A pharmaceutical composition

Abstract

The present application relates to a pharmaceutical composition comprising active ingredient Compound 1, a pharmaceutically acceptable polymer carrier, a surfactant; and other pharmaceutically acceptable adjuvants; wherein the active ingredient, the polymer carrier and optionally at least a part of the surfactant are present in the form of a solid dispersion. The present application discloses for the first time a pharmaceutical composition comprising Compound 1, which has stable product quality and good bioavailability. Based on the characteristics of Compound 1 as a JAK inhibitor, the composition has a wide application prospect in alopecia areata, vitiligo, atopic dermatitis, psoriasis, membranous nephropathy, ankylosing spondylitis, peripheral T-cell lymphoma, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease and the like.

Description

A pharmaceutical composition Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a pharmaceutical composition comprising 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl]azetidin-3-yl]acetonitrile. Background Art

[0002] 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl]azetidin-3-yl]acetonitrile (hereinafter referred to as Compound 1) is a JAK inhibitor having the following structural formula:

[0003] Compound 1 has low solubility in aqueous media (i.e., less than 1 mg / mL in water at 25°C) and poor permeability, resulting in low oral bioavailability. To enhance its bioavailability and improve its drugability, numerous solubilization techniques have been explored, including API micronization, salt formation or crystal formation studies, microemulsions / self-microemulsions, surfactant solubilization, cyclodextrin inclusion, solid dispersions, and cocrystals. There is a need in the art for pharmaceutical compositions with enhanced bioavailability of this compound. Summary of the Invention

[0004] Surprisingly, it was found that the pharmaceutical composition containing the solid dispersion can significantly improve the bioavailability of Compound 1.

[0005] In one aspect, the present application provides a solid dispersion comprising:

[0006] The active ingredient is 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl]azetidin-3-yl]acetonitrile or a pharmaceutically acceptable salt thereof having the following structural formula

[0007] a pharmaceutically acceptable polymer carrier, and a surfactant;

[0008] Among them, the surfactant is selected from sodium lauryl sulfate, vitamin E polyethylene glycol succinate, poloxamer, 15-hydroxystearate polyethylene glycol ester, sodium stearyl fumarate, sodium docusate, cetrimide, benzethonium chloride, cetylpyridinium chloride, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester; polyoxyethylene castor oil derivatives, polyoxyethylene stearate, poloxamer, polysorbate series, fatty acid sorbitan, preferably sodium lauryl sulfate.

[0009] The present application also provides a pharmaceutical composition comprising:

[0010] The active ingredient is 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl]azetidin-3-yl]acetonitrile or a pharmaceutically acceptable salt thereof having the following structural formula

[0011] a pharmaceutically acceptable polymer carrier,

[0012] surfactants; and

[0013] Other pharmaceutically acceptable excipients;

[0014] Wherein, the surfactant is selected from sodium lauryl sulfate, vitamin E polyethylene glycol succinate, poloxamer, 15-hydroxystearate polyethylene glycol ester, sodium stearyl fumarate, sodium docusate, cetrimide, benzethonium chloride, cetylpyridinium chloride, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester; polyoxyethylene castor oil derivatives, polyoxyethylene stearate, poloxamer, polysorbate series, fatty acid sorbitan, preferably sodium lauryl sulfate;

[0015] The active ingredient, the polymer carrier and optionally at least a portion of the surfactant are present in the form of a solid dispersion.

[0016] In one embodiment, the polymer carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), polymethacrylate, hydroxypropyl cellulose (HPC) and cellulose acetate phthalate (CAP); preferably, the polymer carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC); more preferably, the polymer carrier is copovidone.

[0017] In one embodiment, in the solid dispersion, the weight ratio of the active ingredient: the polymer carrier is 1:1 to 1:20, preferably 1:2 to 1:10, and the weight ratio of the active ingredient: the surfactant is 1:0.001 to 1:0.5.

[0018] In one embodiment, based on the total weight of the pharmaceutical composition,

[0019] The active ingredient accounts for 0.1wt% to 30wt%;

[0020] The polymer carrier accounts for 1.0 wt% to 90.0 wt%;

[0021] The surfactant accounts for 0.1wt% to 10.0wt%;

[0022] The total weight of other pharmaceutically acceptable excipients accounts for 10 wt% to 98 wt%.

[0023] In one embodiment, other pharmaceutically acceptable excipients include one or more of a filler, a disintegrant, a glidant, a lubricant, and a binder.

[0024] In one embodiment, the filler is selected from one or more of lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose) and xylitol; preferably, the filler is selected from one or more of microcrystalline cellulose, mannitol, sorbitol and lactose.

[0025] In one embodiment, the filler is microcrystalline cellulose or mannitol, or a combination of microcrystalline cellulose and mannitol;

[0026] When present, the amount of microcrystalline cellulose is 0 wt% to 99.0 wt%, based on the total weight of the pharmaceutical composition; and / or

[0027] When present, the amount of mannitol is 0 wt% to 99.0 wt%, based on the total weight of the pharmaceutical composition.

[0028] In one embodiment, the disintegrant is selected from one or more of croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hypromellose and hydroxypropyl cellulose; preferably, the disintegrant is selected from one or more of croscarmellose sodium, crospovidone, polyvinyl pyrrolidone and microcrystalline cellulose;

[0029] In one embodiment, the disintegrant is croscarmellose sodium;

[0030] When present, the amount of croscarmellose sodium is 0.5 wt% to 20.0 wt%, based on the total weight of the pharmaceutical composition.

[0031] In one embodiment, the glidant is selected from one or both of silicon dioxide and talc. Preferably, the glidant is silicon dioxide;

[0032] When present, the amount of silicon dioxide is 0.1 wt% to 10.0 wt%, based on the total weight of the pharmaceutical composition.

[0033] In one embodiment, the lubricant is selected from one or more of magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium chain triglycerides, poloxamer, polyethylene glycol and talc; preferably, the lubricant is selected from one or both of magnesium stearate and sodium stearyl fumarate.

[0034] In one embodiment, the lubricant is magnesium stearate;

[0035] When present, the amount of magnesium stearate is 0.05 wt% to 2.0 wt%, based on the total weight of the pharmaceutical composition.

[0036] In one embodiment, the pharmaceutical composition comprises the following components based on the total weight of the pharmaceutical composition:

[0037] 0.1 wt% to 30.0 wt% of active ingredient;

[0038] 1.0 wt% to 90.0 wt% of copovidone;

[0039] 0wt% to 99.0wt% mannitol;

[0040] 0 wt% to 99.0 wt% of microcrystalline cellulose;

[0041] 0.5 wt% to 20.0 wt% of cross-linked sodium carboxymethyl cellulose;

[0042] 0.1 wt% to 10.0 wt% of sodium lauryl sulfate;

[0043] 0.1 wt% to 10.0 wt% of silicon dioxide;

[0044] 0.05wt% to 2.0wt% of magnesium stearate;

[0045] The active ingredient, copovidone and optionally at least a portion of sodium lauryl sulfate are present in the form of a solid dispersion.

