figure 11] Solid-state XRPD pattern of the physical stability of prescription F26 under various conditions for 18 days.

Claims (10)

A solid dispersion of a P2X3 receptor antagonist, wherein the solid dispersion comprises: a P2X3 receptor antagonist and a pharmaceutically acceptable carrier; wherein the P2X3 receptor antagonist is selected from the compound represented by the following formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: wherein ^R1 is independently selected from halogen, _C3 - _C6 cycloalkyl, C1- _{C4 alkyl} which is unsubstituted or substituted by 1-5 identical or different halogens; X is halogen; m is selected from an integer of 1, 2 or 3; L is -( _CH2 ) _n- , wherein n is selected from an integer of 0, 1 or 2; ^R2 is independently selected from hydrogen, _C1 - _C6 alkyl which is unsubstituted or substituted by ^Ra , _C3 - _C7 cycloalkyl which is unsubstituted or substituted by ^{Ra ,} 5-8 membered aryl which is unsubstituted or substituted by ^Ra , 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the _C1 - _C6 alkyl which is substituted by ^Ra , the _C3 -C7 cycloalkyl which is substituted by Ra ^, wherein the _5-7 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered heterobicycloalkyl substituted by Ra, the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (═O), -C(O)O-(C 1 -C 4 alkyl), -C(O)-(C 1 -C ₄ alkyl), -(C 1 -C 6 alkylene)-OH, or deuterated C ₁ -C 6 alkyl, which are unsubstituted or substituted with 1-5 identical or different halogens; when there are multiple substituents, ^the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted ^by Ra, the 4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered heterobicycloalkyl substituted by Ra, the Ra is substituted with one or more substituents, and the Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R ^c , -COOR ⁴ , oxo (═O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), -(C ₁ -C ₆ alkylene)-OH, or deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-10 membered aryl substituted by Ra, the 5-10 membered heteroaryl substituted by Ra, the 4-10 membered heterocycloalkyl substituted In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R3 is independently selected from hydrogen, _C1 - _C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; A is independently unsubstituted or substituted by R a 5- to 10-membered heteroaryl group substituted ^{with Re} , wherein the ^Re is substituted with one or more ^substituents , each of which is independently selected from the following substituents: halogen, _C1 - _C3 alkyl which is unsubstituted or substituted with 1-5 identical or different halogens, and -O-( _C1 - _C3 alkyl) which is unsubstituted or substituted with 1-5 identical or different halogens; when there are multiple substituents, these substituents may be the same or different. The solid dispersion of claim 1, wherein the solid dispersion is an amorphous solid dispersion; preferably, the P2X3 receptor antagonist exists in an amorphous form; preferably, the pharmaceutically acceptable carrier is a pharmaceutically acceptable polymer carrier; preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: 1) Cellulose derivative carriers; for example, hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetate succinate LF, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate; 2) Polyacrylic resin carriers; for example, Eudragit L100-55, Eudragit S100, Eudragit L100; 3) Vinyl polymer carriers; for example, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone VA64, and copovidone S630. Preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: hydroxypropyl methylcellulose (HPMC), copovidone PVP, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polymethacrylate, and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; more preferably, selected from any one or more of the following: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and polymethacrylate. Preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: hydroxypropylmethylcellulose E5, copovidone VA64, hydroxypropylmethylcellulose acetate succinate LF, Eudragit L100-55, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; more preferably, selected from any one or more of the following: hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetate succinate LF, Eudragit L100-55. The solid dispersion of claim 1 or 2, wherein the mass ratio of the P2X3 receptor antagonist to the pharmaceutically acceptable carrier is 1:0.1-10, preferably 1:0.5-5, for example, 1:0.5, 1:1, 1:2, 1:3, 1:4, or 1:5; Preferably, the solid dispersion comprises the following components: 10 wt%-60 wt% of the P2X3 receptor antagonist 40 wt%-90 wt% of the pharmaceutically acceptable carrier; Preferably, the solid dispersion comprises the following components: 20 wt%-55 wt% of the P2X3 receptor antagonist 45 wt%-80 wt% of the pharmaceutically acceptable carrier; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25 wt%-50 wt% (e.g., 25 wt%, 33 wt%, 33.3 wt%, 50 wt%) Pharmaceutically acceptable carrier 50 wt%-75 wt% (e.g., 50 wt%, 67 wt%, 66.7 wt%, 75 wt%) Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier accounts for no less than 66.7 wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier accounts for no less than 75 wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25wt%, 33.3wt%, 50wt% Pharmaceutically acceptable carrier: 50wt%, 