WO2025140579A1 - Pharmaceutical composition - Google Patents

Abstract

The present application relates to a pharmaceutical composition, comprising an active ingredient compound 1, a pharmaceutically acceptable polymer carrier, a surfactant and other pharmaceutically acceptable excipients, wherein the active ingredient, the polymer carrier and optionally at least a portion of the surfactant are present in the form of a solid dispersion. Disclosed in the present application is the pharmaceutical composition containing the compound 1 for the first time. The composition has stable product quality and good bioavailability. On the basis of the characteristic that the compound 1 is a JAK inhibitor, the composition has wide application prospects for alopecia areata, vitiligo, atopic dermatitis, psoriasis, membranous nephropathy, ankylosing spondylitis, peripheral T cell lymphoma, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, etc.

Description

A pharmaceutical composition Technical Field

The present invention belongs to the field of pharmaceutical technology, and in particular 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

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 ("Compound 1" below) is a JAK inhibitor having the following structural formula:

Compound 1 has low solubility in aqueous media (i.e., less than 1 mg/mL in water at 25°C), poor permeability, and low oral bioavailability. In order to improve its bioavailability and drugability, many solubilization techniques have been tried, such as micronization of raw materials, salt formation or crystal form research, microemulsion/self-microemulsion, surfactant solubilization, cyclodextrin inclusion, solid dispersion, and co-crystal. The art needs a pharmaceutical composition with high bioavailability of the compound.

Summary of the invention

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

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

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

a pharmaceutically acceptable polymer carrier, and a surfactant;

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.

The present application also provides a pharmaceutical composition comprising:

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

a pharmaceutically acceptable polymer carrier,

Surfactants; and

Other pharmaceutically acceptable excipients;

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;

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

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.

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.

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

The active ingredient accounts for 0.1wt% to 30wt%;

The polymer carrier accounts for 1.0wt% to 90.0wt%;

The surfactant accounts for 0.1wt% to 10.0wt%;

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

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

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.

In one embodiment, 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.

In one embodiment, the disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, polyvinyl pyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hypromellose and hydroxypropyl cellulose; preferably, the disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, polyvinyl pyrrolidone and microcrystalline cellulose;

In one embodiment, the disintegrant is croscarmellose sodium;

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

In one embodiment, the glidant is selected from one or both of silicon dioxide and talc, preferably, the glidant is silicon dioxide;

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

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 two of magnesium stearate and sodium stearyl fumarate.

In one embodiment, 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.

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

0.1 wt% to 30.0 wt% of active ingredient;

1.0wt% to 90.0wt% of copolyvidone;

0wt% to 99.0wt% of mannitol;

0wt% to 99.0wt% of microcrystalline cellulose;

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

0.1wt% to 10.0wt% of sodium lauryl sulfate;

0.1 wt% to 10.0 wt% of silicon dioxide;

0.05wt% to 2.0wt% of magnesium stearate;

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

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

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

In one embodiment, the pharmaceutical composition is a tablet.

The present 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

FIG1 shows the effect of dosage form on the pharmacokinetics of Compound 1;

FIG2 shows the dissolution comparison of compound 1 in different types of formulations;

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

FIG4 shows the effect of the glidant addition method on the dissolution of compound 1;

FIG5 shows the effect of the amount of glidant on the dissolution of compound 1;

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

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

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

FIG9 shows the effect of product hardness on the dissolution of compound 1;

FIG10 shows the effect of coating on the dissolution of Compound 1;

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

FIG. 12 shows the results of the stability test of the crystalline form of Compound 1.

DETAILED DESCRIPTION

The present application is further described in detail below through the accompanying drawings and embodiments. Through these descriptions, the characteristics and advantages of the present application will become clearer and more specific.

The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, 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 noted.

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.

The term "solid dispersion" as used herein refers to a system formed by the active ingredient being 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 in independent molecules. In terms of the entire drug-excipient complex, a solid dispersion may be a relatively large solid substance, such as a pellet, tablet, film or strand; or they may exist as a free-flowing powder 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.