[0046] In one embodiment, the solid dispersion is prepared by spray drying or hot melt extrusion; preferably, the solid dispersion is prepared by spray drying.

[0047] In one embodiment, the pharmaceutical composition is an oral solid preparation, including tablets, granules, powders, dry suspensions or capsules.

[0048] In one embodiment, the pharmaceutical composition is a tablet.

[0049] This application discloses for the first time a pharmaceutical composition comprising compound 1, which has stable product quality and good bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 shows the effect of dosage form on the pharmacokinetics of Compound 1;

[0051] Figure 2 shows the dissolution comparison of compound 1 in different types of formulations;

[0052] FIG3 shows a comparison of the effects of fillers on the dissolution of Compound 1;

[0053] Figure 4 shows the effect of glidant addition method on the dissolution of compound 1;

[0054] Figure 5 shows the effect of glidant dosage on the dissolution of compound 1;

[0055] FIG6 shows the effect of lubricant dosage on the dissolution of compound 1;

[0056] FIG7 shows the effect of disintegrant dosage on the dissolution of compound 1;

[0057] FIG8 shows the effect of surfactant dosage on the dissolution of compound 1;

[0058] Figure 9 shows the effect of product hardness on the dissolution of compound 1;

[0059] Figure 10 shows the effect of coating on the dissolution of Compound 1;

[0060] FIG11 shows the dissolution curve of compound 1 in the stability test;

[0061] FIG12 shows the results of the stability test of the crystal form of Compound 1. DETAILED DESCRIPTION

[0062] The present application will be further described in detail below through the accompanying drawings and examples, through which the features and advantages of the present application will become more clear and distinct.

[0063] The word "exemplary" is used exclusively herein to mean "serving as an example, example, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments. Although various aspects of the embodiments are shown in the drawings, the drawings are not necessarily drawn to scale unless otherwise indicated.

[0064] In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0065] The term "solid dispersion" as used herein refers to a system in which an active ingredient is dispersed in an excipient carrier. In a solid dispersion, one or more active ingredients are highly uniformly dispersed in an inert excipient or skeleton in a molecular, amorphous or microcrystalline state to form a dispersed system. In terms of the state of the drug in the system, a solid dispersion in this sense may include a composition in which the drug is dispersed in an excipient carrier in a discrete state of crystalline or amorphous drugs or as independent molecules. In terms of the entire drug-excipient complex, solid dispersions can be relatively large solid substances such as pellets, tablets, films or strands; or they can exist as free-flowing powders composed of micron- or nano-sized primary particles or aggregates thereof. The final state of the solid dispersion composition depends mainly on the processing technology.

[0066] Methods for preparing solid dispersions are known in the art and generally include dissolving the drug and polymer in a common solvent and evaporating the solvent. The solvent can be selected conventionally based on the properties of the polymer used. Commonly used solvents include acetone, acetone / dichloromethane, methanol / dichloromethane, acetone / water, acetone / methanol, acetone / ethanol, dichloromethane / ethanol, or ethanol / water. Methods for evaporating the solvent include rotary evaporation, spray drying, freeze drying, and thin-film evaporation. Traditional methods for preparing solid dispersions include melt and solvent methods. In recent years, hot-melt extrusion (melt method) has attracted considerable attention from pharmaceutical researchers both domestically and internationally as a novel method for preparing solid dispersions. This method utilizes material transfer, shear mixing, and melt extrusion in a single-screw or twin-screw extruder with sequential heating. Compared to traditional preparation methods, hot-melt extrusion offers advantages such as high production efficiency, the absence of organic solvents, and suitability for industrial production. However, for drugs and carriers with relatively high melting points, melt and hot-melt extrusion methods can easily lead to thermal decomposition of the drug and carrier, limiting their widespread application. Spray drying (solvent method) involves dissolving the drug and carrier material in an organic solvent, then removing the solvent to obtain a uniform dispersion. Compared to hot-melt extrusion, spray drying is more suitable for drugs with poor thermal stability, offering advantages such as a shorter development cycle and ease of scale-up.

[0067] In one aspect, the present application provides a solid dispersion comprising:

[0068] The active ingredient is 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl]azetidin-3-yl]acetonitrile or a pharmaceutically acceptable salt thereof having the following structural formula

[0069] a pharmaceutically acceptable polymer carrier, and

[0070] surfactants;

[0071] Among them, the surfactant is selected from sodium lauryl sulfate, vitamin E polyethylene glycol succinate, 15-hydroxystearate polyethylene glycol ester, sodium stearyl fumarate, sodium docusate, cetrimide, benzethonium chloride, cetylpyridinium chloride, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester; polyoxyethylene castor oil derivatives, polyoxyethylene stearate, poloxamer, polysorbate series, fatty acid sorbitan, preferably sodium lauryl sulfate.

[0072] Compound 1 is a JAK inhibitor that can be used to treat and prevent a variety of autoimmune diseases, including atopic dermatitis, prurigo nodularis, vitiligo, scleroderma, psoriasis, membranous nephropathy, ankylosing spondylitis, peripheral T-cell lymphoma, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and alopecia areata. It is disclosed in CN109867676B, the entire contents of which are incorporated into this application by reference.

[0073] As demonstrated in Example 1 below, the solubility of Compound 1 in different pH media is significantly pH-dependent, with higher solubility in acidic environments and virtually insoluble in neutral and alkaline environments and water. Among the commonly used solvents for spray-drying solid dispersions, acetone has a high solubility for Compound 1.

[0074] In one embodiment, the solid dispersion comprises at least 5 mg of Compound 1, e.g., 5 mg of Compound 1, 15 mg of Compound 1, 45 mg of Compound 1, 75 mg of Compound 1, 100 mg of Compound 1, 150 mg of Compound 1, 250 mg of Compound 1.

[0075] In one embodiment, the solid dispersion comprises up to 5 mg of Compound 1, for example, the solid dispersion comprises 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of Compound 1.

[0076] The solid dispersion of the present application includes a pharmaceutically acceptable polymer carrier. In one embodiment, the above-mentioned polymer carrier is selected from copolyvidone, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), hypromellose (HPMC), polymethacrylate, hydroxypropyl cellulose (HPC) and cellulose acetate phthalate (CAP), and one or more combinations can be used. Preferably, the polymer carrier is selected from copolyvidone, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), hypromellose (HPMC) One or more. In one embodiment, in the solid dispersion, the active ingredient: the weight ratio of the polymer carrier is 1: 1 to 1: 20, for example, 1: 1 to 1: 15, preferably 1: 2 to 1: 10.

[0077] In the present application, the polymer carrier can effectively increase the solubility of compound 1 in pH 6.8 phosphate buffer and can effectively maintain the supersaturated state of compound 1 in the medium. In particular, copovidone has a good solubilizing effect on compound 1 and the ability to maintain supersaturation, and is therefore more preferred.

