Pharmaceutical composition comprising mitochondrial autophagy inducer

Abstract

The present invention relates to a pharmaceutical composition comprising a mitochondrial autophagy inducer as an active substance. The pharmaceutical composition disclosed by the invention is favorable for being prepared into a pharmaceutical preparation, and incompatibility caused by interaction between active substances and auxiliary materials can be avoided, so that the pharmaceutical composition can be stored for a long time.

Description

Technical Field

[0001] The invention relates to a pharmaceutical composition comprising a mitochondrial autophagy inducer, and belongs to the field of pharmaceutical preparations. Background Art

[0002] The compound of formula I and the specific compound thereof (especially TJ0113) are described in CN115894404A, and are a mitochondrial autophagy inducer, which can be used to inhibit or alleviate various acute or chronic diseases caused by mitochondrial autophagy dysfunction. The general formula and the structure of compound TJ0113 are as follows:

[0003]

[0004] The prior art does not have any research on the pharmaceutical composition or preparation of the compound. The inventors of the present application found that the mitochondrial autophagy inducer compound is prone to stability problems when it is prepared into a preparation. The reason is that the compound is easy to interact with a variety of excipients commonly used in the pharmaceutical industry, resulting in incompatibility, which is not conducive to long-term storage. Therefore, there is an urgent need in the art to develop a pharmaceutical composition to solve the incompatibility problem between the mitochondrial autophagy inducer compound and the excipients, so as to obtain a preparation that can be stored for a long time. Summary of the invention

[0005] The inventors of the present application have conducted extensive research to solve the above-mentioned problems, and thus developed a pharmaceutical composition containing a mitochondrial autophagy inducer that can overcome the incompatibility problem. Specifically, the present invention includes but is not limited to the following technical contents:

[0006] 1. A pharmaceutical composition, characterized in that it comprises a compound of formula I or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a lubricant, and does not contain any of the following ingredients: hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, magnesium stearate, talc, mannitol, cross-linked sodium carboxymethyl cellulose,

[0007]

[0008] In the formula, R 2 For hydrogen, C 1～4 Alkyl, C 3～6 Cycloalkyl, four- to six-membered epoxyalkyl;

[0009] R 3 for

[0010] Among them, R 3-1 Hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, C 3～6Cycloalkyl, three to six-membered epoxyalkyl, -N(R 3 -2 R 3-2a )、-CH2C(O)R 3-2 、-CH2C(O)OR 3-2 、-CH2C(O)NR 3-2 R 3-2a ,

[0011] R 3-2 and R 3-2a are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl,

[0012] Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, or is supported by at least one R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, said R 3-3 For hydrogen, halogen, C 1～4 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～4 Alkoxy, three to six membered epoxyalkyl, C 1～4 Haloalkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl,

[0013] R 3-3a and R 3-3b are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl;

[0014] R 4 for

[0015] Among them, R 4-1 is phenyl, and is supported by at least one R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one R 4 -11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For halogen, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Haloalkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C1～4 Alkyl or C 3～6 Cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0016] R 4-2 C 1～4 Alkyl, C 3～6 Cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form 4 to 8 membered rings,

[0017] R 4-3 C 1～4 Alkyl or C 1～4 Alkoxy;

[0018] R 5 The number of R is 0 to 5. 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Haloalkyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5 -1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Alkyl, C in which at least one hydrogen is replaced by a halogen 2～4 alkenyl or C in which at least one hydrogen atom is replaced by halogen 2～4Alkynyl.

[0019] 2. A pharmaceutical composition according to technical content 1, wherein the diluent comprises microcrystalline cellulose and pregelatinized starch.

[0020] 3. The pharmaceutical composition according to technical content 1 or 2, wherein the disintegrant is sodium starch glycolate.

[0021] 4. A pharmaceutical composition according to any one of technical contents 1-3, wherein the lubricant is sodium stearyl fumarate.

[0022] 5. A pharmaceutical composition according to any one of technical contents 1 to 4, wherein R 2 is hydrogen or C 1～4 alkyl;

[0023] R 3 for

[0024] Among them, R 3-1 Hydrogen, hydroxyl, C 1～4 Alkyl or C 1～4 Alkoxy,

[0025] R 4 for

[0026] Among them, R 4-1 is phenyl, and is supported by at least one R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one R 4 -11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For halogen, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Haloalkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 Alkyl or C 3～6 Cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring,

[0027] R 4-2 C 1～4 Alkyl, C 3～6 Cycloalkyl, or when R2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form 4 to 8 membered rings,

[0028] R 4-3 C 1～4 Alkyl or C 1～4 Alkoxy;

[0029] R 5 The number of R is 0 to 3. 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Haloalkyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5 -1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Alkyl, C in which at least one hydrogen is replaced by a halogen 2～4 alkenyl or C in which at least one hydrogen atom is replaced by halogen 2～4 Alkynyl.

[0030] 6. The pharmaceutical composition according to technical content 5, wherein R 2 is hydrogen or C 1～4 alkyl,

[0031] R 3 for R 3-1Hydroxyl or C 1～4 Alkoxy,

[0032] R 4 for

[0033] Among them, R 4-1 is phenyl, and is supported by at least one R 4-11 substituted phenyl, 5- or 6-membered monocyclic heteroaryl, or at least one R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, said R 4-11 For halogen, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Alkoxy, or C 1～4 haloalkyl; and

[0034] R 5 The number of is 0.

[0035] 7. The pharmaceutical composition according to technical content 6, wherein R 2 For hydrogen,

[0036] R 3 for R 3-1 is hydroxyl group,

[0037] R 4 for

[0038] Among them, R 4-1 For at least one R 4-11 Substituted phenyl, the R 4-11 For halogen, C 1～4 Alkyl, C 1～4 Alkoxy, or C 1～4 haloalkyl; and

[0039] R 5 The number of is 0.

[0040] 8. The pharmaceutical composition according to technical content 7, wherein the compound of formula I is TJ0113

[0041]

[0042] 9. The pharmaceutical composition according to technical content 8, wherein the TJ0113 is in the solid form of a sodium salt represented by the following formula:

[0043]

[0044] Wherein X is 0.1-2, for example 1.

[0045] 10. A pharmaceutical composition according to technical content 9, wherein the X-ray powder diffraction pattern of the solid form shows the following characteristic peaks at 2θ (Cu Kα rays): 7.06° (±0.2°) and 20.87° (±0.2°).

