An oral formulation containing a JAK inhibitor or its salt or its crystalline form, its preparation method and application.

Abstract

This invention provides an oral formulation, specifically, the oral formulation comprising a JAK inhibitor and pharmaceutical excipients, wherein the JAK inhibitor comprises a compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, or their crystalline forms. The oral formulation of this invention is characterized by rapid dissolution. The oral formulation of this invention has a simple process and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to oral preparations of a class of [1,2,4]triazolo[1,5-a]pyridine compounds and their isomers or pharmaceutically acceptable salts or their crystal forms, as well as their preparation methods and applications, wherein the oral preparations are characterized by rapid dissolution. Background Technology

[0002] JAK kinases are a family of intracellular non-receptor tyrosine kinases, comprising four members: JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are expressed in all human tissues and cells, while JAK3 is primarily expressed in hematopoietic cells. JAK kinases are involved in inflammation, autoimmune diseases, proliferative disorders, transplant rejection (or graft-versus-host disease), diseases involving impaired cartilage turnover, congenital cartilage malformations, and / or diseases associated with excessive IL-6 secretion. Studies have confirmed that inhibiting the JAK signaling pathway is believed to regulate multiple signaling pathways related to inflammation, autoimmune diseases, proliferative disorders, transplant rejection, diseases involving impaired cartilage turnover, congenital cartilage malformations, and / or diseases associated with excessive IL-6 secretion.

[0003] The four families of JAK kinases selectively bind to different cytokine receptors, exerting different physiological functions. Downstream of JAKs is the signal transducers and activators of transcription (STAT) family. The JAK-STAT pathway transduces extracellular signals from various cytokines, interferons, most interleukins, and endocrine factors to the cell nucleus and is responsible for the expression of protein-coding genes. When cytokines bind to their receptors, JAK family members autophosphorylate and / or transphosphorylate each other, followed by STAT phosphorylation, and then migration into the cell nucleus to regulate transcription.

[0004] The JAK-STAT pathway is one of the main research directions in the pathogenesis of rheumatoid arthritis (RA). Studies have shown that many cytokines, such as IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-15, IL-17, and IL-21, play an important role in the pathogenesis of RA by influencing the JAK-STAT pathway. This signaling pathway is continuously activated in the pathogenesis of RA and participates in processes such as synovial cell proliferation and the release of inflammatory cytokines. Therefore, targeted blocking of the JAK-STAT pathway can achieve the goal of regulating cell activity and improving the pathological process of RA.

[0005] WO / 2020 / 038457 discloses a series of JAK kinase inhibitors satisfying Formula I of [1,2,4]triazolo[1,5-a]pyridine compounds, their isomers, or pharmaceutically acceptable salts thereof:

[0006]

[0007] These compounds are known to be small-molecule JAK kinase inhibitors with significant JAK kinase inhibitory activity and high selectivity, and are expected to be used in the treatment of rheumatoid arthritis. Oral formulations of these JAK kinase inhibitors have not yet been disclosed.

[0008] These compounds include those shown in Formula II, with the chemical name (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-azaspiro[3.5]non-7-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)cyclopropaneformamide:

[0009]

[0010] (II)

[0011] The aforementioned literature also did not disclose how to obtain oral formulations that dissolve rapidly and completely. Therefore, further research is needed to discover oral formulations that dissolve well and are stable, and whose preparation process is simple and suitable for large-scale industrial production. Summary of the Invention

[0012] The purpose of this invention is to provide an oral formulation that dissolves rapidly and has good stability, and the preparation process of this oral formulation is simple and suitable for large-scale industrial production.

[0013] This invention provides an oral formulation comprising a JAK inhibitor and a pharmaceutical excipient, wherein the JAK inhibitor comprises a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof:

[0014] ,

[0015] in,

[0016] E1 and E2 are independently selected from single bonds, -CH2- or -(CH2)2-, respectively;

[0017] L1 is selected from single bond, -(CH2)g-, -C(=O)-, or -C(=O)-(CH2)h-;

[0018] m is 1 or 2;

[0019] n is 1 or 2;

[0020] g is 1, 2, or 3;

[0021] h is 1, 2, or 3;

[0022] R1 is selected from H, CN, and C. 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl or 3- to 6-membered cycloalkyl groups may be optionally substituted with 1, 2, or 3 Ra groups;

[0023] R2 is selected from H, F, Cl, Br, I, or C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. b replace;

[0024] R3, R4, and R5 are each independently selected from H, F, Cl, Br, I, or C. 1-3 Alkyl, wherein the C 1-3 The alkyl group may be optionally substituted with 1, 2 or 3 Rc;

[0025] R6, R7, and R8 are each independently selected from H, F, Cl, Br, I, or C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. d replace;

[0026] Each R a Each is independently selected from H, F, Cl, Br, I, CN, or C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0027] Each R b Each is independently selected from F, Cl, Br, or I;

[0028] Each R c Each is independently selected from F, Cl, Br, or I;

[0029] Each R d Each is independently selected from F, Cl, Br, or I;

[0030] Each R is independently selected from F, Cl, Br, or I;

[0031] The pharmaceutical excipients include fillers, disintegrants, binders, lubricants or surfactants, or combinations of two or more of them.