[0078] The solid dispersion of the present application also includes a pharmaceutically acceptable surfactant. The surfactant is selected from sodium lauryl sulfate, vitamin E polyethylene glycol succinate, 15-hydroxystearic acid polyethylene glycol ester, sodium stearyl fumarate, sodium docusate, cetrimide, benzethonium chloride, hexadecyl pyridinium chloride, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester; polyoxyethylene castor oil derivatives, polyoxyethylene stearate, poloxamer, polysorbate series, fatty acid sorbitan, preferably sodium lauryl sulfate (SDS). The inventors of the present application unexpectedly found that, compared with different surfactants, SDS has a very clear solubilizing ability for compound 1, can very effectively increase the solubility of compound 1, and can maintain its supersaturated state for a long time. In one embodiment, the active ingredient: the weight ratio of the surfactant is 1: 0.001 to 1: 0.5. Within the above range, the surfactant can achieve a better balance in terms of the solubilizing ability of compound 1 and the ability to maintain supersaturation.

[0079] The solid dispersion of the present application can be used as one of the components for preparing subsequent pharmaceutical compositions. In addition, the inventors of the present application have also found that when preparing a pharmaceutical composition in combination with other excipients such as fillers, disintegrants, glidants, lubricants and adhesives, simply mixing the components of the solid dispersion, especially the active ingredient and the polymer carrier, with these other excipients to prepare the pharmaceutical composition does not achieve the effect of solubilization. It is necessary to first make the active ingredient and the polymer carrier into a solid dispersion, and then combine them with other excipients such as fillers, disintegrants, glidants, lubricants and adhesives to prepare the pharmaceutical composition, so that effects such as solubilization can be well achieved.

[0080] Methods for preparing solid dispersions are known in the art and generally include the steps of dissolving the drug and the polymer in a common solvent and evaporating the solvent. The solvent can be selected in a conventional manner according to the properties of the polymer used. Commonly used solvents are: acetone, acetone / dichloromethane, methanol / dichloromethane, acetone / water, acetone / methanol, acetone / ethanol, dichloromethane / ethanol or ethanol / water. Methods for evaporating the solvent include rotary evaporation, spray drying, freeze drying and thin film evaporation. The present application can use a spray drying method to prepare a solid dispersion sample comprising compound 1 and a polymer: compound 1 and a polymer carrier are dissolved in a low boiling point solvent, and a spray dryer is used to prepare a solid dispersion sample comprising compound 1 and a polymer. Based on the solubility of compound 1 and the polymer carrier in different solvents, acetone can be used as a solvent.

[0081] For example, when the polymer carrier is copolyvidone, compound 1, copolyvidone and SDS are dissolved in acetone, and the acetone solution is spray-dried using a spray dryer at an inlet air temperature of 100°C and an outlet air temperature of 50°C to obtain the solid dispersion of the present application.

[0082] In a second aspect, the present application provides a pharmaceutical composition comprising:

[0083] The active ingredient is 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl]azetidin-3-yl]acetonitrile or a pharmaceutically acceptable salt thereof having the following structural formula

[0084] a pharmaceutically acceptable polymer carrier,

[0085] surfactants; and

[0086] Other pharmaceutically acceptable excipients;

[0087] Wherein, the surfactant is selected from sodium lauryl sulfate, vitamin E polyethylene glycol succinate, 15-hydroxystearate polyethylene glycol ester, sodium stearyl fumarate, sodium docusate, cetrimide, benzethonium chloride, cetylpyridinium chloride, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester; polyoxyethylene castor oil derivatives, polyoxyethylene stearate, poloxamer, polysorbate series, fatty acid sorbitan, preferably sodium lauryl sulfate;

[0088] The active ingredient, the polymer carrier and optionally at least a portion of the surfactant are present in the form of a solid dispersion.

[0089] In the pharmaceutical composition of the present application, the active ingredient and the polymer carrier need to be first prepared as a solid dispersion, and then combined with other excipients in the form of a solid dispersion to further prepare the pharmaceutical composition.

[0090] Regarding the surfactant SDS, it can be first prepared as a solid dispersion together with the active ingredient and the polymer carrier, and then combined with other excipients in the form of a solid dispersion to further prepare a pharmaceutical composition. Alternatively, the active ingredient and the polymer carrier can be first prepared as a solid dispersion, and then combined with other excipients to prepare the pharmaceutical composition. The inventors of this application have discovered that using the latter method, the surfactant can also very effectively increase the solubility of Compound 1 and maintain its supersaturated state for a long time. Of course, when preparing a pharmaceutical composition, it is also possible to first prepare a portion of the surfactant together with the active ingredient and the polymer carrier as a solid dispersion, and then combine another portion of the surfactant with the solid dispersion together with other excipients, which is also within the scope of protection of this application. The ratio of these two portions of surfactant can be selected as needed. The surfactant prepared as a solid dispersion together with the active ingredient and the polymer carrier can account for 0wt%-100wt% of the total surfactant amount, for example, 30wt%-100wt%, or 60wt%-100wt%, or 70wt%-100wt%.

[0091] In this pharmaceutical composition, the selection of the polymer carrier and its ratio to the active ingredient can be referred to the aforementioned solid dispersion part of this application, and the relevant description is also applicable to the pharmaceutical composition part of this application and will not be repeated here.

[0092] In one embodiment, based on the total weight of the pharmaceutical composition,

[0093] The active ingredient accounts for 0.1wt% to 30wt%;

[0094] The polymer carrier accounts for 1.0 wt% to 90.0 wt%;

[0095] The surfactant accounts for 0.1wt% to 10.0wt%.

[0096] The pharmaceutical composition of the present application further comprises other pharmaceutically acceptable excipients, the total weight of which accounts for 10 wt% to 98 wt% based on the total weight of the pharmaceutical composition.

[0097] In the pharmaceutical composition of the present application, the amount of the polymer carrier and other pharmaceutically acceptable excipients can vary widely and can be adjusted according to the content of the active ingredient API and demand. For example, based on the total weight of the pharmaceutical composition, the polymer carrier can account for 1.0 wt% to 90.0 wt%, for example, less than or equal to 85 wt%, less than or equal to 80 wt%, less than or equal to 75 wt%, or less than or equal to 70 wt%.

[0098] Other pharmaceutically acceptable excipients can be various excipients commonly used in pharmaceuticals, such as one or more of fillers, disintegrants, glidants, lubricants, and binders. The total amount of other pharmaceutical excipients can be the sum of the amounts of other pharmaceutical excipients excluding the polymer carrier and surfactant. For example, based on the total weight of the pharmaceutical composition, the other pharmaceutically acceptable excipients account for 10 wt% to 98 wt%, for example, 12 wt% to 98 wt%.

[0099] The pharmaceutical composition of the present invention may include a filler. In one embodiment, the filler may be selected from lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulfate, and xylitol, one or a combination of which may be used. Preferably, microcrystalline cellulose, mannitol, sorbitol, lactose, one or a combination of which may be used.