[0046] 11. A pharmaceutical composition according to any one of technical contents 1-10, comprising compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sodium stearyl fumarate.

[0047] 12. The pharmaceutical composition according to technical content 11, which is composed of compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sodium stearyl fumarate.

[0048] 13. A pharmaceutical composition according to any one of technical contents 1 to 12, wherein the content percentage of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1.0 wt% to 50 wt%, the content percentage of the diluent in the pharmaceutical composition is 30 wt% to 90 wt%, the content percentage of the disintegrant in the pharmaceutical composition is 0.1 wt% to 25 wt%, and the content percentage of the lubricant in the pharmaceutical composition is 0.01 wt% to 5.0 wt%.

[0049] 14. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of technical contents 1 to 13, wherein the pharmaceutical preparation is selected from tablets, capsules, granules, powders, and pills.

[0050] 15. The pharmaceutical preparation according to technical content 14 is a capsule, which consists of a capsule shell and contents, and the contents are the pharmaceutical composition according to any one of technical contents 1-13.

[0051] Preferably, in the aforementioned technical scheme involving the solid form of the sodium salt of compound TJ0113, its X-ray powder diffraction pattern shows at least one characteristic peak selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), 17.58° (±0.2°), 20.87° (±0.2°), 10.54° (±0.2°), and 23.91° (±0.2°) 2θ. More preferably, the solid form of the sodium salt of the compound of formula (I) exhibits at least one (more preferably at least two, more preferably at least three) characteristic peaks of 2θ selected from 7.06° (± 0.2°), 18.07° (± 0.2°), 25.02° (± 0.2°), 17.58° (± 0.2°), 20.87° (± 0.2°), 10.54° (± 0.2°), 23.91° (± 0.2°), 27.65° (± 0.2°), 27.05° (± 0.2°), 21.68° (± 0.2°), 25.91° (± 0.2°) in the X-ray powder diffraction pattern. More preferably, the solid form of the sodium salt of the compound of formula (I) (also referred to herein as "D crystal form") exhibits a characteristic peak of 2θ of 7.06° (± 0.2°), 18.07° (± 0.2°), 25.02° (± 0.2°), 17.58° (± 0.2°), 20.87° (± 0.2°), 10.54° (± 0.2°), 23.91° (± 0.2°), 27.65° (± 0.2°), 27.05° (± 0.2°), 21.68° (± 0.2°), 25.91° (± 0.2°). Figure 8 Roughly the same X-ray powder diffraction patterns.

[0052] The D-crystalline solid form of the sodium salt of compound TJ0113 has an endothermic peak at 183.79°C (±3°C) and an exothermic peak at 210.79°C (±3°C) according to the differential scanning calorimetry curve. The solid form of the sodium salt of the compound of formula (I) of the present invention has a thermogravimetric analysis curve similar to that of Fig. 9 Roughly the same thermogravimetric analysis (DSC) curves.

[0053] In some preferred embodiments, the thermogravimetric analysis curve of the D-crystalline solid form of the sodium salt of the compound TJ0113 shows Fig.10 Roughly the same thermogravimetric analysis curves.

[0054] In some preferred embodiments, the pharmaceutical composition includes the following components in parts by weight:

[0055] 20-30 parts of a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0056] Diluent: 50-80 parts;

[0057] Disintegrants……1-10 parts;

[0058] Lubricant……0.1-3 parts.

[0059] In some preferred embodiments, the pharmaceutical composition includes the following components in parts by weight:

[0060] 23-28 parts of a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0061] Diluent...60-70 parts;

[0062] Disintegrants…3-8 parts;

[0063] Lubricant……0.1-1 part.

[0064] In some preferred embodiments, the diluent is selected from at least one of microcrystalline cellulose, lactose, mannitol, starch and dextrin.

[0065] In some preferred embodiments, the disintegrant is selected from at least one of sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone.

[0066] In some preferred embodiments, the lubricant is selected from at least one of magnesium stearate, sodium stearyl fumarate and talc.

[0067] In some preferred embodiments, the pharmaceutical composition may also include a thickener (e.g., gelatin, gelatin arabic), a preservative (e.g., benzoate, sorbate), a binder (e.g., a mixture of powdered sugar and syrup, polyvinyl pyrrolidone), a sweetener (e.g., sucrose, aspartame), a stabilizer (e.g., ascorbic acid, sodium thiosulfate) and / or a glidant (e.g., colloidal silicon dioxide, talc).

[0068] In some preferred embodiments, the diluent is microcrystalline cellulose and pregelatinized starch.

[0069] In some preferred embodiments, the disintegrant is sodium starch glycolate.

[0070] In some preferred embodiments, the lubricant is sodium stearyl fumarate. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 The effect of the diluent type on the dissolution results in Example 2 is shown (paddle method + sinker, 50 rpm).

[0072] Figure 2 The effect of the diluent ratio on the dissolution results in Example 2 is shown (basket method, 75 rpm).

[0073] Figure 3 The effect of disintegrant type on dissolution results in Example 3 is shown (basket method, 75 rpm).

[0074] Figure 4 The effect of the solubilizing agent on the dissolution in Example 3 is shown (basket method, 75 rpm).

[0075] Figure 5The dissolution test results of 20 mg capsules in Example 3 are shown (paddle method + sinker, 75 rpm).

[0076] Figure 6 The dissolution results of 20 mg capsules of F14 in Example 4 are shown (paddle method + sinker, 75 rpm).

[0077] Figure 7 The stability dissolution results of 100 mg capsules of F13 in Example 4 are shown (paddle method + sinker, 75 rpm).

[0078] Figure 8 The figure shows the X-ray powder diffraction pattern of the D crystal form of the sodium salt of the compound TJ0113.

[0079] Fig. 9 The differential scanning calorimetry curve of the D crystal form of the sodium salt of compound TJ0113 is shown.

[0080] Fig.10 The thermogravimetric analysis curve of the D-type of the sodium salt of compound TJ0113 is shown.

[0081] Fig.11 The XRPD patterns of the samples before and after dry granulation in Example 5 are shown. DETAILED DESCRIPTION

[0082] The compound of formula I or its pharmaceutically acceptable salt (such as compound TJ0113) is also referred to herein as "active ingredient" or "API". Those skilled in the art will appreciate that the compounds of formula I have similar properties due to their similar structures, and therefore the compounds within the scope thereof are all suitable for the formulations defined in the present invention.