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. Traditional methods for preparing solid dispersions include melting methods and solvent methods. In recent years, hot melt extrusion (melting method) as a new method for preparing solid dispersions has attracted much attention from pharmaceutical researchers at home and abroad. This method realizes the transfer, shear mixing and melt extrusion of materials in a single-screw or twin-screw extruder that is heated in stages. Compared with traditional preparation methods, hot melt extrusion has the characteristics of high production efficiency, no need for organic solvents, and is suitable for industrial production. However, for drugs and carriers with higher melting points, melting methods and hot melt extrusion methods easily lead to thermal decomposition of drugs and carriers, thereby limiting the wide application of this method. Spray drying (solvent method) is to dissolve the drug and carrier material in an organic solvent, and then remove the organic solvent to obtain a uniformly dispersed dispersion. Compared with hot melt extrusion, spray drying is more suitable for drugs with poor thermal stability, with a short development cycle and conducive to batch expansion.

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

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

a pharmaceutically acceptable polymer carrier, and

Surfactants;

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.

Compound 1 is a JAK inhibitor that can be used to treat and prevent a variety of 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. It is disclosed in CN109867676B, the entire contents of which are incorporated into this application as a reference.

As shown in Example 1 below, in different pH media, the solubility of compound 1 has obvious pH dependence, with higher solubility in acidic environments and almost insoluble in neutral, alkaline environments and water. Among the commonly used solvents for preparing solid dispersions by spray drying, acetone has a higher solubility for compound 1.

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.

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.

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, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (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, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC) One or more. In one embodiment, in the solid dispersion, the weight ratio of the active ingredient: the polymer carrier is 1: 1 to 1: 20, for example, 1: 1 to 1: 15, preferably 1: 2 to 1: 10.

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.

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, trimethyl ammonium bromide, benzathonium 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 inventor of the present application unexpectedly found that, compared with different surfactants, SDS has a very clear solubilizing ability for compound 1, can be very effective to increase the solubility of compound 1, and can maintain its supersaturated state for a long time. In one embodiment, the weight ratio of the active ingredient: 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.

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 pharmaceutical compositions in combination with other excipients such as fillers, disintegrants, glidants, lubricants and adhesives, the components of the solid dispersion, especially the active ingredient and the polymer carrier, are simply mixed with these other excipients to prepare the pharmaceutical composition, and the effect of solubilization cannot be achieved. It is necessary to first make the active ingredient and the polymer carrier into a solid dispersion, and then combine with other excipients such as fillers, disintegrants, glidants, lubricants and adhesives to prepare the pharmaceutical composition, so that the effects of solubilization can be well achieved.

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 solvents 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 solid dispersion sample comprising compound 1 and a polymer is prepared using a spray dryer. Based on the solubility of compound 1 and the polymer carrier in different solvents, acetone can be used as a solvent.

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.

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

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

a pharmaceutically acceptable polymer carrier,

Surfactants; and

Other pharmaceutically acceptable excipients;

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;

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

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.

For 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 the present application have found that the surfactant can also be very effective in increasing the solubility of compound 1 by adopting the latter method, and can maintain its supersaturated state for a long time. Of course, when preparing the pharmaceutical composition, a part of the surfactant can also be first prepared as a solid dispersion together with the active ingredient and the polymer carrier, and then another part of the surfactant can be combined with the solid dispersion together with other excipients, which is also within the scope of protection of the present application. The ratio of these two parts of the surfactant can be selected as needed, and the surfactant first prepared as a solid dispersion together with the active ingredient and the polymer carrier can account for 0wt%-100wt% of the total surfactant dosage, for example, 30wt%-100wt%, or 60wt%-100wt%, or 70wt%-100wt%.

In the pharmaceutical composition, the selection of the polymer carrier and the ratio of the polymer carrier to the active ingredient can be referred to the aforementioned solid dispersion section of the present application, and the relevant description is also applicable to the pharmaceutical composition section of the present application, which will not be repeated here.

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

The active ingredient accounts for 0.1wt% to 30wt%;

The polymer carrier accounts for 1.0wt% to 90.0wt%;

The surfactant accounts for 0.1wt% to 10.0wt%.

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.

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

Other pharmaceutically acceptable excipients may be various excipients commonly used in drugs, such as one or more of fillers, disintegrants, glidants, lubricants and binders, etc., and their total amount may be the sum of the amounts of other pharmaceutical excipients except polymer carriers and surfactants. For example, based on the total weight of the pharmaceutical composition, other pharmaceutically acceptable excipients account for 10wt% to 98wt%, for example, 12wt% to 98wt%.

The pharmaceutical composition of the present invention may contain 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, and one or a combination of these may be used. Preferably, microcrystalline cellulose, mannitol, sorbitol, lactose, or a combination of these may be used.

In one embodiment, the filler may be 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.