[0100] In one embodiment, the filler may be microcrystalline cellulose or mannitol or a combination of microcrystalline cellulose and mannitol.

[0101] When present, the amount of microcrystalline cellulose is 0 wt% to 99.0 wt%, based on the total weight of the pharmaceutical composition; and / or

[0102] When present, the amount of mannitol is 0 wt% to 99.0 wt%, based on the total weight of the pharmaceutical composition.

[0103] The filler in this invention functions as both a binder and a partial disintegrant. Research has shown that combining mannitol and microcrystalline cellulose effectively improves the granule appearance during dry granulation, facilitating subsequent processing. Furthermore, combining mannitol and microcrystalline cellulose in appropriate proportions can improve and maintain the product's dissolution behavior, a phenomenon particularly evident in stability studies. Preferably, the weight ratio of mannitol to microcrystalline cellulose is 1:0.25-4.

[0104] The pharmaceutical composition of the present invention may include a disintegrant. In one embodiment, the disintegrant may be selected from croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, and microcrystalline cellulose, or one or a combination thereof. Preferably, crospovidone, polyvinyl pyrrolidone, and microcrystalline cellulose, or one or a combination thereof, may be used.

[0105] In one embodiment, the disintegrant may be cross-linked carboxymethyl cellulose sodium, and the amount used is 0.5 wt% to 20.0 wt%, based on the total weight of the pharmaceutical composition.

[0106] The pharmaceutical composition of the present invention may comprise a glidant. In one embodiment, the glidant may be selected from silicon dioxide and / or talc.

[0107] In one embodiment, the glidant may be silicon dioxide, and the amount used is 0.1 wt% to 10.0 wt%, based on the total weight of the pharmaceutical composition.

[0108] The pharmaceutical composition of the present invention may include a lubricant. In one embodiment, the lubricant may be selected from magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol, and talc, one or a combination of which may be used. Preferably, magnesium stearate and sodium stearyl fumarate, one or a combination of which may be used.

[0109] In one embodiment, the lubricant may be magnesium stearate in an amount of 0.05 wt % to 2.0 wt %, based on the total weight of the pharmaceutical composition.

[0110] In one embodiment, the pharmaceutical composition comprises the following components based on the total weight of the pharmaceutical composition:

[0111] 0.1 wt% to 30.0 wt% of compound 1;

[0112] 1.0 wt% to 90.0 wt% of copovidone;

[0113] 0 wt% to 90.0 wt% of mannitol;

[0114] 0 wt% to 90.0 wt% of microcrystalline cellulose;

[0115] 0.5 wt% to 20.0 wt% of cross-linked sodium carboxymethyl cellulose;

[0116] 0.1 wt% to 10.0 wt% of sodium lauryl sulfate;

[0117] 0.1 wt% to 10.0 wt% of silicon dioxide;

[0118] 0.05wt% to 2.0wt% magnesium stearate.

[0119] In one embodiment, a pharmaceutical composition comprising Compound 1 is provided, wherein the pharmaceutical composition comprises the following components based on the total weight of the pharmaceutical composition:

[0120] 0.1 wt% to 30.0 wt% of compound 1;

[0121] 1.0 wt% to 90.0 wt% of copovidone;

[0122] 0 wt% to 99.0 wt% of microcrystalline cellulose;

[0123] 0.5 wt% to 20.0 wt% of cross-linked sodium carboxymethyl cellulose;

[0124] 0.1 wt% to 10.0 wt% of sodium lauryl sulfate;

[0125] 0.1 wt% to 10.0 wt% of silicon dioxide;

[0126] 0.05wt% to 2.0wt% magnesium stearate.

[0127] and / or

[0128] 0.1 wt% to 30.0 wt% of compound 1;

[0129] 1.0 wt% to 90.0 wt% of copovidone;

[0130] 0wt% to 99.0wt% mannitol;

[0131] 0.5 wt% to 20.0 wt% of cross-linked sodium carboxymethyl cellulose;

[0132] 0.1 wt% to 10.0 wt% of sodium lauryl sulfate;

[0133] 0.1 wt% to 10.0 wt% of silicon dioxide;

[0134] 0.05wt% to 2.0wt% magnesium stearate.

[0135] and / or

[0136] 0.1 wt% to 30.0 wt% of compound 1;

[0137] 1.0 wt% to 90.0 wt% of copovidone;

[0138] 0wt% to 99.0wt% mannitol;

[0139] 0 wt% to 99.0 wt% of microcrystalline cellulose;

[0140] 0.5 wt% to 20.0 wt% of cross-linked sodium carboxymethyl cellulose;

[0141] 0.1 wt% to 10.0 wt% of sodium lauryl sulfate;

[0142] 0.1 wt% to 10.0 wt% of silicon dioxide;

[0143] 0.05wt% to 2.0wt% magnesium stearate.

[0144] The pharmaceutical composition may optionally contain one or more colorants, fragrances, flavoring agents to enhance its visual appeal, change its taste and smell, increase its recognition, etc. These changes will not directly affect the therapeutic effect of the pharmaceutical composition.

[0145] The pharmaceutical composition may also be coated to achieve the purpose of protecting the coated components, distinguishing specifications, increasing recognition, changing drug dissolution behavior, etc.

[0146] On the other hand, in order to ensure the formability of the pharmaceutical composition and the convenience of use and circulation, the tablets thereof should also have an appropriate hardness, such as a hardness of 40N-150N.

[0147] The method for testing dissolution in the present invention is the second method of dissolution and release determination method of Part IV 0931 of the Chinese Pharmacopoeia 2020 edition, specifically as follows: paddle method 75rpm, 900ml pH6.8 phosphate medium, 37±0.5℃, sampling 10ml at 10min, 15min, 30min, 45min, 60min, 90min, and 120min after administration, using a 0.45μm polypropylene filter membrane to discard 5ml of the initial filtrate, taking the subsequent filtrate to test the content of compound 1, and calculating the dissolution ratio according to the theoretical content.

[0148] Based on the property of compound 1 as a JAK inhibitor, the solid dispersion and pharmaceutical composition containing compound 1 of the present application can also be used to treat and prevent various autoimmune diseases including atopic dermatitis, nodular prurigo, vitiligo, scleroderma, psoriasis, membranous nephropathy, ankylosing spondylitis, peripheral T-cell lymphoma, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease and alopecia areata.

[0149] In one embodiment, the pharmaceutical composition is an oral solid preparation, including tablets, granules, powders, dry suspensions or capsules, especially tablets.

[0150] For example, tablets can be prepared using the following process:

[0151] (1) Dry granulation: Use a three-dimensional mixer to mix the solid dispersion containing compound 1 with a glidant, lubricant, disintegrant, surfactant, and filler, and then use a dry granulator to form granules. Specifically, the solid dispersion containing compound 1 is mixed with colloidal silicon dioxide, cross-linked sodium carboxymethyl cellulose, sodium lauryl sulfate, mannitol, and microcrystalline cellulose at a mixing speed of 15 rpm for 20 minutes. Use a dry granulator at 40-45 kg / cm 2 Under the main pressure of , the material is pressed into large pieces, and then the crushed large pieces are sieved through a 20-mesh screen to make granules.