[0083] The inventors of the present application have found that there are incompatibility issues between the active ingredient and the excipients hydroxypropylcellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, talc, sugar alcohol (especially mannitol) and croscarboxymethylcellulose sodium, as detailed in the experimental content of the embodiment section. Therefore, the preparation of the present invention does not contain these excipients with compatibility issues.

[0084] In the pharmaceutical composition of the present invention, the percentage of active ingredient in the pharmaceutical composition can be, for example, 1.0wt% to 50wt%, such as 1.0wt%, 2.0wt%, 5.0wt%, 8.0wt%, 10.0wt%, 12wt%, 15wt% to 25wt%, 30wt%, 35wt%, 40wt%, 50wt%, for example, 10.0wt% to 40wt%, or 16wt% to 30wt%, preferably 20wt% to 25wt%, or about 25wt%.

[0085] Diluent refers to an excipient used to increase the volume or weight of a solid pharmaceutical preparation, also known as a filler. In addition to the aforementioned excipients with compatibility issues, the pharmaceutical composition of the present invention may contain diluents known in the art, such as lactose, microcrystalline cellulose, and pregelatinized starch. From the perspective of accelerating dissolution, a mixture of microcrystalline cellulose and pregelatinized starch is preferred; as verified by the experiments in the examples, the ratio of the two has little effect on the dissolution effect, for example, it can be 5:1-0.5:1, preferably 3:1-1:1. The content percentage of the diluent in the pharmaceutical composition can be, for example, 30wt% to 90wt%, such as 30wt%, 35wt%, 40wt%, 50wt%, 55wt%, 60wt%, 65wt%, 70wt% to 75wt%, 80wt%, 85wt%, 90wt%, for example, 40wt% to 85wt%, or 55wt% to 80wt%, preferably 65wt% to 75wt%, or about 70wt%, wherein the content percentage of the pregelatinized starch in the pharmaceutical composition can be, for example, 1.0wt% to 50wt%, such as 1.0wt%, 2.0wt%, 5.0wt%, 8.0wt%, 10.0wt%, 12wt%, 15wt% to 25wt%, 30wt%, 35wt%, 40wt%, 50wt%, for example, 10.0wt% to 30wt%, or 12wt% to 30wt%, preferably 15wt% to 25wt%. The diluent used in the present application is, for example, commercially available microcrystalline cellulose 102 (available from Microcellulose Weissenborn GmbH + Co. KG) and pregelatinized starch STARCH (Purchased from Colorcon).

[0086] Disintegrants refer to adjuvants that are used to promote solid preparations to break rapidly into fine particles in gastrointestinal fluid. In addition to the aforementioned adjuvants with compatibility problems, the pharmaceutical composition of the present invention can include disintegrants known in the art, such as sodium carboxymethyl starch. The content percentage of disintegrants in the pharmaceutical composition can be, for example, 0.1wt% to 25wt%, such as 0.1wt%, 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 2.7wt% to 3.0wt%, 3.2wt%, 3.5wt%, 4.0wt%, 5.0wt%, 7wt%, 8.0wt%, 10.0wt%, 12wt%, 15wt%, 20wt%, 25wt%, for example, 0.5wt% to 7wt%, or 1.0wt% to 5wt%, preferably 2.5wt% to 3.5wt%, or about 3wt%. The disintegrant used in the present application is, for example, commercially available croscarmellose sodium SD711 (available from DuPont Nutrition USA).

[0087] Lubricants refer to excipients used to reduce friction between particles and improve powder fluidity, which can reduce the weight and active substance content differences between preparations. The more commonly used lubricants in the pharmaceutical industry are magnesium stearate and talc, but the inventors of the present application found that both belong to the aforementioned excipients with compatibility issues, so the pharmaceutical composition of the present invention needs to use other lubricants, such as sodium stearyl fumarate. Lubricants in this application can be added internally or externally. Internal addition refers to adding when preparing particles so that the content of ingredients between particles is uniform; external addition refers to adding between the prepared particles so that the number of particles contained in each unit of preparation is uniform. Unless otherwise specified, the lubricant content described herein refers to the total content of internal and external lubricants. The content percentage of lubricant in the pharmaceutical composition can be, for example, 0.01wt% to 5.0wt%, such as 0.01wt%, 0.1wt%, 0.2wt%, 0.3wt%, 0.5wt% to 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 4.0wt%, 5.0wt%, for example, 0.1wt% to 2.0wt%, or 0.2wt% to 1.5wt%, preferably 0.5wt% to 1.0wt%, or about 1wt%. The lubricant used in the present application is, for example, commercially available sodium stearyl fumarate (purchased from Moehs Cantabra).

[0088] In addition, the pharmaceutical composition of the present invention may contain other types of excipients as needed, as long as they do not belong to the aforementioned excipients with compatibility issues, such as adhesives, colorants, flavoring agents, wetting agents, preservatives, solubilizers, etc.

[0089] The present invention also relates to a pharmaceutical preparation, which comprises the pharmaceutical composition described herein, wherein the pharmaceutical preparation is a solid pharmaceutical preparation known in the art, such as tablets, capsules, granules, powders, pills, etc. In addition to the pharmaceutical composition, the pharmaceutical preparation may also contain other ingredients known in the art. For example, in the case of tablets, the preparation may have a coating in addition to the pharmaceutical composition; in the case of capsules, the preparation may have a capsule shell in addition to the pharmaceutical composition. The aforementioned coating or capsule shell may be a coating (e.g., a film coating, a controlled release coating) or a capsule shell (e.g., a gelatin capsule shell) known in the art, respectively, and both may be obtained using methods known in the art.

[0090] The pharmaceutical composition and pharmaceutical preparation of the present invention can be prepared by conventional methods in the art. For example, in the case of granules, dry preparation, wet granulation and other methods known in the art can be used for preparation; the granules can be further prepared into tablets by tableting, or filled into capsule shells to prepare capsules, etc.

[0091] The "halogen" and "halogen" mentioned in the present invention include fluorine, chlorine, bromine and iodine.

[0092] The term "about" used in the context of this specification indicates a range of 10% above and below the corresponding numerical value. For example, if the concentration of a certain component is about 5mM, it indicates that its concentration is 4.5-5.5mM; if the concentration range of a certain component is about 5-10mM, it indicates that its concentration range is 4.5-11mM. Unless otherwise specified, the percentages used herein are weight percentages (wt%), which are usually expressed as based on the total weight of the pharmaceutical composition or preparation.