66.7wt%, 75wt% The pharmaceutically acceptable carrier is selected from hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist: 25wt% Pharmaceutically acceptable carrier: 75wt% The pharmaceutically acceptable carrier is selected from hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist: 33.3wt% Pharmaceutically acceptable carrier 66.7 wt% The pharmaceutically acceptable carrier is selected from hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hydroxypropylmethylcellulose acetate succinate LF, wherein the proportion of hydroxypropylmethylcellulose acetate succinate LF is not less than 75 wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25 wt% Hydroxypropylmethylcellulose acetate succinate LF 75 wt%; Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hydroxypropylmethylcellulose acetate succinate (LF), wherein the proportion of hydroxypropylmethylcellulose acetate succinate (LF) is not less than 66.7 wt %. Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 33.3 wt % Hydroxypropylmethylcellulose acetate succinate (LF) 66.7 wt %. Preferably, the solid dispersion optionally further comprises a solvent. Preferably, the solvent is a volatile solvent. Preferably, the solvent is selected from any one or more of the following: dichloromethane, ethanol, acetone, methanol; preferably acetone or a dichloromethane-methanol mixed solvent. Preferably, the solid dispersion optionally further comprises any one or more of the following: sweeteners, flavorings, coloring agents, surfactants, fillers, lubricants, disintegrants, disintegration promoters, recrystallization inhibitors, defoaming agents, antioxidants, and pH adjusters. The solid dispersion according to any one of claims 1 to 3, wherein the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs is: wherein ^R1 is independently selected from halogen, _C3 - _C6 cycloalkyl, C1- _{C4 alkyl} which is unsubstituted or substituted by 1-5 identical or different halogens; X is halogen; m is selected from an integer of 1, 2 or 3; L is -( _CH2 ) _n- , wherein n is selected from an integer of 0, 1 or 2; ^R2 is independently selected from hydrogen, _C1 - _C6 alkyl which is unsubstituted or substituted by ^Ra , _C3 - _C7 cycloalkyl which is unsubstituted or substituted by ^{Ra ,} 5-8 membered aryl which is unsubstituted or substituted by ^Ra , 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the _C1 - _C6 alkyl which is substituted by ^Ra , the _C3 -C7 cycloalkyl which is substituted by Ra ^, wherein the _5-7 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the substitutions independently refer to one or more of the following substituents: C 1 -C 4 alkyl, halogen, -OH, -NR b R ^c , -COOR 4 , oxo (=O), -C(O)O-(C 1 -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), or deuterated C ₁ -C 6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the 5-8 membered aryl substituted ^by Ra, the 5-10 membered heteroaryl substituted by ^Ra , the ^4-7 membered heterocycloalkyl substituted by Ra, or the 6-12 membered heterobicycloalkyl substituted by Ra, the substitutions independently refer to one or more of the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR b R c , -COOR 4 , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C 1 -C 4 alkyl), or deuterated C ₁ -C ₆ alkyl, which are unsubstituted or substituted by 1 to 5 identical or different halogens. In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R3 is independently selected from hydrogen, _C1 - _C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; A is independently unsubstituted or substituted by R wherein the 5- to 10-membered heteroaryl group is substituted by ^{R e} , wherein the R ^e is substituted by one or more substituents, and the R ^e is independently selected from the following substituents: halogen, C ₁ -C ₃ alkyl group which is unsubstituted or substituted by 1-5 identical or different halogens, and -O-(C ₁ -C ₃ alkyl group which is unsubstituted or substituted by 1-5 identical or different halogens); when there are multiple substituents, the substituents are the same or different; preferably, when R ¹ is a halogen, the halogen is F, Cl, Br, I, preferably Cl; preferably, when R ¹ is an unsubstituted C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl; preferably, when R When ^R1 is a _C1 - _C4 alkyl group substituted by 1-5 identical or different halogens, the C1- _{C4 alkyl} group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl; Preferably, when ^R1 is a C1- _{C4 alkyl} group substituted by 1-5 identical or different halogens, the halogen is F, Cl, Br, I, preferably Cl or F; Preferably, when X is a halogen, the halogen is one of F or Cl; Preferably, m is selected from an integer of 1, 2 or 3, preferably 1; Preferably, when L is -( _CH2 ) _n- , n is an integer of 0, 1 or 2, preferably n is 0 or 1; Preferably, when ^R2 is a _C1 -C4 alkyl group which is unsubstituted or substituted by ^Ra Preferably, when R ₂ is a C ₁ -C ₆ alkyl group which is unsubstituted or substituted by ^Ra , the C ₁ -C ₆ alkyl group is preferably a C 1 -C 4 alkyl group, preferably a sec-butyl group; Preferably, when R ² is a C ₁ -C ₆ alkyl group which is unsubstituted or substituted by Ra, the C ₁ -C ₆ alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; Preferably, when R ² is a C ₃ -C ₇ cycloalkyl group which is unsubstituted or substituted ^{by Ra} , the