[0152] (2) Total mixing: The dry granulated granules are mixed with colloidal silicon dioxide and magnesium stearate.

[0153] (3) Tabletting: Use a rotary tablet press to press the mixed material into tablets, wherein the hardness of the tablets is controlled to be between 40N and 150N, the weight difference of the tablets is controlled to not exceed ±3% of the theoretical weight, and no broken, cracked or crushed tablets are detected.

[0154] (4) Packaging: Medicinal high-density polyethylene bottles or aluminum-aluminum blisters can be used for packaging as needed.

[0155] Example 1. Solubility test of compound 1

[0156] The inventors tested the solubility of Compound 1 (API) in various commonly used media. The results are shown in Table 1.

[0157] Table 1 Solubility of compound 1 in different solvents (25°C)

[0158] The results showed that the solubility of compound 1 in different pH media was significantly pH-dependent, with higher solubility in acidic environments and almost insoluble in neutral and alkaline environments and water. Among the commonly used solvents for spray drying to prepare solid dispersions, acetone has a high solubility for compound 1.

[0159] Example 2: Testing of polymer solubility

[0160] To prepare a solid dispersion using the spray drying method, the polymer and compound 1 must first be completely dissolved in an appropriate solvent before proceeding with subsequent operations. Therefore, the inventors also tested the solubility of common polymers in low-boiling-point solvents. The results are shown in Table 2.

[0161] Table 2 Solubility of polymers in different solvents (25°C) S means the solubility is greater than 5%; I means the solubility is less than 1%; PS means the solubility is between 1% and 5%

[0162] Example 3: Investigation of the solubilization ability of polymers on compound 1

[0163] Based on the solubility test results of Compound 1 and the polymer in Example 1 and Example 2, methanol was selected to dissolve the polymer, and acetone was selected to dissolve Compound 1. The two solutions were mixed and then micro-rotary evaporation was used to prepare solid dispersion samples of Compound 1 and different polymers. The solubility of the samples in pH 6.8 phosphate buffer was tested. The results are shown in Table 3.

[0164] Table 3 Investigation of the solubilization ability of polymers on compound 1 (37°C)

[0165] The above results show that all the polymers examined effectively increased the solubility of compound 1 in pH 6.8 phosphate buffer, and all the polymers effectively maintained the supersaturated state of compound 1 in the medium.

[0166] Relatively speaking, different types of polymers exhibited different solubilization properties for Compound 1. Enteric-coated materials HPMCP HP55 and HPMCAS LF exhibited similar solubilization properties: an increase in polymer ratio inhibited the solubility of Compound 1 under initial conditions, but the solubility gradually increased with prolonged dissolution time. PVP K30, on the other hand, exhibited higher solubility for Compound 1 under initial conditions, but this gradually decreased over time. After Kollidon VA64 and HPMC E5 solubilized Compound 1, the solubility remained relatively stable over time.

[0167] Regarding the effect of the ratio of polymer to compound 1 on the solubilization effect, the above results show that, except for the increase in the amount of enteric materials HPMCP HP55 and HPMCAS LF to 1:10, which leads to a decrease in the solubility of compound 1 under initial conditions, there is no obvious difference in the solubility of compound 1 when the ratio of other polymers is within the range of 1:2 to 1:10.

[0168] In general, Kollidon VA64 has a good solubilization effect on compound 1 and ability to maintain supersaturation.

[0169] Example 4: Investigation of the Solubilization Ability of Compound 1 by Surfactants

[0170] Under the same conditions, a small amount of water or methanol was used to dissolve the surfactant, which was then added to the mixed solution of compound 1 and the polymer shown in Example 3. The micro-rotary evaporation method was also used to prepare a solid dispersion sample of compound 1 + polymer + surfactant. The solubility of the sample in pH 6.8 phosphate buffer was tested, and the results are shown in Table 4.

[0171] Table 4 Investigation of the solubilization ability of compound 1 by surfactant type (37°C)

[0172] Comparing the above results, it can be seen that under the same conditions, sodium dodecyl sulfate (SDS) has a clear solubilizing ability for compound 1, can very effectively increase the solubility of compound 1, and can maintain its supersaturated state for a long time.

[0173] Based on the above results, we further investigated the effect of SDS ratio on the solubilization ability of compound 1. The results are shown in Table 5.

[0174] Table 5 Investigation of the effect of surfactant ratio on the solubilization ability of compound 1 (37°C)

[0175] From the results in Table 5, it can be seen that the addition of SDS to the solid dispersion of compound 1 can effectively increase the solubility of the compound, and under appropriate circumstances, the amount of SDS in the formulation should be increased.

[0176] Based on the above results, we further investigated the effect of SDS addition method on the solubilization ability of compound 1. The results are shown in Table 6.

[0177] Table 6 Investigation of the solubilization ability of compound 1 by surfactant addition method (37°C)

[0178] The results showed that at the same SDS dosage ratio, the direct powder mixing process was also beneficial for the solubilization of compound 1.

[0179] Example 5: Effect of Dosage Form on In Vivo Exposure of Compound 1

[0180] Pharmacokinetic (PK) testing was conducted using three formulations: ordinary tablets containing micronized Compound 1 directly mixed and compressed (particle size controlled to be D90 ≤ 5 μm) (Table 7), ordinary tablets containing a solid dispersion of Compound 1 (Table 8), and enteric-coated tablets containing a solid dispersion of Compound 1 (Table 9).

[0181] The PK testing method involved administering a single oral dose of 50 mg of the formulation to beagle dogs aged 1-3 years. Blood samples were collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration to measure the concentration of Compound 1 in the blood. The effects of Compound 1 on the blood concentration were plotted against time to evaluate its effects in the beagle dogs.

[0182] Table 7 PK test formula composition of compound 1 (common tablets containing compound 1)

[0183] Table 8 PK test formula composition of compound 1 (common tablets containing compound 1 solid dispersion)

[0184] Table 9 PK test formula composition of compound 1 (enteric-coated tablets containing compound 1 solid dispersion)

[0185] In Formulations 2 and 3 above, acetone was used to dissolve copovidone and Compound 1. The dissolved material was spray-dried at an inlet air temperature of 100°C and an outlet air temperature of 50°C to prepare a solid dispersion of Compound 1 and copovidone. This solid dispersion was then mixed with other excipients and pressed into tablets. Formulation 1 directly mixed Compound 1 with all the excipients and pressed into tablets.