[0093] In some preferred embodiments, the solid form of the sodium salt of the TJ0113 compound (especially the D crystal form) is prepared by the following method: obtaining the TJ0113 compound (for example, obtained by the method described in the prior art CN115894404A), then dissolving the TJ0113 compound in a reaction medium, and adding a base containing sodium to react to obtain the solid form.

[0094] In some preferred embodiments, the reaction medium is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile and ethyl acetate, or a mixture of at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile and ethyl acetate and water, such as acetone, a mixture of acetone and water, or a mixture of acetonitrile and water.

[0095] In some preferred embodiments, the sodium-containing base is selected from at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium acetate, sodium formate, sodium methoxide, sodium ethoxide and sodium tert-butoxide.

[0096] In some preferred embodiments, in the reaction system, the molar ratio of the TJ0113 compound to the base containing sodium is 1:(0.9-1.1).

[0097] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C (preferably 40-50°C), and a sodium bicarbonate solution is added. After the solid precipitates, the mixture is kept warm and allowed to stand for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain a solid form of the sodium salt of the TJ0113 compound.

[0098] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, cooled to room temperature, and then a sodium bicarbonate solution is added with stirring. After the solid precipitates, the mixture is kept warm and allowed to stand for at least 20 minutes (preferably at least 30 minutes) to obtain a solid form of the sodium salt of the TJ0113 compound.

[0099] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, a sodium bicarbonate solution is added and stirred, and after the solid precipitates, the mixture is kept warm and stirred for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain a solid form of the sodium salt of the TJ0113 compound.

[0100] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, a methanol solution of sodium methoxide is added and stirred, and after the solid precipitates, the mixture is kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes), and then cooled to room temperature and stirred for at least 50 minutes (preferably at least 60 minutes) to obtain a solid form of the sodium salt of the TJ0113 compound.

[0101] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, a sodium bicarbonate solution is added and stirred, and the mixture is kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes) after the solid is precipitated, to obtain a solid form of the sodium salt of the TJ0113 compound.

[0102] The following preparation examples provide examples of the preparation method of the D crystal form, wherein the TJ0113 compounds are all obtained by the method described in the prior art CN115894404A.

[0103] Preparation Example

[0104] Preparation Example 1

[0105] Weigh 0.100g of TJ0113 compound and add 4ml of acetone. Heat to about 45℃ and stir to dissolve. Add 0.223g of sodium methoxide methanol solution at about 45℃. There is a small amount of solid when adding. Stir to dissolve. After stirring, solids slowly precipitate. Keep warm at about 45℃ for 1h. After keeping warm, cool to about 20℃ and stir for 1h. Filter and rinse with a small amount of acetone. Vacuum dry at room temperature (without heating) for about 20h. Determine it as D crystal form by the following characterization method.

[0106] Material Name Feeding amount Molecular weight Source (Batch No.) TJ0113 0.100 484.34 E020388-072-12 5% sodium methoxide methanol solution 0.223 54 Self-configured acetone 4ml N / A 5055R210601M

[0107] Preparation Example 2

[0108] Weigh 3.00g of TJ0113 compound and add 120ml of acetone. Heat to about 45℃ and stir to dissolve. Add 5.20g of 10% sodium bicarbonate aqueous solution at about 45℃. A small amount of solid will appear when adding. Stir to dissolve. After stirring, solid will slowly precipitate. Keep the temperature at about 45℃ for 1h. After the temperature is maintained, cool to about 20℃ and stir for 1h. Filter and rinse with a small amount of acetone.

[0109] The product was vacuum dried at room temperature (without heating) for about 20 hours and was determined to be crystal form D by the following characterization method.

[0110] Material Name Feeding amount Molecular weight Source (Batch No.) TJ0113 3.00 484.34 E020388-103-15 10% sodium bicarbonate aqueous solution 5.20 84 Self-configured acetone 120ml N / A 5055R220201M

[0111] Characterization

[0112] X-ray diffraction: PANalytacal Empyrean X-ray powder diffraction analyzer was used to analyze the D crystal form prepared above. The scanning parameters are as follows.

[0113]

[0114] The X-ray powder diffraction patterns of the D crystal form prepared by Preparation Examples 1 and 2 are as follows: Figure 8 As shown, the peak positions and intensities of the characteristic peaks are given below.

[0115]

[0116] Differential scanning calorimetry and DSC spectrum: The prepared D crystal form was tested using a TA Q200 / 2000 differential scanning calorimeter, and the test parameters were as follows:

[0117] parameter DSC method Linear temperature rise Sample tray Aluminum crucible, with lid and holes Temperature range 30℃-250℃ Scan rate (℃ / min) 10 Protective gas Nitrogen

[0118] The DSC spectrum of crystal form D is as follows Fig. 9 As shown, the differential scanning calorimetry curve of the D crystal form has an endothermic peak at 183.79°C (±3°C) and an exothermic peak at 210.79°C±3°C.

[0119] Thermogravimetric analysis and TGA spectrum: The prepared D crystal form was tested using a TA Q500 / 5000 thermogravimetric analyzer, and the test parameters are as follows:

[0120] parameter TGA method Linear temperature rise Sample tray Aluminum crucible, with lid and holes Temperature range 30℃-250℃ Scan rate (℃ / min) 10 Protective gas Nitrogen

[0121] The TGA spectrum of crystal form D is as follows Fig.10 As shown, the thermogravimetric analysis curve of Form D shows that the sample has no weight loss before decomposition.

[0122] Example

[0123] The technical scheme and implementation mode of the present invention are illustrated by the capsule preparation of compound TJ0113. It should be understood that these examples are not intended to limit the scope of protection of the present invention, especially not to limit the active ingredient and specific dosage form. The "active ingredient" or "API" described in the example section is TJ0113, which is a solid form of sodium salt of D crystal form and is prepared according to the above preparation example, and the raw material product batch number is: A16569-028P1.

[0124] Example 1 Compatibility test of active ingredient (API) with various excipients

[0125] The experimental steps are as follows:

[0126] 1. Take out samples according to the sampling time points set in the raw material and excipient compatibility plan (see Table 1).

[0127] 2. Record the appearance of the sample. Abnormal appearance includes (1) agglomeration, (2) liquefaction, and (3) discoloration.

[0128] 3. Check the moisture absorption and weight gain of the sample.

[0129] 4. Use HPLC method to detect the content and related substances of the samples.

[0130] The HPLC method parameters for content and related substance detection are detailed in Table 2 below.