[0032] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein each R a Each is independently selected from H, F, Cl, Br, I, or CN.

[0033] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein R1 is selected from H, CN, C 1-3 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-3 Alkyl groups and 3- to 5-membered cycloalkyl groups may be optionally substituted with 1, 2, or 3 Ra groups.

[0034] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein R1 is selected from H, CN, CH3, , or The CH3, , or It can be replaced by 1, 2 or 3 Ra.

[0035] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein R1 is selected from H, CN, CF3, CHF2, , , , or .

[0036] In this invention, as one embodiment, the compound of formula (I), its isomer or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, F, Cl, Br or I.

[0037] In this invention, as one embodiment, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein R3, R4 and R5 are independently selected from H, F, Cl, Br or I, respectively.

[0038] In this invention, as one embodiment, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein R6, R7 and R8 are independently selected from H, F, Cl, Br or I, respectively.

[0039] In this invention, as one embodiment, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein L1 is selected from single bond, -CH2-, -(CH2)2-, -C(=O)- or -C(=O)-(CH2)-.

[0040] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from , , , or .

[0041] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from , , , , , , , , , or .

[0042] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from , , , , , , , , , , , , , , , , or .

[0043] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof are selected from...

[0044]

[0045] ,

[0046] in,

[0047] L1 is as defined in claim 1 or 9;

[0048] R1 is defined as in claims 1 to 5;

[0049] R2 is as defined in claim 1 or 6;

[0050] R3, R4 and R5 are as defined in claim 1 or 7;

[0051] R6, R7 and R8 are as defined in claim 1 or 8.

[0052] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof are selected from...

[0053] ,

[0054] in,

[0055] L1 is as defined in claim 1 or 9;

[0056] R a As defined in claim 1 or 2;

[0057] R2 is as defined in claim 1 or 6;

[0058] R3, R4 and R5 are as defined in claim 1 or 7;

[0059] R6, R7 and R8 are as defined in claim 1 or 8.

[0060] In this invention, as one embodiment, JAK inhibitors include the following compounds, their isomers, or pharmaceutically acceptable salts thereof.

[0061]

[0062] .

[0063] In this invention, as one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof are selected from...

[0064]

[0065] .

[0066] In this invention, as one embodiment, the oral formulation includes one or more fillers.

[0067] In this invention, as one embodiment, the oral formulation includes one or more disintegrants.

[0068] In this invention, as one embodiment, the oral formulation includes one or more adhesives.

[0069] In this invention, as one embodiment, the oral formulation further includes one or more lubricants.

[0070] In this invention, as one embodiment, the oral formulation further includes one or more surfactants.

[0071] In this invention, as one embodiment, the oral formulation includes one or more fillers and one or more disintegrants.

[0072] In this invention, as one embodiment, the oral formulation includes one or more fillers, one or more disintegrants, and one or more binders.

[0073] In this invention, as one embodiment, the oral formulation includes one or more fillers, one or more disintegrants, one or more binders, and one or more lubricants.

[0074] In this invention, as one embodiment, the oral formulation includes one or more fillers, one or more disintegrants, one or more binders, one or more lubricants, and one or more surfactants.

[0075] In this invention, as one embodiment, the filler is selected from microcrystalline cellulose, lactose, pregelatinized starch or anhydrous dicalcium phosphate, or a combination of two or more of them.

[0076] In this invention, as one embodiment, the disintegrant is selected from croscarmellose sodium, carboxymethyl starch sodium, croscarmellose or dry starch, or a combination of two or more of them.

[0077] In this invention, as one embodiment, the adhesive is selected from carboxypropyl methylcellulose, hydroxypropyl cellulose, povidone, methylcellulose or ethylcellulose, or a combination of two or more of them.

[0078] In this invention, as one embodiment, the lubricant is selected from magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol or sodium dodecyl sulfate, or a combination of two or more of them.

[0079] In this invention, as one embodiment, the surfactant is selected from sodium dodecyl sulfate.

[0080] The present invention provides an oral formulation comprising (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-azaspiro[3.5]non-7-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, and one or more fillers, one or more disintegrants, one or more binders, one or more lubricants and one or more surfactants.

[0081] In this invention, as one embodiment, the crystal form of the compound of (II) or its pharmaceutically acceptable salt is...

[0082] It can be crystallized in types A, B, C, or D.

[0083] In this invention, as one embodiment, the XRPD spectrum analysis data of the A-crystal form of the compound of formula (II) is as follows:

[0084]

[0085] In this invention, as one embodiment, the XRPD spectra of the B-crystal form of the compound of formula (II) are as follows:

[0086]

[0087] In this invention, as one embodiment, the XRPD spectra of the C-crystal form of the compound of formula (II) are as follows:

[0088]

[0089] In this invention, as one embodiment, the XRPD spectra of the D crystal form of the compound of formula (II) are as follows:

[0090]

[0091] In this invention, as one embodiment, the XRPD diagram of the A crystal form of the compound of formula (II) is shown below. Figure 6 As shown.

[0092] In this invention, as one embodiment, the XRPD diagram of the B crystal form of the compound of formula (II) is shown below. Figure 8 As shown.