[0186] The PK results of the pharmaceutical composition containing compound 1 in beagle dogs are shown in Figure 1. The results show that the peak concentration (Cmax) of compound 1 in formula 2 and formula 3 prepared using solid dispersion technology is significantly higher than that of formula 1 containing micronized compound 1 directly physically mixed. This shows that solid dispersion technology effectively increases the in vivo exposure of compound 1 and makes it easier for compound 1 to reach the concentration required for its treatment of diseases. For formula 2 and formula 3, the Cmax of formula 2 is significantly higher than that of formula 1 containing micronized compound 1 directly physically mixed. max Greater and peak time (t max ) is shorter, which allows the product to take effect earlier after administration.

[0187] In summary, the formulations prepared with copolyvidone VA64 showed a smaller t max and a larger C max This will be more conducive to the therapeutic effect of the product.

[0188] The dissolution curves of the three formulations were tested, and the results are shown in Figure 2. It can be seen that the dissolution of the three formulations showed a relatively consistent trend with the PK test results in beagle dogs. In the dissolution curve, formulation 2 also showed a faster dissolution rate and reached the dissolution platform faster.

[0189] Example 6: Screening of fillers

[0190] The effects of different proportions of filler dosage on product dissolution and stability were investigated.

[0191] Preparation process:

[0192] (1) Preparation of solid dispersion samples: Compound 1 and copolyvidone VA64 were dissolved in acetone, and the dissolved materials were spray-dried at an inlet air temperature of 100°C and an outlet air temperature of 50°C to prepare a solid dispersion.

[0193] (2) Dry granulation: The solid dispersion containing compound 1 was mixed with colloidal silicon dioxide, cross-linked sodium carboxymethyl cellulose, sodium lauryl sulfate, mannitol, and microcrystalline cellulose at a mixing speed of 15 rpm for 20 min. A dry granulator was used at 40-45 kg / cm 2 Under the main pressure of , the material is pressed into large pieces, and then the crushed large pieces are sieved through a 20-mesh screen to make granules.

[0194] (3) Total mixing: The dry granulated granules are mixed with colloidal silicon dioxide and magnesium stearate.

[0195] (4) Tabletting: Use a rotary tablet press to press the mixed material into tablets, wherein the hardness of the tablets is controlled to be between 40N and 150N, the weight difference of the tablets is controlled to be no more than ±3% of the theoretical weight, and no broken, cracked or crushed tablets are detected.

[0196] The screening formula design of fillers is shown in Table 10.

[0197] Table 10 Formulation design for filler screening "Adding inside the granules" means adding during the dry granulation step (2); "adding outside the granules" means adding during the total mixing step (3). The same applies below.

[0198] The stability test results of the above prescription under accelerated conditions are shown in Table 11 below

[0199] Table 11 Effect of fillers on the stability of compound 1 formulation

[0200] Comparing the above results, it can be seen that when the total dosage of mannitol and microcrystalline cellulose is within the range of 0%-86%, as shown in Figure 3, the formulation can achieve dissolution of more than 80% within 90 minutes and complete dissolution within 120 minutes. Relatively speaking, when mannitol and microcrystalline cellulose are used simultaneously and their dosages are maintained at the same level, the dissolution of the formulation shows a trend of faster dissolution.

[0201] Example 7: Screening of glidants

[0202] The effects of silicon dioxide dosage and addition method on product formulation process and dissolution were investigated.

[0203] First, the effect of silicon dioxide on the dry granulation process was investigated: silicon dioxide was added or not added during the dry granulation process (as shown in Table 12) to examine the feasibility of the process. The process was the same as that of Example 6, and the results are shown in Table 13.

[0204] Table 12 Effect of the method of adding glidants on the formulation design

[0205] Table 13 Effect of glidant addition method on dry granulation (dry granulation)

[0206] The above results indicate that removing the silicon dioxide from the granules reduces material fluidity during dry granulation, leading to increased sticking to the rollers and reduced feasibility of continuous production. Therefore, the role of internal flow aids is clear to ensure ease of industrial production.

[0207] The above granules were continued to be used for tableting process to investigate the effect of adding the glidant. The results are shown in Table 14.

[0208] Table 14 Effect of glidant addition method on dry granulation (tablet compression)

[0209] From the above results, it can be seen that adding silicon dioxide to the particles is also beneficial to increasing the fluidity of the particles and ensuring the smooth implementation of continuous production.

[0210] The effect of the addition method of the glidant on the dissolution of the preparation is shown in Figure 4. It can be seen that different addition methods of the glidant have no obvious effect on the dissolution of the preparation.

[0211] The effect of the amount of glidant on the formulation process and dissolution was further investigated, as shown in Tables 15 and 16.

[0212] Table 15 Effect of the amount of glidant on the formulation design

[0213] Table 16 Investigation of the effect of flow aid dosage on the formulation process

[0214] The above results show that the dosage of the glidant is within the range of 0.3%-10%, which does not significantly affect the preparation process.

[0215] The effect of glidant dosage on the dissolution of the preparation is shown in Figure 5. It can be seen that within the range of 0.3%-10%, the glidant dosage does not significantly affect the dissolution behavior of the preparation.

[0216] Example 8: Lubricant screening

[0217] The effects of lubricant dosage and addition method on product formulation process and dissolution were investigated.

[0218] First, the effect of lubricant on the dry granulation process was investigated: magnesium stearate was added or not added during the dry granulation process to examine the feasibility of the process. The process was the same as that of Example 6, as shown in Tables 17 and 18.

[0219] Table 17 Effect of lubricant addition method on formulation design

[0220] Table 18 Investigation of the influence of lubricant dosage on the formulation process

[0221] During the preparation production process, it was found that the feasibility of the preparation process was poor when lubricants were added to either the dry granulation or tableting process alone. However, after lubricants were added to both processes, the process feasibility of the samples was good.

[0222] The effect of lubricant dosage on the dissolution of the preparation was further investigated using the formulation design in Table 19.

[0223] Table 19 Effect of lubricant dosage on formulation design

[0224] Figure 6 shows the effect of lubricant dosage on dissolution. Within the range of 0.05% to 2%, the dissolution rate decreases with increasing lubricant dosage. Therefore, the glidant dosage should be controlled within this range to avoid over-lubrication, which could affect the quality of the formulation.

[0225] Example 9: Screening of disintegrants

[0226] The formulation design shown in Table 20 was used to investigate the effect of different disintegrant dosages on compound dissolution.

[0227] The preparation process is the same as that shown in Example 6.

[0228] Table 20 Formulation design for disintegrant screening

[0229] The effects of different disintegrant dosages on the dissolution profile of Compound 1 are shown in Figure 7. It can be seen that when the disintegrant dosage is low (≤5%), the dissolution rate of the preparation is slow. When the disintegrant dosage is high (≥15%), the dissolution rate of the preparation does not continue to increase with the increase in disintegrant dosage.

[0230] Example 10: Study of surfactants in complete formulations

[0231] The effect of sodium dodecyl sulfate (SDS) on product dissolution was investigated in the complete formulation using the formulation design shown in Table 21. The formulation process was the same as that shown in Example 6.

[0232] Table 21 Prescription design of surfactant investigation

[0233] *Solid dispersion does not contain surfactant SDS. Solid dispersion is prepared with surfactant SDS and other excipients to prepare tablets.