[0131] Commonly used excipients for oral solid preparations were selected and mixed with TJ0113 API in different proportions, placed under different conditions, and taken out at different time points to judge the compatibility of API and excipients based on appearance, hygroscopic weight gain, content and related substances. According to the excipient manual, all excipients used are commonly used excipients for oral solid preparations, and have been included in the current edition of the Chinese Pharmacopoeia, and the properties of each excipient are stable. In order to objectively evaluate the compatibility of API and the excipients used, compatibility tests were conducted on API and various excipients.

[0132] The proportion of raw materials and excipients is based on the "Basic Technical Guidelines for the Study of Chemical Drug Preparations" and the preparation specifications. The excipients with a larger amount (such as lactose and microcrystalline cellulose) are mixed at a ratio of 1:5 for the main drug: diluent; the excipients with a moderate amount (such as cross-linked carboxymethyl cellulose sodium) are mixed at a ratio of 1:1 for the main drug: disintegrant; the excipients with a smaller amount (such as magnesium stearate) are mixed at a ratio of 10:1 for the main drug: lubricant. For the information of the manufacturers of the raw materials and excipients for the compatibility experiment and the proportion of the raw materials and excipients, please refer to the following Table 1:

[0133] Table 1. Main sample information and raw material ratio of raw material and auxiliary material compatibility test

[0134]

[0135]

[0136] Table 2. Chromatographic measurement conditions

[0137]

[0138] The samples were placed under experimental conditions of high temperature (60°C), high humidity (92.5%RH), acceleration (40°C / 75%RH) and illumination (visible light 5500Lux±500Lux, near-ultraviolet light 85μw / cm2), and samples were taken for inspection on day 0, day 9, and day 30. The samples were submitted for relevant index testing (test items include appearance, moisture absorption weight gain, content and related substances), and the test results were compared with the control sample (raw material). The relevant results are shown in Table 3-9 below.

[0139] Table 3. Appearance test results

[0140]

[0141]

[0142] Table 4. Moisture absorption and weight gain test results

[0143]

[0144] Table 5. Content test results

[0145]

[0146]

[0147] *N / A: Since there was no significant change in the results of the substance at 30 days, the 10-day sample was not tested.

[0148] The test results of the relevant substances are as follows.

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158] The following is a discussion of the experimental results on the compatibility of the API with multiple excipients:

[0159] (1) Appearance:

[0160] After being opened and placed under accelerated conditions of 40°C / 75% RH for 30 days, except for the mixed sample of API+crospovidone XL-10 which turned into red powder, the mixed samples of API and API and other excipients turned into gray powder.

[0161] After being opened and placed under high humidity 92.5% RH for 30 days, the API and API + colloidal silica The mixed samples of 200Pharma, API+magnesium stearate LIGAMED MF-2-V-MB, API+sodium stearyl fumarate, API+talc LUZENACPHARMA, API+empty gelatin capsules and 0# opaque rich yellow (cap color number: 41.813, body color number: 41.813)-CN, US turned into gray powder, and the mixed samples of API+hydroxypropylcellulose EXF and API+cross-linked polyvinylpyrrolidone XL-10 turned into red.

[0162] After being opened and placed under high humidity 92.5% RH for 30 days, API + pregelatinized starch STARCH The mixed samples of API+hydroxypropylcellulose EXF, API+crospovidone XL-10 and API+sodium starch glycolate VIVASTAR P showed agglomeration.

[0163] After being opened and placed under light conditions for 10 days, the surfaces of the API and the mixed samples of API and other excipients turned red, while the lower layer did not change color.

[0164] Apart from this, no significant appearance changes were observed in mixed samples of API and other excipients.

[0165] (2) Hygroscopic weight gain:

[0166] After being opened and placed under high humidity 92.5% RH for 30 days, API, API + microcrystalline cellulose 102, API + pregelatinized starch STARCH The mixed samples of API+hydroxypropylcellulose EXF, API+sodium carboxymethyl starch VIVASTAR P, API+cross-linked sodium carboxymethyl cellulose SD711, API+cross-linked polyvinylpyrrolidone XL-10, API+magnesium stearate LIGAMED MF-2-V-MB and API+empty gelatin capsule 0# opaque rich yellow color had a large moisture absorption and weight gain.

[0167] (3) Content:

[0168] The content results show that after being opened and placed at high temperature 60℃, high humidity 92.5%RH and accelerated 40℃ / 75%RH for 30 days, and after being placed under light conditions for 10 days, the content of API and the mixed samples of API and various excipients did not change significantly.

[0169] (4) Related substances:

[0170] After being opened and placed at high temperature of 60℃ for 30 days, the mixed sample of API+mannitol 100SD showed a slight increase of related substances at RRT1.29 and RRT1.73.

[0171] The mixed sample of API + sodium starch glycolate (VIVASTAR P) had a slight increase in related substances at RRT 1.29. The mixed sample of API + crospovidone XL-10 had a slight increase in related substances at RRT 0.46.

[0172] After being opened and placed for 30 days under accelerated conditions of 40℃ / 75%RH, the API had significant increases in related substances at RRT0.46, RRT1.16, RRT1.63 and RRT1.73, and slight increases at RRT1.41 and RRT1.43. The mixed sample of API+lactose Tablettose80 had slight increases in related substances at RRT0.89. The mixed sample of API+mannitol 100SD had slight increases in related substances at RRT0.46, RRT0.89, RRT1.65 / 1.70 and RRT1.73. The mixed sample of API+hydroxypropylcellulose EXF had slight increases in related substances at RRT0.46, RRT0.89, RRT1.10, RRT1.24 and RRT1.33, and significant increases at RRT1.41. The mixed sample of API+sodium starch glycolate VIVASTAR P had slight increases in related substances at RRT1.29. The mixed sample of API + crospovidone XL-10 showed slight increase in related substances at RRT0.46, RRT0.89 and RRT1.10, and significant increase in related substances at RRT1.24, RRT1.33, RRT1.37 and RRT1.41. API + colloidal silicon dioxide The mixed sample of 200Pharma had significant increases in related substances at RRT0.46 and RRT0.89. The mixed sample of API + magnesium stearate LIGAMED MF-2-V-MB had slight increases in related substances at RRT0.46 and RRT1.63, and significant increases at RRT1.16 and RRT1.73. The mixed sample of API + sodium stearyl fumarate had slight increases in related substances at RRT1.16. The mixed sample of API + talc LUZENAC PHARMA had slight increases in related substances at RRT1.73.