[0093] In this invention, as one embodiment, the XRPD diagram of the C-crystal form of the compound of formula (II) is shown below. Figure 11 As shown.

[0094] In this invention, as one embodiment, the XRPD diagram of the D crystal form of the compound of formula (II) is shown below. Figure 13 As shown.

[0095] In the oral formulation provided by the present invention, the pharmacologically acceptable salt of the active ingredient may be selected from (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-azaspiro[3.5]non-7-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof, and the content of the active ingredient is 1% to 50% of the total weight of the composition, preferably 5% to 40%, more preferably 6% to 30%, more preferably 8% to 25%, and by way of example, it may be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.

[0096] The oral formulations provided in this invention may further include one or more of fillers, disintegrants, binders, lubricants, and surfactants.

[0097] In the oral formulations provided by this invention, the filler may include, but is not limited to, lactose, microcrystalline cellulose, pregelatinized starch, anhydrous dicalcium phosphate, calcium sulfate, calcium carbonate, dextrin, maltose, mannitol, sorbitol, trehalose, and xylitol. In a preferred embodiment of this invention, the filler is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, and anhydrous dicalcium phosphate. In a more preferred embodiment, the filler is a mixture of lactose and microcrystalline cellulose.

[0098] In the oral formulations provided by this invention, the content of the filler can be 0% to 78.5% of the total weight of the pharmaceutical composition, preferably 10% to 70%, more preferably 20% to 60%, and even more preferably 30% to 50%. For example, it can be 30%, 31.75%, 37.25%, 39.25%, 41.75%, 42.25%, or 43.75%. The weight ratio of lactose to microcrystalline cellulose is 0:1, 5:3, 3:1, 1:1, or 1:0; preferably 1:1.

[0099] In the oral formulations provided by this invention, the disintegrant may include, but is not limited to, sodium croscarmellose, sodium carboxymethyl starch, crospovidone, dry starch, low-substituted hydroxypropyl cellulose, alginate, chitosan, and corn starch. In a preferred embodiment of this invention, the disintegrant in the composition may include, but is not limited to, one or more of sodium croscarmellose, sodium carboxymethyl starch, or crospovidone. In a preferred embodiment of this invention, the disintegrant is sodium croscarmellose.

[0100] In the oral formulations provided by the present invention, the content of the disintegrant can be 1% to 25% of the total weight of the pharmaceutical composition, preferably 2% to 16%, more preferably 4%, 8%, or 12%.

[0101] In the oral formulations provided in this invention, the binder may include, but is not limited to, one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, pregelatinized starch, sodium carboxymethyl cellulose, and methylcellulose.

[0102] In the oral formulation provided in this invention, the content of the binder is based on the total weight of the composition, and the content of the binder is about 0.1% to 5%, preferably 1% to 4%, more preferably 2% to 3%, and most preferably 1.5% (calculated as 20mg, containing 3mg of binder).

[0103] The oral formulation provided in this invention may also contain one or more lubricants, such as magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, wherein the lubricant content is 0.1% to 5% of the total weight of the composition, preferably 0.5% to 3%, more preferably 1%.

[0104] The oral formulation provided by the present invention may also contain one or more surfactants, such as sodium dodecyl sulfate (SDS), and the content of said surfactant is about 0.1% to 5% based on the total weight of the composition; preferably 1% to 3%; most preferably 2%.

[0105] In a preferred embodiment of the present invention, a pharmaceutical composition is provided comprising the following components by weight:

[0106] 1) 1%~50% of (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-azaspiro[3.5]non-7-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof;

[0107] 2) 0%~78.5% filler, selected from one or both of lactose and microcrystalline cellulose;

[0108] 3) 1%~25% of disintegrants, selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose;

[0109] 4) 0.1%~5% of adhesive, selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone;

[0110] 5) 0.1%~5% lubricant, selected from magnesium stearate;

[0111] 6) 0.1%~5% surfactant, selected from sodium dodecyl sulfate (SDS).

[0112] In another preferred embodiment of the present invention, a pharmaceutical composition is provided comprising, by weight, the following components:

[0113] 1) 8%~25% of (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-azaspiro[3.5]non-7-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof;

[0114] 2) 30-50% filler, selected from one or both of lactose and microcrystalline cellulose;

[0115] 3) 2%~16% of disintegrants, selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose;

[0116] 4) 1%~4% of adhesive, selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone;

[0117] 5) 0.5%~3% lubricant, selected from magnesium stearate;

[0118] 6) 1%~3% surfactant, selected from sodium dodecyl sulfate (SDS).

[0119] The oral formulations of the present invention can be prepared using methods commonly used in the art, such as wet granulation, dry granulation, and one-step granulation, to prepare pharmaceutical composition granules, which are then compressed into tablets. The pharmaceutical compositions of the present invention can also be prepared into tablets using a direct powder compression method. In one embodiment of the present invention, the filler, disintegrant, binder, lubricant, or surfactant can be added internally or externally; as an example, the filler can be added internally or externally; the disintegrant can be added internally or externally; the binder can be added internally or externally; the lubricant can be added internally or externally; and the surfactant can be added internally or externally.