[0234] The effect of the surfactant SDS on the dissolution of Compound 1 is shown in Figure 8. As can be seen, the dissolution rate of Compound 1 gradually increases with increasing SDS dosage, until the SDS dosage reaches 5%, at which point the rate of increase slows. Therefore, while ensuring clinical safety, the SDS dosage should be appropriately increased to ensure faster dissolution of the product.

[0235] Example 11: Screening of Preparation Hardness

[0236] Using the formulation design in Table 22, tablet hardness, a key formulation quality attribute, was also investigated during the formulation and process studies.

[0237] Table 22 Prescription design for preparation hardness investigation

[0238] The effect of product hardness on the dissolution of compound 1 is shown in Figure 9. It can be seen that within the investigation range of 40-150N, the dissolution of the preparation is less affected by the hardness.

[0239] Example 12: Study on formulation specifications

[0240] The prescription composition of the present invention mainly includes two parts, one part is a solid dispersion containing compound 1, and the other part is an excipient without active ingredients. Therefore, when determining the product dosage form and specifications, the solid dispersion can be directly prepared into a separate product such as a powder, granules, capsules, tablets, etc. using an appropriate process. It is also possible to add other excipients to the solid dispersion and then prepare it into the corresponding dosage form. Therefore, the specifications of this product can be flexibly set. The following Tables 23 and 24 list the prescription compositions of several specifications of products, and the preparation process is the same as that of Example 6. In view of the similarity of the prescription compositions of all samples, some samples were selected for stability testing. The results are shown in Table 25.

[0241] Table 23 Example of selection of dosage form strength (1)

[0242] Table 24 Example of selection of dosage form strength (2)

[0243] Table 25 Stability test results of the preparation

[0244] The above results show that there is no significant difference in the stability of products with different strengths. The formulation strength can be reasonably selected according to clinical treatment needs.

[0245] Example 13: Study on the Effect of Coating on Formulations

[0246] The products of this invention can be coated as needed. The coating material can be either a non-functional, standard film coating material to enhance identification and differentiate product specifications, or a coating material with specific functions, such as using a functional coating material to impart targeted, timed, or rate-release properties. Coating can also enhance tablet stability, such as reducing the effects of light, moisture, and other factors on the tablet core.

[0247] Using the formulation design in Table 26, the effects of coating on product dissolution and stability were tested using film coating and enteric coating, respectively.

[0248] The preparation process of the tablet core is the same as the preparation process shown in Example 6.

[0249] The coating process involves preparing a coating solution with 10% solids content using purified water and coating the core tablets until the average coating weight gain reaches the theoretical weight. After coating, the product moisture content should be controlled to no more than 5%.

[0250] Table 26 Effect of coating on formulation design

[0251] The stability results are shown in Table 27.

[0252] Table 27 Effect of coating on formulation stability

[0253] The effect of coating on product dissolution is shown in Figure 10.

[0254] From the above results, it can be seen that the coating has no significant effect on the stability and dissolution of the product.

[0255] Example 14: Effect of Solid Dispersion Preparation Process on Products

[0256] Solid dispersions containing compound 1 were prepared by spray drying and hot melt extrusion processes, respectively, and the differences between the solid dispersions obtained by the two processes were tested.

[0257] The spray drying process is the same as the preparation process shown in Example 6.

[0258] The hot melt extrusion process is as follows:

[0259] Compound 1 and copovidone VA64 were mixed in a weight ratio of 1:9. The mixture was melt-extruded at 180°C using a twin-screw hot-melt extruder (e.g., a Pharma 11 twin-screw extruder). The mixture was cooled and pulverized to a size of less than 40 mesh. The mixture was then mixed with the remaining material and granulated according to the dry granulation process described in Example 6. The resulting mixture was then prepared into tablets according to the subsequent process.

[0260] The formulations of the products prepared by the two processes are shown in Table 28 below.

[0261] Table 28 Prescription composition of process investigation samples

[0262] Table 29 Effect of process on the solubility of solid dispersion compound 1

[0263] Table 30 Effect of process on formulation stability

[0264] The solubility and stability results are shown in Tables 29 and 30. From the above results, it can be seen that both hot melt extrusion and spray drying processes are suitable for the preparation of compound 1 solid dispersion.

[0265] Example 15: Composition study of different dosage forms

[0266] As previously mentioned, the tableting process of Compound 1 produces multiple intermediates. These intermediates can be processed through appropriate processes to create new dosage forms to meet the needs of different patient groups and indications. The following describes the composition of various products.

[0267] Using the formulation in Table 31, a solid dispersion containing Compound 1 was prepared using the spray drying process described in Example 6. The following excipients were added to the solid dispersion, mixed thoroughly, and packaged in a double-layer aluminum-plastic composite film bag (to reduce the effect of humidity on the product) to obtain a powder for patient use.

[0268] Table 31 Powder prescription composition

[0269] A solid dispersion containing Compound 1 was prepared using the formulation in Table 32 using the spray drying process described in Example 6. The solid dispersion was mixed with the following excipients, including a suspending agent, and packaged in a double-layer aluminum-plastic composite film bag (to reduce the effects of humidity on the product) to produce a dry suspension suitable for patient use.

[0270] Table 32 Dry suspension formulation composition

[0271] Using the formulation in Table 33, a solid dispersion containing Compound 1 was prepared using the spray drying process described in Example 6. The solid dispersion was uniformly mixed with the following excipients, and granules were prepared using the dry granulation process described in Example 6. The granules were then packaged into double-layer aluminum-plastic composite film bags (to reduce the effects of humidity on the product) to produce granules suitable for patient use.

[0272] Table 33 Granules prescription composition

[0273] A solid dispersion containing Compound 1 was prepared using the formulation in Table 34 using the spray drying process described in Example 6. The solid dispersion was uniformly mixed with the following excipients and granules were prepared using the dry granulation process described in Example 6. The granules were then encapsulated into capsule shells to form capsules. The capsules can also be packaged in double aluminum blisters (to reduce the effects of humidity on the product) for easier use and storage.

[0274] Table 34 Capsule prescription composition

[0275] Professionals and technicians in this field can also continue to research and develop the preparation of Compound 1 according to the method shown in the present invention. These research and development are carried out based on the existing professional knowledge in this field and therefore will also fall within the scope of protection of this application.

[0276] Example 16: Study on the stability of the formulation

[0277] The formulation composition of Table 35 was used, and the preparation process was the same as in Example 6. The stability of the formulation of the present invention was tested under accelerated conditions, with test items including dissolution, related substances, and crystal form. The results are shown in Table 36.

[0278] Table 35 Prescription composition of stability test samples

[0279] Table 36 Test results of stability samples

[0280] The dissolution curve comparison of the stability test products is shown in Figure 11, and the crystal form test (XRD diffraction pattern) results are shown in Figure 12.