[0173] After being opened and placed under high humidity conditions of 92.5% RH for 30 days, the API had significant increases in related substances at RRT0.46, RRT1.16, RRT1.64 and RRT1.73, and slight increases at RRT1.41 and RRT1.74. The mixed sample of API+mannitol 100SD had significant increases in related substances at RRT1.16. The mixed sample of API+hydroxypropylcellulose EXF had significant increases in related substances at RRT0.89, RRT1.10, RRT1.29 and RRT1.41, and slight increases at RRT1.33. The mixed sample of API+cross-linked polyvinylpyrrolidone XL-10 had significant increases in related substances at RRT0.89, RRT1.10, RRT1.16, RRT1.29 and RRT1.41, and slight increases at RRT1.33. API+colloidal silicon dioxide The mixed sample of 200Pharma had significant increases in related substances at RRT0.46 and RRT1.73, and a slight increase at RRT1.54. The mixed sample of API + magnesium stearate LIGAMED MF-2-V-MB had significant increases in related substances at RRT1.16, and a slight increase at RRT1.73. The mixed sample of API + sodium stearyl fumarate had a slight increase in related substances at RRT1.16. The mixed sample of API + talc LUZENAC PHARMA had significant increases in related substances at RRT1.16, and a slight increase in related substances at RRT1.21.

[0174] After being opened and placed under light conditions for 10 days, API had a slight increase in related substances at RRT0.89 and RRT1.29. The mixed sample of API + cross-linked sodium carboxymethyl cellulose SD711 had a significant increase in related substances at RRT1.29. The mixed samples of API + cross-linked polyvinylpyrrolidone XL-10 and API + sodium stearyl fumarate had a slight increase in related substances at RRT1.29. The mixed sample of API + talc LUZENAC PHARMA had a significant increase at RRT1.16 and a slight increase at RRT1.73.

[0175] In summary, the compatibility test results of raw materials and excipients showed that API was unstable under high humidity, light and accelerated conditions, and API was not compatible with hydroxypropylcellulose EXF, crospovidone XL-10, and colloidal silicon dioxide. The mixed samples of 200Pharma and magnesium stearate LIGAMED MF-2-V-MB were incompatible under accelerated 40°C / 75%RH and high humidity 92.5%RH conditions. The mixed samples of API and talc LUZENAC PHARMA were incompatible under high humidity 92.5%RH open and light conditions. The mixed samples of API and mannitol 100SD were incompatible under high humidity 92.5%RH conditions. The mixed samples of API + cross-linked sodium carboxymethylcellulose SD711 were incompatible under light conditions.

[0176] Example 2: Effect of diluent on dissolution performance

[0177] Considering that TJ0113 itself is unstable under high humidity conditions and combined with the compatibility results of raw materials and excipients, the effect of diluent type on the preparation process and capsule dissolution was investigated on this basis. The dissolution method used in this application to measure dissolution is shown in Table 10.

[0178] Table 10. Dissolution methods

[0179]

[0180]

[0181] This example uses 100 mg capsules as the main research object, with a total content weight of 420 mg, and uses 0# opaque yellowish gelatin hollow capsules, all of which are filled with dry granulation. Table 11 lists the specific ingredients of experimental numbers F6 and F7, which use different types of diluents. The effect of the type of diluent on the dissolution results is shown in Tables 12 and Figure 1 In this study, dissolution method 1 was used for evaluation.

[0182] Table 11. Specific ingredients of F6 and F7

[0183]

[0184] Table 12. Effect of diluent type on dissolution results (dissolution method 1)

[0185]

[0186] Depend on Figure 1 The dissolution results show that the dissolution of F7 is significantly higher than that of F6 (especially within the first 20 minutes), indicating that the combination of microcrystalline cellulose and pregelatinized starch unexpectedly improves the dissolution rate of the API. Therefore, the diluent types selected are microcrystalline cellulose 102 and pregelatinized starch STARCH

[0187] Because the API of the present invention has a significant increase in related substances under high humidity conditions, the pregelatinized starch STARCH (Shanda TM ) can absorb the free water that enters the tablet core and lock in the water to avoid interaction with the drug. Therefore, different ratios of pregelatinized starch STARCH The specific composition is shown in Table 13, and the dissolution results are shown in Tables 14 and Figure 2 , in which dissolution method 2 was used for evaluation.

[0188] Table 13. Specific ingredients of F11 and F12

[0189]

[0190] Table 14. Effect of diluent ratio on dissolution results (dissolution method 2)

[0191]

[0192] The dissolution results show that there is no significant difference between F11 and F12, indicating that the proportion of pregelatinized starch has no significant effect on the dissolution rate. Carry out subsequent process development.

[0193] Example 3: Effect of disintegrants and solubilizers on dissolution performance

[0194] Based on the experimental results of Example 2, the dissolution rate of the capsule was used as an indicator to examine the type of disintegrant. The specific compositions of Experiments F7 and F10 are shown in Table 15, where F10 changed the type of disintegrant, and the other conditions were the same as in Example 2. The dissolution results are shown in Tables 16 and Figure 3 , in which dissolution method 2 was used for evaluation.

[0195] Table 15. Specific composition of F7 and F10

[0196]

[0197] Table 16. Effect of disintegrant type on dissolution results (dissolution method 2)

[0198]

[0199] From the above results, it can be seen that the dissolution of F10 is slightly higher than that of F7 before 30 minutes and has a smaller RSD%, so the disintegrant type is selected as sodium starch glycolate.

[0200] On this basis, the effect of adding a solubilizer on the dissolution rate of the product was further investigated. The compositions of F7 and F8 are shown in Table 17, where a solubilizer was added to F8, and the other conditions were the same as those in Example 2. The dissolution results are shown in Tables 18 and Figure 4 , in which dissolution method 2 was used for evaluation.

[0201] Table 17. Specific composition of F7 and F8

[0202]

[0203]

[0204] Table 18. Effect of solubilizer on dissolution results (dissolution method 2)

[0205]

[0206] From the above results, it can be seen that there is no significant difference in the dissolution results of experiments F7 and F8, indicating that the addition of the solubilizer Kolliphor SLS Fine has no significant effect on the dissolution rate. Therefore, it was finally determined not to use Kolliphor SLS Fine as a solubilizer.

[0207] The 20 mg capsules have the same proportion of the 100 mg capsules and the same process. The composition and dissolution results of the 20 mg capsules (evaluated using dissolution method 3) are shown in Tables 19 and 20 and Figure 5 .