[0120] The oral formulation of the present invention dissolves very rapidly and completely. According to the second method (paddle method) of General Chapter 0931 of Part IV of the 2015 edition of the Chinese Pharmacopoeia, using 0.01 mol / L hydrochloric acid solution as the dissolution medium, preferably 900 ml of 0.01 mol / L hydrochloric acid solution, the composition of the present invention was subjected to a dissolution test at 37 ± 0.5 °C and a paddle speed of 50 rpm. The dissolution rate was greater than or equal to 80% after 10 or 15 minutes, preferably greater than 90% after 15 or 20 minutes, and more preferably greater than or equal to 95% after 30 or 45 minutes.

[0121] The oral formulation of the present invention was placed in a petri dish and its stability was investigated under high temperature (60°C), high humidity (relative humidity 75% ± 1%, 15.5-60°C) and light (illuminance 4500 lx ± 500 lx). Samples were taken at 5 days, 10 days and 30 days, and the changes in related substances, content and dissolution were determined by HPLC. The results showed that the composition provided by the present invention is stable. Compared with the results of day 0, the results of the influencing factors at 5 days, 10 days and 30 days showed no significant differences in related substances, dissolution and content.

[0122] The oral formulation of the present invention was placed in an environment with a temperature of 40℃±2℃ and a relative humidity of 75%±5% for stability testing for 1 month. Then, the changes in related substances, content and dissolution were determined by HPLC. The results showed that the composition provided by the present invention was stable. Compared with the results of day 0, there were no significant differences in related substances, dissolution and content after 1 month.

[0123] Definitions and Explanations

[0124] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0125] The term "pharmaceutically acceptable" as used in this invention refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0126] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0127] The "pharmaceutical compositions" described in this invention are generally intended for oral administration. Pharmaceutical compositions for oral administration may further comprise sweeteners, flavoring agents, coloring agents, coating agents, and / or preservatives to provide a palatable formulation. In one embodiment, the pharmaceutical composition is in the form of a tablet. Tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing a free-flowing form of the active ingredient, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, or preservative. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored.

[0128] The term "pharmaceutical formulation" as used in this invention refers to a method in which different chemical substances (including active pharmaceutical ingredients) are combined to produce a final pharmaceutical product. Pharmaceutical formulations include enteral formulations (tablets, capsules), parenteral formulations (liquids, lyophilized powders), or topical formulations (skin, inhalable).

[0129] The "pharmaceutically acceptable excipients, carriers, or diluents" of this invention include, but are not limited to, any adjuvants, carriers, excipients, retention aids, additives, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers permitted by the relevant government regulatory authorities for acceptable use in humans or livestock.

[0130] The term "filler" refers to substances that improve the compressibility and uniformity of a drug. Fillers include starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, corn starch, dextrose, ethyl cellulose, fructose, maltodextrin, maltose, medium-chain triglycerides, anhydrous calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and sugar alcohols such as erythritol, isomaltitol, lactitol, mannitol, sorbitol, trehalose, and xylitol.

[0131] The term "disintegrant" refers to an excipient that causes tablets to rapidly break down into small particles in gastrointestinal fluids. It is primarily used to eliminate binding forces caused by adhesion and / or high compression, thereby disintegrating the tablet in water. Disintegrants include dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, microcrystalline cellulose, alginate, sodium alginate, etc.

[0132] The term "binder" refers to an additive that possesses inherent viscosity and imparts suitable viscosity to materials that are not viscous or have insufficient viscosity, promoting the aggregation of solid powders into larger particles and contributing to the formation of more robust dosage forms. Binders include starch paste, cellulose derivatives, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, povidone, gelatin, 50%–70% sucrose solution, sodium alginate solution, etc.

[0133] The term "lubricant" refers to a substance that prevents material from agglomerating and adhering to the punch and its surface, or to the material adhering to a capsule filling machine. Lubricants can improve the surface properties of particles, such as improving the electrostatic distribution of the particle surface, improving the surface roughness of the particle, reducing friction, improving the selective adsorption of gases, and weakening the van der Waals forces between particles. Lubricants include magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, hydrogenated castor oil, cottonseed oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitate, medium-chain triglycerides, mineral oil, light mineral oil, octyl dodecyl alcohol, poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, etc.

[0134] The autoimmune diseases described in this invention refer to rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), systemic lupus erythematosus, dermatomyositis, ankylosing spondylitis, multiple sclerosis, type I diabetes, psoriasis, vitiligo, Sjögren's syndrome, etc., or other inflammatory skin diseases such as atopic dermatitis, eczema, lichen planus, lichen luster, lichen sclerosus, panniculitis, acne, hidradenitis suppurativa, etc. Attached Figure Description

[0135] Figure 1 Dissolution curves of tablets from Examples 1-7 in 0.01 mol / L hydrochloric acid solution;

[0136] Figure 2 Dissolution curves of tablets from Examples 1, 8, and 9 in 0.01 mol / L hydrochloric acid solution;

[0137] Figure 3 Example 1: Dissolution curves of tablets 10-13 in 0.01 mol / L hydrochloric acid solution;

[0138] Figure 4 Dissolution curves of tablets 14-18 in 0.01 mol / L hydrochloric acid solution in Example 1;

[0139] Figure 5 Dissolution curves of tablets from Examples 1 and 19 in 0.01 mol / L hydrochloric acid solution;

[0140] Figure 6 XRPD pattern of crystal form A;

[0141] Figure 7 DSC spectrum of crystal form A;

[0142] Figure 8 XRPD pattern of B crystal form;

[0143] Figure 9 DSC pattern of B crystal form;

[0144] Figure 10 TGA pattern of B crystal form;

[0145] Figure 11 XRPD pattern of C-type crystal;

[0146] Figure 12 DSC pattern of C-type crystal;

[0147] Figure 13 XRPD pattern of D crystal form. Detailed Implementation

[0148] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.