[0281] From the above results, it can be seen that the pharmaceutical composition containing compound 1 shown in the present invention has good stability. This property provides a good basis for the use of such pharmaceutical compositions for the prevention and treatment of diseases, etc., and ensures a good market application prospect for the product.

[0282] The present application has been described above in conjunction with preferred embodiments, but these embodiments are merely exemplary and serve only as an illustrative example. On this basis, various replacements and improvements can be made to the present application, all of which fall within the scope of protection of the present application.

Claims

1. A solid dispersion, comprising: Active ingredient, which is 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl]azetidin-3-yl]acetonitrile with the following structural formula or a pharmaceutically acceptable salt thereof a pharmaceutically acceptable polymeric carrier, and a surfactant; Among them, The surfactant is selected from sodium dodecyl sulfate, polyethylene glycol vitamin E succinate, poloxamer, polyethylene glycol 15-hydroxystearate, sodium stearyl fumarate, sodium dioctyl sulfosuccinate, cetrimonium bromide, benzethonium chloride, cetylpyridinium chloride, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester; polyoxyethylene castor oil derivative, polyoxyethylene stearate, poloxamer, polysorbate series, sorbitan fatty acid ester; the surfactant is preferably sodium dodecyl sulfate.

2. The solid dispersion according to claim 1, wherein The polymeric carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), polymethacrylate, hydroxypropyl cellulose (HPC) and cellulose acetate phthalate (CAP); preferably, the polymeric carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC); more preferably, the polymeric carrier is copovidone.

3. The solid dispersion according to claim 1, wherein, The weight ratio of the active ingredient to the polymeric carrier is from 1:1 to 1:20, preferably from 1:2 to 1:10; the weight ratio of the active ingredient to the surfactant is from 1:0.001 to 1:0.

5.

4. A pharmaceutical composition, comprising: Active ingredient, which is 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl]azetidin-3-yl]acetonitrile with the following structural formula or a pharmaceutically acceptable salt thereof a pharmaceutically acceptable polymeric carrier, a surfactant; and other pharmaceutically acceptable excipients; Among them, The surfactant is selected from sodium dodecyl sulfate, polyethylene glycol vitamin E succinate, poloxamer, polyethylene glycol 15-hydroxystearate, sodium stearyl fumarate, sodium dioctyl sulfosuccinate, cetrimonium bromide, benzethonium chloride, cetylpyridinium chloride, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester; polyoxyethylene castor oil derivative, polyoxyethylene stearate, poloxamer, polysorbate series, sorbitan fatty acid ester; the surfactant is preferably sodium dodecyl sulfate; wherein the active ingredient, the polymeric carrier and optionally at least a portion of the surfactant are present in the form of a solid dispersion.

5. The pharmaceutical composition according to claim 4, wherein, The polymeric carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), polymethacrylate, hydroxypropyl cellulose (HPC) and cellulose acetate phthalate (CAP); preferably, the polymeric carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC); more preferably, the polymeric carrier is copovidone.

6. The pharmaceutical composition according to claim 4, wherein, In the solid dispersion, the weight ratio of the active ingredient to the polymer carrier is 1:1 to 1:20, preferably 1:2 to 1:10; the weight ratio of the active ingredient to the surfactant is 1:0.001 to 1:0.

5.

7. The pharmaceutical composition according to claim 4, wherein, Based on the total weight of the pharmaceutical composition, the active ingredient accounts for 0.1 wt% to 30 wt%; the polymer carrier accounts for 1.0 wt% to 90.0 wt%; the surfactant accounts for 0.1 wt% to 10.0 wt%; the total weight of other pharmaceutically acceptable excipients accounts for 10 wt% to 98 wt%.

8. The pharmaceutical composition according to claim 4, wherein The other pharmaceutically acceptable excipients include one or more of fillers, disintegrants, glidants, lubricants, and binders.

9. The pharmaceutical composition according to claim 8, wherein, The fillers are selected from one or more of lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, cellulose derivatives (such as microcrystalline cellulose, cellulose), and xylitol; preferably, the fillers are selected from one or more of microcrystalline cellulose, mannitol, sorbitol, and lactose.

10. The pharmaceutical composition according to claim 9, wherein, The filler is microcrystalline cellulose or mannitol, or a combination of microcrystalline cellulose and mannitol; when present, the amount of microcrystalline cellulose is 0 wt% to 99.0 wt%, based on the total weight of the pharmaceutical composition; and / or when present, the amount of mannitol is 0 wt% to 99.0 wt%, based on the total weight of the pharmaceutical composition.

11. The pharmaceutical composition according to claim 8, wherein, The disintegrants are selected from one or more of sodium croscarmellose, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hypromellose, and hydroxypropyl cellulose; preferably, the disintegrants are selected from one or more of sodium croscarmellose, crospovidone, polyvinylpyrrolidone, and microcrystalline cellulose.

12. The pharmaceutical composition according to claim 8, wherein, The disintegrant is sodium croscarmellose; when present, the amount of sodium croscarmellose is 0.5 wt% to 20.0 wt%, based on the total weight of the pharmaceutical composition.

13. The pharmaceutical composition according to claim 8, wherein, The glidants are selected from one or two of silica and talc powder; preferably, the glidant is silica; when present, the amount of silica is 0.1 wt% to 10.0 wt%, based on the total weight of the pharmaceutical composition.

14. The pharmaceutical composition according to claim 8, wherein, The lubricants are selected from one or more of magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol, and talc powder; preferably, the lubricants are selected from one or two of magnesium stearate and sodium stearyl fumarate.

15. The pharmaceutical composition according to claim 8, wherein, The lubricant is magnesium stearate; when present, the amount of magnesium stearate is 0.05 wt% to 2.0 wt%, based on the total weight of the pharmaceutical composition.

16. The pharmaceutical composition according to claim 4, wherein, The pharmaceutical composition contains the following components based on the total weight of the pharmaceutical composition: 0.1 wt% to 30.0 wt% of the active ingredient; 1.0 wt% to 90.0 wt% of copovidone; 0 wt% to 99.0 wt% of mannitol; 0 wt% to 99.0 wt% of microcrystalline cellulose; 0.5 wt% to 20.0 wt% of sodium croscarmellose; Sodium dodecyl sulfate of 0.1 wt% to 10.0 wt%; Silica of 0.1 wt% to 10.0 wt%; Magnesium stearate of 0.05 wt% to 2.0 wt%; Wherein, the active ingredient, copovidone and optionally at least a part of the sodium dodecyl sulfate exist in the form of a solid dispersion.

17. The pharmaceutical composition according to any one of claims 4-16, wherein, The solid dispersion is prepared by a spray drying or hot melt extrusion process; preferably, the solid dispersion is prepared by a spray drying process.

18. The pharmaceutical composition according to any one of claims 4-16, wherein, The pharmaceutical composition is an oral solid preparation, including tablets, granules, powders, dry suspensions or capsules.

19. The pharmaceutical composition according to any one of claims 4-16, wherein, The pharmaceutical composition is a tablet.