[0208] Table 19. Specific composition of 20 mg capsules

[0209]

[0210]

[0211] Table 20. Dissolution results of 20 mg capsules (dissolution method 3)

[0212]

[0213] From the above data, it can be seen that the 20 mg capsule can be dissolved quickly and completely, which is in line with expectations, indicating that its specific composition design is reasonable.

[0214] Example 4: Overall stability test of the preparation

[0215] The process flow of the preparation in this embodiment is as follows:

[0216] API and microcrystalline cellulose 102 are sieved through 50 meshes; the sieved API and microcrystalline cellulose 102 are mixed with pregelatinized starch STARCH Pass through 50 mesh sieve twice; after sieving, API, microcrystalline cellulose 102, pregelatinized starch STARCH and sodium carboxymethyl starch VIVASTAR P for premixing; after premixing, internal sodium stearyl fumarate is added to the materials for main mixing; after the main mixing, dry granulation is performed; after dry granulation, external sodium stearyl fumarate is added to the materials for total mixing; finally, the total mixed granules are filled into capsules.

[0217] The specific process flow and parameters are as follows:

[0218] 1. Weighing

[0219] Weigh TJ0113, microcrystalline cellulose 102, and pregelatinized starch STARCH according to the prescription amount. Sodium starch glycolate VIVASTAR P and sodium stearyl fumarate.

[0220] 2. Sieve

[0221] First, microcrystalline cellulose 102 and the raw material drug are sieved through a 50-mesh sieve to obtain a sieved mixture 1; then the sieved mixture 1 and pregelatinized starch STARCH Pass them through a 50-mesh sieve twice; pass the sodium carboxymethyl starch VIVASTAR P through a 50-mesh sieve, and pass the internal and external sodium stearyl fumarate through a 30-mesh sieve respectively.

[0222] 3. Premix

[0223] Put the raw materials and auxiliary materials except sodium stearyl fumarate into the hopper of the hopper mixer and mix for 20 minutes at a mixing speed of 20 rpm.

[0224] 4. Main Mix

[0225] After the premixing is completed, add sodium stearyl fumarate (internal addition) into the hopper and start the main mixing for 5 minutes at a mixing speed of 20 rpm.

[0226] 5. Dry granulation and granulation

[0227] The main mixed powder was placed in a dry granulator for granulation. The granulation parameters were: feeding speed 28 rpm, roller pressure 30 kg / cm 2 The belt-like product obtained by dry granulation was crushed, and the secondary granulation screen was a circular screen with an aperture of 0.8 mm, and the granulation speed was 150 rpm.

[0228] 6. Total Mixing

[0229] The granulated dry granules and the sieved sodium stearyl fumarate (external addition) were mixed in the hopper of a hopper mixer for 5 minutes at a mixing speed of 20 rpm.

[0230] 7. Capsule filling

[0231] The total mixed granules are placed in a capsule filling machine for capsule filling. The 20 mg specification is filled into 4# gelatin hollow capsule shells, and the 100 mg specification is filled into 0# gelatin hollow capsule shells.

[0232] Preliminary laboratory stability study

[0233] In order to investigate the rationality and stability of the formulation prototype, a preliminary stability study was conducted on laboratory samples.

[0234] The sample batches used for stability study were F14 and F13. The specific composition and sample information are shown in Tables 21 and 22.

[0235] Table 21. Specific composition of F14 and F13

[0236]

[0237] Table 22. Sample information for stability test

[0238]

[0239]

[0240] The placement conditions of the two specifications of samples F13 and F14 are the same. The specific placement conditions are shown in Table 23.

[0241] Table 23. Sample storage conditions for stability testing

[0242] Placement conditions 10 days 30 days Backup 40℃ / 75%RH(open) 1 bottle 1 bottle N / A 40℃ / 75%RH(closed) 1 bottle 1 bottle N / A 40℃ / 75%RH(closed cup + 1g desiccant) 1 bottle 1 bottle N / A 40℃ / 75%RH(closed cup + 2g desiccant) N / A N / A 1 bottle 30℃ / 65%RH(closed cup + 1g desiccant) 1 bottle 1 bottle N / A 25℃ / 60%RH(closed cup + 1g desiccant) 1 bottle 1 bottle N / A 2-8℃(closed cup + 1g desiccant) 1 bottle 1 bottle N / A

[0243] The dissolution results of stability study are shown in Table 24 and Figure 6 and 7 The results of stability study on related substances are shown in Table 25.

[0244] Table 24. Dissolution stability results of 20 mg and 100 mg capsules (using dissolution method 3 evaluation)

[0245]

[0246] Analysis of results: From the above data, compared with the 0-day dissolution data, there was no significant change in the dissolution of 20 mg and 100 mg capsules after being placed at 40°C / 75% RH (closed mouth) and 40°C / 75% RH (closed mouth + 2g desiccant) for 30 days.

[0247]

[0248] Result analysis: After 20mg capsules were placed at 40℃ / 75%RH (closed) for 30 days, the related substances at RRT=1.16, RRT=1.37 / 1.38 and RRT=1.82 / 1.73 increased. After 100mg capsules were placed at 40℃ / 75%RH (closed) for 30 days, the related substances at RRT=1.37 / 1.38 increased. After 20mg and 100mg capsules were placed under other conditions for 30 days, the related substances did not change significantly.

[0249] Based on the dissolution and related substance results, the product packaging was finally determined to be 45mL and 75mL oral solid medicinal high-density polyethylene bottles and oral solid medicinal polypropylene child-safe combination bottle caps with aluminum foil seals plus two medicinal solid paper bags containing 1g of silica gel desiccant in English. The storage conditions are "protect from light, seal, and store at 2-8℃".

[0250] Example 5: Effect of dry granulation on the crystal form of the API

[0251] In this test case, the effect of dry granulation on the crystalline form of the API was investigated. The formulation composition is shown in F13 in Table 21, and the XRPD results are shown in Fig. 9 The XRPD operation was the same as in the preparation example. The obtained XRPD pattern is shown in Fig.11 In which curve A16569-028P1 represents the API; curve 41458-088-14 / 13-20 / 100mg-BL represents the mixed powder before dry granulation; curve 41488-011-14 / 13-20 / 100mg-BL-BE represents the blank excipient before dry granulation; curve 41458-088-14 / 13-20 / 100mg-DG-4 represents the dry granules after dry granulation. It can be seen from the above curves that the main characteristic peaks of the XRPD spectrum of the intermediate active sample before and after dry granulation have no obvious changes, and it is preliminarily judged that the dry granulation process has no effect on the API crystal form.