[0149] Examples 1-7

[0150] The pulverized TUL01101, lactose, microcrystalline cellulose, croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, and substituted hydroxypropyl cellulose were wet-granulated according to the proportions in Table 1 using a high-efficiency wet mixing granulator. A granulation solution of 3.4% hydroxypropyl methylcellulose and 2.3% sodium dodecyl sulfate was used as the granulation solution. After granulation, wet granulation and drying were performed. Then, the dried granules (moisture content <3%) were dry-granulated, and croscarmellose sodium or carboxymethyl starch sodium, croscarmellose, low-substituted hydroxypropyl cellulose, and magnesium stearate were added. After mixing evenly, the mixture was compressed into tablets.

[0151] Table 1

[0152]

[0153] Experiment Example 1: Dissolution Experiment

[0154] According to the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method), the dissolution rate of the tablets in Examples 1-7 was determined. 900 ml of 0.01 mol / L hydrochloric acid solution was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5 °C with a paddle speed of 50 rpm. The results showed that compound TUL01101 in Examples 4, 6, and 7 dissolved slowly, failing to completely dissolve after 45 minutes. In the other examples, compound TUL01101 dissolved completely with similar dissolution behavior. Based on the results of the above examples, croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose ketone were preferred as disintegrants. Because TUL01101 is moisture-sensitive, croscarmellose sodium, with its relatively low hygroscopicity, was the most preferred disintegrant. Since increasing the amount of disintegrant did not significantly improve the dissolution behavior, the preferred amount of disintegrant was 8.0%. The dissolution data are shown in Table 2, and the dissolution curves are shown in [Table 2]. Figure 1 .

[0155] Table 2

[0156]

[0157] Experimental Example 2: Stability Study

[0158] (1) Influencing Factors Experiment

[0159] The tablets of Example 1 were placed in a petri dish and their stability was investigated under high temperature (60°C), high humidity (relative humidity 75%±1%, 15.5~60°C) and light (illuminance 4500lx±500lx). Samples were taken at 5 days, 10 days and 30 days, and the changes in related substances, content and dissolution were determined by HPLC. The results showed that the tablets of Example 1 were stable. Compared with the results of day 0, there were no significant differences in related substances, dissolution and content at 5 days, 10 days and 30 days. The data are shown in Table 3.

[0160] Table 3

[0161]

[0162] (2) Accelerated testing

[0163] The tablets of Example 1 were placed in an environment with a temperature of 40℃±2℃ and a relative humidity of 75%±5% for stability testing for 1 month. Then, the changes in related substances, content and dissolution were determined by HPLC. The results showed that the tablets of Example 1 were stable. Compared with the results of day 0, there were no significant differences in related substances, dissolution and content after 1 month. The data are shown in Table 4.

[0164] Table 4

[0165]

[0166] Examples 8-9

[0167] The pulverized TUL01101, lactose, microcrystalline cellulose, and croscarmellose sodium were wet-granulated according to the proportions in Table 5 using a high-efficiency wet mixing granulator. The granulation solution was 3.4% hydroxypropyl methylcellulose or hydroxypropyl cellulose, povidone, and 2.3% sodium dodecyl sulfate aqueous solution. After granulation, wet granulation and drying were performed. Then, the dried granules (moisture content <3%) were dry-granulated, and croscarmellose sodium and magnesium stearate were added. After mixing evenly, the mixture was compressed into tablets.

[0168] Table 5

[0169]

[0170] Experiment Example 3: Dissolution Experiment

[0171] According to the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method), the dissolution rate of the tablets in Examples 1 and 8-9 was determined. 900 ml of 0.01 mol / L hydrochloric acid solution was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5 °C with a paddle speed of 50 rpm. The results showed that TUL01101 was completely dissolved in Examples 1, 8, and 9, and the dissolution behavior was similar. Based on the results of the above examples, the type of binder has no significant effect on the dissolution behavior of the formulation. The dissolution data are shown in Table 6, and the dissolution curves are shown in [Table 6]. Figure 2 .

[0172] Table 6

[0173]

[0174] Examples 10-13

[0175] The pulverized TUL01101, lactose, microcrystalline cellulose, pregelatinized starch, anhydrous dicalcium phosphate, and croscarmellose sodium were wet-granulated according to the proportions in Table 7 using a high-efficiency wet mixing granulator. A granulation solution of 3.4% hydroxypropyl methylcellulose and 2.3% sodium dodecyl sulfate was used as the granulation solution. After granulation, wet granulation and drying were performed. Then, the dried granules (moisture content <3%) were dry-granulated, and croscarmellose sodium and magnesium stearate were added. After mixing evenly, the mixture was compressed into tablets.