C ₃ -C ₇ alkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, preferably a cyclopropyl group; Preferably, when R 2 is an unsubstituted or substituted by Ra, the C 3 -C 7 alkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, preferably a cyclopropyl group; Preferably, when R ² is an unsubstituted or substituted by Ra, the C 1 -C 6 alkyl group is preferably a sec-butyl group Preferably, when ^R2 is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted with Ra, the 4-7 membered heterocycloalkyl group is a 4-, 5- or 6-membered heterocycloalkyl group; Preferably, when ^R2 is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted with ^Ra , the heteroatom in the 4-7 membered heterocycloalkyl group is one or more of N, S, O and P, preferably one or more of N or O; Preferably, when ^R2 is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted ^{with Ra} , the number of heteroatoms in the 4-7 membered heterocycloalkyl group is 1 to 3, preferably 1 or 2; Preferably, when ^R2 is a 4-7 membered heterocycloalkyl group which is unsubstituted or substituted with ^Ra , the number of ^Ra is 1 to 3, preferably 1; Preferably, ^Ra is a hydroxyl group; Preferably, when ^Ra is a halogen, the halogen is F, Cl, Br, I, preferably F or Cl; Preferably, when ^Ra is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ alkyl group, preferably a methyl group; Preferably, when ^Ra is a deuterated C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ deuterated alkyl group, preferably ; Preferably, when ^Ra is -( _C1 - _C6 alkylene)-OH, the _C1 - _C6 alkylene is _C1 - _C4 alkylene, preferably methylene, ethylene, n-propylene or isopropylene, more preferably methylene; Preferably, ^R3 is hydrogen; Preferably, when ^R3 is unsubstituted _C1 - _C4 alkyl, the _C1 - _C4 alkyl is methyl, ethyl, n-propyl, isopropyl, preferably methyl; Preferably, when A is a 5- to 10-membered heteroaryl substituted by ^Re , the 5- to 10-membered heteroaryl is a 6-membered heteroaryl, preferably pyrimidine or oxazine; Preferably, when A is a 5- to 10-membered heteroaryl substituted by ^Re , the R ^e is substituted with a monosubstituted group; preferably, when A is a 5- to 10-membered heteroaryl group substituted with ^Re , said ^Re is a C ₁ -C ₃ alkyl group substituted with 1-5 identical or different halogens, preferably a trifluoromethyl group; preferably, when A is a 5- to 10-membered heteroaryl group substituted with ^Re , said ^Re is an unsubstituted C ₁ -C ₃ alkyl group, preferably a methyl group; preferably, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 or ; Preferably, -LR ² is or ; Preferably, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ; Preferably, R ¹ is methyl, ethyl or Cl; Preferably, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ; Preferably, -LR ² is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ; Preferably, R ³ is methyl or hydrogen; Preferably, A is selected from 、 or Preferably, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra, C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by Ra; the C ₁ -C ₆ alkyl which is substituted by ^Ra , the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR ^b R ^c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; ... In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; Preferably, the compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra, C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by Ra; the C ₁ -C ₆ alkyl which is substituted by ^Ra , the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR ^b R ^c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; ... In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; Preferably, the compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra, C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by Ra; the C ₁ -C ₆ alkyl which is substituted by ^Ra , the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR ^b R ^c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; ... In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; Preferably, the compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra , C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by ^Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by Ra, the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR ^b R ^c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; ... In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; Preferably, the compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is independently selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra, C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by ^Ra , the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR ^b R ^c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; ... In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; ^Rb and ^Rc are independently selected from hydrogen or _C1 - _C4 alkyl; Preferably, the compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are: wherein R ¹ is independently selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra, C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by ^Ra , the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR ^b R ^c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; ... In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; ^R4 is independently selected from hydrogen or _C1 - _C4 alkyl; Preferably, the compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are: wherein R ¹ is independently selected from halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH ₂ ) _n -, wherein n is selected from an integer 0, 1 or ² ; R ² is independently selected from hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by ^Ra, C ₃ -C ₇ cycloalkyl which is unsubstituted or substituted by ^Ra , 5-8 membered aryl which is unsubstituted or substituted by ^Ra, 5-10 membered heteroaryl which is unsubstituted or substituted by Ra, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by ^Ra , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by ^Ra ; the C ₁ -C ₆ alkyl which is substituted by ^Ra , the C ₃ -C ₇ cycloalkyl which is substituted by ^Ra , the wherein the 5-8 membered aryl substituted by ^Ra , the 5-10 membered heteroaryl substituted by ^Ra , the 4-7 membered heterocycloalkyl substituted by ^Ra , or the 6-12 membered heterobicycloalkyl substituted by ^Ra , the ^Ra is substituted with one or more substituents, and the ^Ras are each independently selected from the following substituents: C ₁ -C ₄ alkyl, halogen, -OH, -NR ^b R ^c , -COOR ⁴ , oxo (=O), -C(O)O-(C ₁ -C ₄ alkyl), -C(O)-(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkylene)-OH, and deuterated C ₁ -C ₆ alkyl; when there are multiple substituents, the substituents are the same or different; ... In the 5-10 membered heteroaryl group substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl group which is unsubstituted or substituted by ^Ra , the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; R ^<4> is independently selected from hydrogen or C _<1> -C _<4> alkyl; R ^<b> and R ^<c> are independently selected from hydrogen or C _<1> -C _<4> alkyl. The solid dispersion according to any one of claims 1 to 4, wherein the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any one of the following compounds: . The solid dispersion according to any one of claims 1 to 4, wherein the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any one of the following compounds: Preferably, the P2X3 receptor antagonist is selected from the compound represented by Formula A (Formula I-27), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: Formula A. A method for preparing a solid dispersion as described in any one of claims 1 to 6, wherein the preparation method comprises the following steps: (1) adding each component to a solvent and stirring to dissolve; (2) drying the dissolved solution to obtain the solid dispersion; Preferably, step (1) is specifically: first adding a pharmaceutically acceptable carrier to the solvent and stirring to dissolve; then adding a P2X3 receptor antagonist and continuing to stir to dissolve; Preferably, the drying method of step (2) is selected from spray drying; Preferably, step (2) is specifically: filtering the dissolved solution into a transfer tank, and then drying the filtered solution to obtain the solid dispersion; Preferably, the solid dispersion is filtered through a precision filter press of a certain pore size and then transferred to a transfer tank; Preferably, after the drying treatment in step (2), the dried solid dispersion is optionally further subjected to pressure reduction drying; Preferably, in step (1), the stirring time is not less than 60 minutes (for example, not less than 120 minutes); preferably 60 to 120 minutes, 120 to 180 minutes; Preferably, in step (2), the pore size of the precision filter press is 1 μm to 22 μm, preferably 5 μm; Preferably, in step (2), the feed frequency of the spray drying is 5 Hz to 50 Hz, preferably 10 Hz to 20 Hz; and/or, atomization pressure of 0.1 MPa-1.0 MPa, preferably 0.1 MPa-0.2 MPa; and/or, inlet air temperature of 60°C-120°C, preferably 85°C-110°C; and/or, outlet air temperature of 40°C-70°C, preferably 50°C-55°C. A pharmaceutical composition, wherein the pharmaceutical composition comprises the solid dispersion according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier, diluent or excipient. Use of the solid dispersion of any one of claims 1 to 6 or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating and/or preventing a P2X3-related disease, wherein: Preferably, the P2X3-related disease is pain, a respiratory disease, or a genitourinary disease; Preferably, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine, or visceral pain; and/or the genitourinary system disease is decreased bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, or cystitis; and/or the respiratory system disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, obstructive apnea, chronic cough, refractory chronic cough, and acute cough. A method for treating and/or preventing a P2X3-related disease, comprising administering an effective amount of the solid dispersion of any one of claims 1 to 6 or the pharmaceutical composition of claim 8 to a patient suffering from a P2X3-related disease. Preferably, the P2X3-related disease is pain, a respiratory disease, or a genitourinary disease. Preferably, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine pain, or visceral pain. and/or the genitourinary system disease is decreased bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, or cystitis; and/or the respiratory system disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma and obstructive apnea, chronic cough, refractory chronic cough, and acute cough.