Claims

1. A pharmaceutical composition, characterized in that The invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a lubricant, and does not contain any of the following ingredients: hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, magnesium stearate, talc, mannitol, cross-linked sodium carboxymethyl cellulose, In the formula, R 2 For hydrogen, C 1～4 Alkyl, C 3～6 Cycloalkyl, four- to six-membered epoxyalkyl; R 3 for Among them, R 3-1 Hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, C 3～6 Cycloalkyl, three to six-membered epoxyalkyl, -N(R 3-2 R 3 -2a )、-CH2C(O)R 3-2 、-CH2C(O)OR 3-2 、-CH2C(O)NR 3-2 R 3-2a , R 3-2 and R 3-2a are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl, Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, or is supported by at least one R 3-3 substituted 5- or 6-membered monocyclic heteroaryl, said R 3-3 For hydrogen, halogen, C 1～4 Alkyl, three to six-membered cycloalkyl, hydroxyl, C 1～4 Alkoxy, three to six membered epoxyalkyl, C 1～4 Haloalkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl, R 3-3a and R 3-3b are independently hydrogen, C 1～4 Alkyl or three to six-membered cycloalkyl; R 4 for Among them, R 4-1 is phenyl, and is supported by at least one R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For halogen, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Haloalkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 Alkyl or C 3～6 Cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring, R 4-2 C 1～4 Alkyl, C 3～6 Cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form 4 to 8 membered rings, R 4-3 C 1～4 Alkyl or C 1～4 Alkoxy; R 5 The number of R is 0 to 5. 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Haloalkyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Alkyl, C in which at least one hydrogen is replaced by a halogen 2～4 alkenyl or C in which at least one hydrogen atom is replaced by a halogen 2～4 Alkynyl.

2. The pharmaceutical composition according to claim 1, wherein the diluent comprises microcrystalline cellulose and pregelatinized starch.

3. The pharmaceutical composition according to claim 1 or 2, wherein the disintegrant is sodium starch glycolate.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the lubricant is sodium stearyl fumarate.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein R 2 is hydrogen or C 1～4 alkyl; R 3 for in, R 3-1 Hydrogen, hydroxyl, C 1～4 Alkyl or C 1～4 Alkoxy, R 4 for Among them, R 4-1 is phenyl, and is supported by at least one R 4-11 Substituted phenyl, 5- or 6-membered monocyclic heteroaryl, at least one R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one R 4-11 substituted 8- to 10-membered fused bicyclic heteroaryl, wherein R 4-11 For halogen, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1～4 Haloalkyl, C 1～4 Haloalkoxy or R 4-1a and R 4-1b are independently hydrogen, C 1～4 Alkyl or C 3～6 Cycloalkyl, and R 4-1a and R 4-1b Can bond to each other to form a ring, R 4-2 C 1～4 Alkyl, C 3～6 Cycloalkyl, or when R 2 C 1～4 When alkyl, R 4-2 With R 2 Bonded to form 4 to 8 membered rings, R 4-3 C 1～4 Alkyl or C 1～4 Alkoxy; R 5 The number of R is 0 to 3. 5 When the number is not 0, each is independently selected from halogen, nitro, nitrile, -N + (R 5-1 )3. C 1～4 Haloalkyl, -C(O)OR 5-1 、-C(O)R 5-1 、-C(O)N(R 5-1 R 5-1a )、-S(O)2R 5-1 、-S(O)R 5-1 、-N=C(R 5-1 R 5-1a ), hydroxyl, C 1～4 Alkyl, phenyl, at least one hydrogen is replaced by R 5-1 Substituted phenyl, C 1～4 Alkoxy, -N(R 5-1 R 5-1a )、-N(R 5-1 )C(O)R 5-1a 、-OC(O)R 5-1 、-OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 , where R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Alkyl, C in which at least one hydrogen is replaced by a halogen 2～4 alkenyl or C in which at least one hydrogen atom is replaced by a halogen 2～4 Alkynyl.

6. The pharmaceutical composition according to claim 5, wherein R 2 is hydrogen or C 1～4 alkyl, R 3 for R 3-1 Hydroxyl or C 1～4 Alkoxy, R 4 for Among them, R 4-1 is phenyl, and is supported by at least one R 4-11 substituted phenyl, 5- or 6-membered monocyclic heteroaryl, or at least one R 4-11 substituted 5- or 6-membered monocyclic heteroaryl, said R 4-11 For halogen, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Alkoxy, or C 1～4 haloalkyl; and R 5 The number of is 0.

7. The pharmaceutical composition according to claim 6, wherein R 2 For hydrogen, R 3 for R 3-1 is hydroxyl group, R 4 for Among them, R 4-1 For at least one R 4-11 Substituted phenyl, the R 4-11 For halogen, C 1～4 Alkyl, C 1～4 Alkoxy, or C 1～4 haloalkyl; and R 5 The number of is 0.

8. The pharmaceutical composition according to claim 7, wherein the compound of formula I is TJ0113 9. The pharmaceutical composition according to claim 8, wherein the TJ0113 is in the solid form of a sodium salt represented by the following formula: Wherein X is 0.1-2, for example 1. 10 . The pharmaceutical composition according to claim 9 , wherein the solid form exhibits the following characteristic peaks at 2θ (Cu Kα ray) in an X-ray powder diffraction pattern: 7.06° (±0.2°) and 20.87° (±0.2°). 11 . The pharmaceutical composition according to any one of claims 1 to 10 , comprising compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, and sodium stearyl fumarate. 12 . The pharmaceutical composition according to claim 11 , which is composed of compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sodium stearyl fumarate.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the content percentage of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1.0 wt % to 50 wt %, the content percentage of the diluent in the pharmaceutical composition is 30 wt % to 90 wt %, the content percentage of the disintegrant in the pharmaceutical composition is 0.1 wt % to 25 wt %, and the content percentage of the lubricant in the pharmaceutical composition is 0.01 wt % to 5.0 wt %.

14. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical preparation is selected from tablets, capsules, granules, powders, and pills.

15. The pharmaceutical preparation according to claim 14, which is a capsule, which consists of a capsule shell and contents, and the contents are the pharmaceutical composition according to any one of claims 1 to 13.

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