[0176] Table 7

[0177]

[0178] Experiment Example 4: Dissolution Experiment

[0179] According to the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method), the dissolution rate of the tablets in Examples 1 and 10-13 was determined. 900 ml of 0.01 mol / L hydrochloric acid solution was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5 °C with a paddle speed of 50 rpm. The results showed that in Example 12, compound TUL01101 dissolved slowly and was not completely dissolved, while in the other examples, compound TUL01101 was completely dissolved. Based on the results of the above examples, the type and amount of filler affect the dissolution behavior of the formulation. The dissolution data are shown in Table 8, and the dissolution curves are shown in [Figure 8]. Figure 3 .

[0180] Table 8

[0181]

[0182] Examples 14-18

[0183] The pulverized TUL01101, lactose, microcrystalline cellulose, and croscarmellose sodium were wet-granulated according to the proportions in Table 9 using a high-efficiency wet mixing granulator. A granulation solution of 3.4% hydroxypropyl methylcellulose and 2.3% sodium dodecyl sulfate was used as the granulation solution. After granulation, wet granulation and drying were performed. Then, the dried granules (moisture content < 3%) were dry-granulated, and croscarmellose sodium and magnesium stearate were added. After mixing evenly, the mixture was compressed into tablets.

[0184] Table 9

[0185]

[0186] Experiment Example 5 Dissolution Experiment

[0187] According to the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method), the dissolution rate of the tablets in Examples 1 and 14-18 was determined. 900 ml of 0.01 mol / L hydrochloric acid solution was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5 °C with a paddle speed of 50 rpm. The results showed that in Example 18, compound TUL01101 dissolved slowly. This was because the single-dose formulation in Example 18 contained a large amount of the active ingredient, limiting the solubility of the active ingredient and thus slowing the dissolution behavior. The dissolution behavior of the other formulations was similar. The dissolution data are shown in Table 10 below, and the dissolution curves are shown in [Table 10]. Figure 4 .

[0188] Table 10

[0189]

[0190] Example 19

[0191] The pulverized TUL01101, lactose, microcrystalline cellulose, sodium dodecyl sulfate, croscarmellose sodium, and magnesium stearate were mixed evenly according to the proportions in Table 11 and then directly compressed into tablets.

[0192] Table 11

[0193]

[0194] Experiment Example 6 Dissolution Experiment

[0195] According to the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method), the dissolution rate of the tablets in Examples 1 and 19 was determined. 900 ml of 0.01 mol / L hydrochloric acid solution was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5 °C with a paddle speed of 50 rpm. The dissolution data are shown in Table 12 below, and the dissolution curves are shown in [Figure 1]. Figure 5The results showed that in Example 19, compound TUL01101 dissolved slowly and failed to dissolve completely. Based on the results of the above examples, the wet granulation process is preferred.

[0196] Table 12

[0197]

[0198] Preparation of Compound (II) in Example 20

[0199]

[0200] Step 1: At -78°C, LiHMDS (1 M, 51.2 mL) was added dropwise to a THF (150 mL) solution containing compound 1-1 (10.2 g, 42.6 mmol). After stirring at -78°C for 1 hour, a THF (150 mL) solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (16.7 g, 46.9 mmol) was added to the reaction mixture, and the mixture was stirred at 15°C for 12 hours. The reaction was quenched with 250 mL of saturated ammonium chloride, diluted with 200 mL of water, and then extracted with ethyl acetate (200 mL * 3). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain compound 1-2. The crude product was used directly in the next reaction without purification.

[0201] 1H NMR (400 MHz, CDCl3) δ 5.63 (br s, 1H), 3.50-3.65 (m, 4H), 2.34 (br s, 4H), 1.88 (br t, J=5.90 Hz, 2H), 1.37 (s, 9H).

[0202] Step 2: Potassium acetate (12.7 g, 129.3 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (3.5 g, 4.3 mmol) were added to a 100 mL DMF solution containing compounds 1-2 (16 g, 43.1 mmol) and pinacol diboronate (12.0 g, 47.4 mmol). The mixture was purged three times with nitrogen and stirred at 70 °C for 3 hours under a nitrogen atmosphere. The reaction solution was dispersed in a mixture of 300 mL water and 400 mL ethyl acetate. The organic phase was separated, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compounds 1-3.

[0203] 1H NMR (400MHz, CDCl3) δ 6.46 (br s, 1H), 3.71 - 3.53 (m, 4H), 2.31 (br d, J=3.0 Hz, 2H), 2.24 - 2.16 (m, 2H), 1.74 (t, J=6.3 Hz, 2H), 1.44 (s,9H), 1.26 (s,12H).

[0204] Step 3: Under a nitrogen atmosphere, potassium carbonate (3.8 g, 27.3 mmol) and Pd(dppf)Cl2.CH2Cl2 (744 mg, 911.0 μmol) were added to a solution containing dioxane (60 mL) and water (15 mL) of compounds 1-3 (3.5 g, 10.0 mmol) and N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (2.6 g, 9.1 mmol). The reaction solution was stirred at 90 °C for 3 hours. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain compounds 1-4. LCMS (ESI) m / z: 424.3 [M + H]+.

[0205] Step 4: Hydrochloric acid / ethyl acetate (4 M, 30 mL) was added to a solution of dichloromethane (10 mL) containing compounds 1-4 (3.5 g, 8.2 mmol). The reaction mixture was stirred at 25 °C for 0.5 hours. A solid precipitated out, which was filtered and dried to give compounds 1-5 (3.3 g hydrochloride, crude product), which were used directly in the next step of the reaction without purification.

[0206] LCMS (ESI) m / z: 324.1[M + H]+.

[0207] Step 5: Under a nitrogen atmosphere, Pd / C (1 g, 10%) was added to a methanol (100 mL) solution containing compounds 1-5 (3.0 g, 8.34 mmol, hydrochloride). The suspension was purged three times with hydrogen, and then stirred for 12 hours at 30°C under a hydrogen atmosphere (30 psi). The reaction solution was filtered and concentrated to obtain compounds 1-6 (3 g hydrochloride, crude product), which were used directly in the next step of the reaction without purification.

[0208] LCMS (ESI) m / z: 326.2 [M + H]+.

[0209] Step 6: Compounds 1-6 (0.87 g, 2.40 mmol, hydrochloride) were dissolved in N,N-dimethylformamide (10 mL), HOBt (487 mg, 3.6 mmol) and EDCI (691 mg, 3.6 mmol) were added, followed by (1S)-2,2-difluorocyclopropylformic acid (323 mg, 2.6 mmol) and diisopropylethylamine (621 mg, 4.8 mmol). The reaction solution was reacted at 15 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (neutral system) to obtain compound (II).

[0210] 1H NMR (400MHz, CD3OD) δ 7.32-7.73 (m, 2H), 6.95 (br s, 1H), 3.62-4.22 (m, 4H), 3.45 (br s, 1H), 3.18-3.37 (m, 1H), 2.61 (br s, 1H), 1.45-2.27(m, 10H), 0.78-1.17(m, 4H). LCMS (ESI) m / z: 430.0[M + H]+.

[0211] Example 21 Preparation methods of various crystal forms

[0212] Weigh 50 mg of compound (II) and add it to a 2.0 mL glass vial. Add 0.4 mL of a solvent mixture of methanol and water (volume ratio 1:1). The resulting suspension is then stirred on a heated magnetic stirrer (40°C) after adding a magnetic stir bar. After stirring for 100 hours, the suspended sample is centrifuged and then placed in a vacuum drying oven at 35°C overnight. The dried sample is then tested for XRPD (e.g., ...). Figure 6 As shown), it is determined to be the A crystal form of compound (II), and DSC (such as) is detected simultaneously. Figure 7 (As shown).

[0213] Approximately 50 mg of compound (II) was weighed and added to a 2.0 mL glass vial, along with 0.4 mL of ethyl acetate. After adding a magnetic stir bar, the sample was placed on a heated magnetic stirrer (40°C) and stirred. After stirring for 100 hours, the suspended sample was centrifuged and then placed in a vacuum drying oven at 35°C overnight. The dried sample was then tested for XRPD (e.g., ...). Figure 8 As shown), it is determined to be the B crystal form of compound (II), and DSC (such as) is detected simultaneously. Figure 9 (as shown) and TGA (as shown) Figure 10 (As shown).

[0214] The A crystal form of compound (II) was heated to 170°C, and XRPD was detected. Figure 11 As shown), the crystal form changes, and the new crystal form obtained is the C crystal form of compound (II). Simultaneously, DSC (such as...) is detected. Figure 12 (As shown).

[0215] Approximately 50 mg of compound (II) was weighed and added to a 2.0 mL glass vial, along with 0.4 mL of a solvent mixture of ethanol and water (volume ratio 1:1) to obtain a suspension. After adding a magnetic stir bar, the sample was placed on a heated magnetic stirrer (40°C) and stirred. After stirring for 100 hours, the suspended sample was centrifuged and then placed in a vacuum drying oven at 35°C overnight. The dried sample was then tested for XRPD (e.g., ...). Figure 13 As shown), it is determined to be the D crystal form of compound (II).

[0216] Example 22: Solid stability study of the B crystal form of compound (II)

[0217] Accurately weigh approximately 5 mg of crystal form B and place it in a dry, clean glass bottle, spreading it into a thin layer as the official test sample. Place the sample under the influence factor test conditions (60℃, 92.5%RH) and accelerated conditions (40℃ / 75%RH and 60℃ / 75%RH), ensuring complete exposure. Cover the sample with aluminum foil and poke small holes. Samples are taken for analysis at 5 and 10 days. Samples placed under light conditions (1,200,000 Lux visible light, 200W UV) are placed under complete exposure at room temperature.

[0218] Experimental results show that the crystal form did not change under the influencing conditions (high temperature -60℃, high humidity -92.5%RH, light) and accelerated conditions (40℃ / 75%RH and 60℃ / 75%RH).

[0219] Example 23: Study on the biological solubility of the B crystal form of compound (II)

[0220] 1. Solubility experiment of biological media with B-type crystal form

[0221] Weigh approximately 2 mg of sample B crystal form into sample vials, and then add 1.0 mL of each of the following solvents: pure water, SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under feeding conditions). Shake well. Place the vials on a constant temperature shaker at 37 ℃. After shaking for 24 hours, centrifuge and test the solubility of the supernatant. Dilute the supernatant (using ACN / H2O (1 / 1)) by a certain factor (the compounds have low solubility; all supernatants except SGF are diluted by two times, and SGF is diluted by 10 times), and determine their concentrations by HPLC.

[0222] 2. Preparation of diluent and mobile phase

[0223] Diluent: Acetonitrile:Water 1:1. Mobile phase A: 0.1% TFA aqueous solution, e.g., transfer 1 mL of TFA to 1 L of pure water, mix thoroughly, and degas by sonication. Mobile phase B: 100% acetonitrile.

[0224] 3. Preparation of reference standards and sample solutions

[0225] STD solution preparation: Use crystal form B as the reference standard. Weigh approximately 5 mg of the reference standard into a glass bottle, dissolve it in 10 mL of diluent, sonicate for approximately 10 minutes to ensure complete dissolution, cool to room temperature, and shake well. Prepare two parallel aliquots, labeled STD1 and STD2. Dilute the corresponding STD1 solution 10, 100, 1000, and 2000 times with diluent to create a standard curve for testing.

[0226] Preparation of sample solution: Dilute the supernatant (diluent ACN / H2O (1 / 1)) by a certain factor (the compounds have low solubility, so all supernatants except SGF are diluted by two times, and SGF is diluted by 10 times), shake well, and place in a 1.5 mL liquid chromatography vial for testing. Determine its concentration by HPLC.

[0227] 4. Results of biological vector solubility (as shown in Table 13)

[0228] Table 13 Solubility results of biological media in B-type crystal form

[0229]

[0230] Experimental conclusion: The B crystal form exhibits good solubility in simulated biological media, a characteristic that facilitates obtaining good in vivo bioavailability.

Claims

1. An oral formulation containing a JAK inhibitor, characterized in that, The oral formulation comprises a JAK inhibitor, a filler, a disintegrant, a binder, a lubricant, and a surfactant, wherein the JAK inhibitor is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof or a crystal form thereof. (II) The content of the JAK inhibitor is 1% to 25% of the total weight of the composition; The filler is selected from a mixture of microcrystalline cellulose and lactose; The content of the filler microcrystalline cellulose is 30% to 50% of the total weight of the composition; The content of the filler lactose is 30% to 50% of the total weight of the composition; The disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, and croscarmellose. The content of the disintegrant is 2% to 16% of the total weight of the composition; The adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone; The content of the adhesive is 1% to 4% of the total weight of the composition; The lubricant is selected from magnesium stearate; The lubricant content is 0.1% to 5% of the total weight of the composition; The surfactant is selected from sodium dodecyl sulfate; The surfactant content is 0.1% to 5% of the total weight; The crystal form of the compound of formula (II) It is a type B crystal; The XRPD characteristic peaks of the B crystal form of the compound of formula (II) include: 。 2. The oral formulation according to claim 1, characterized in that, The content of the JAK inhibitor is 10%, 15% or 20% of the total weight of the composition.

3. The oral formulation according to claim 1, characterized in that, The content of the filler microcrystalline cellulose is 31.75%, 37.25%, 39.25%, 41.75%, 42.25% or 43.75% of the total weight of the composition.

4. The oral formulation according to claim 1, characterized in that, The content of the filler lactose is 31.75%, 37.25%, 39.25%, 41.75%, 42.25%, or 43.75% of the total weight of the composition.

5. The oral formulation according to claim 1, characterized in that, The content of the disintegrant is 4%, 8% or 12% of the total weight of the composition.

6. The oral formulation according to claim 1, characterized in that, The adhesive content is 2% to 3% of the total weight of the composition.

7. The oral formulation according to claim 1, characterized in that, The adhesive content is 1.5% of the total weight of the composition.

8. The oral formulation according to claim 1, characterized in that, The lubricant content is 0.5% to 3% of the total weight of the composition.

9. The oral formulation according to claim 8, characterized in that, The lubricant content is 1% of the total weight of the composition.

10. The oral formulation according to claim 1, characterized in that, The surfactant content is 1% to 3% of the total weight.

11. The oral formulation according to claim 10, characterized in that, The surfactant content is 2% of the total weight.

12. The oral formulation according to claim 1, characterized in that, The XRPD diagram of the B crystal form of the compound of formula (II) is shown in Figure 8.

13. The method for preparing an oral formulation according to any one of claims 1 to 12, wherein the preparation method is wet granulation.

14. The method for preparing an oral formulation according to claim 13, wherein the filler, disintegrant, binder, lubricant, or surfactant is added internally or externally.

15. Use of the oral formulation according to any one of claims 1 to 12 in the preparation of a medicament for treating an autoimmune disease, wherein the autoimmune disease is rheumatoid arthritis.

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