The filler in the present invention has the functions of both a binder and a partial disintegrant. During the research process, it was found that the combination of mannitol and microcrystalline cellulose can effectively improve the appearance of the particles during the dry granulation process, which is more conducive to the implementation of subsequent processes. And the combination of mannitol and microcrystalline cellulose in an appropriate proportion can improve and maintain the dissolution behavior of the product, especially in stability studies, this phenomenon will be more obvious. Preferably, the weight ratio of mannitol to microcrystalline cellulose is 1:0.25-4.

The pharmaceutical composition of the present invention may contain a disintegrant. In one embodiment, the disintegrant may be selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, and one or a combination of several thereof may be used. Preferably, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, and one or a combination of several thereof may be used.

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.

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

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.

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, and one or a combination thereof may be used. Preferably, magnesium stearate, sodium stearyl fumarate, one or a combination thereof may be used.

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.

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

0.1 wt% to 30.0 wt% of compound 1;

1.0wt% to 90.0wt% of copolyvidone;

0wt% to 90.0wt% of mannitol;

0wt% to 90.0wt% of microcrystalline cellulose;

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

0.1wt% to 10.0wt% of sodium lauryl sulfate;

0.1 wt% to 10.0 wt% of silicon dioxide;

0.05wt% to 2.0wt% magnesium stearate.

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:

0.1 wt% to 30.0 wt% of compound 1;

1.0wt% to 90.0wt% of copolyvidone;

0wt% to 99.0wt% of microcrystalline cellulose;

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

0.1wt% to 10.0wt% of sodium lauryl sulfate;

0.1 wt% to 10.0 wt% of silicon dioxide;

0.05wt% to 2.0wt% magnesium stearate.

and/or

0.1 wt% to 30.0 wt% of compound 1;

1.0wt% to 90.0wt% of copolyvidone;

0wt% to 99.0wt% of mannitol;

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

0.1wt% to 10.0wt% of sodium lauryl sulfate;

0.1 wt% to 10.0 wt% of silicon dioxide;

0.05wt% to 2.0wt% magnesium stearate.

and/or

0.1 wt% to 30.0 wt% of compound 1;

1.0wt% to 90.0wt% of copolyvidone;

0wt% to 99.0wt% of mannitol;

0wt% to 99.0wt% of microcrystalline cellulose;

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

0.1wt% to 10.0wt% of sodium lauryl sulfate;

0.1 wt% to 10.0 wt% of silicon dioxide;

0.05wt% to 2.0wt% magnesium stearate.

The pharmaceutical composition may optionally contain one or more colorants, fragrances, flavoring agents to enhance its visual appeal, change taste and smell, increase recognition, etc. These changes will not play a direct role in the therapeutic effect of the pharmaceutical composition.

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.

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

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 2020 edition of the Chinese Pharmacopoeia, which is 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 based on the theoretical content.

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.

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

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

(1) Dry granulation: Use a three-dimensional mixer to mix the solid dispersion containing compound 1 with a glidant, a lubricant, a disintegrant, a surfactant, and a 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 a main pressure of 40 to 45 kg/ ^cm2 to press the material into large pieces, and then use a 20-mesh screen to sieve the crushed large pieces to form granules.

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

(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 be no more than ±3% of the theoretical weight, and no broken, cracked or crushed tablets shall be detected.

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

Example 1. Test of the solubility of compound 1

The inventors tested the solubility of compound 1 (API) in different commonly used media. The results are shown in Table 1.

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

The results showed that the solubility of compound 1 in different pH media was significantly pH-dependent. It had a higher solubility in acidic environments and was almost insoluble in neutral, alkaline environments and water. Among the commonly used solvents for preparing solid dispersions by spray drying, acetone had a higher solubility for compound 1.

Example 2: Testing of polymer solubility

To prepare a solid dispersion using the spray drying method, it is necessary to first dissolve the polymer and compound 1 completely in an appropriate solvent before performing subsequent operations. Therefore, the inventors also tested the solubility of common polymers in low-boiling point solvents. The results are shown in Table 2.

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%

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

According to the test results of the solubility 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. After the two solutions were mixed, the solid dispersion samples of compound 1 and different polymers were prepared by micro-rotary evaporation. The solubility of the samples in pH 6.8 phosphate buffer was tested, and the results are shown in Table 3.

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

From the above results, it can be seen that all the polymers examined effectively increased the solubility of compound 1 in pH 6.8 phosphate buffer, and all polymers effectively maintained the supersaturated state of compound 1 in the medium.

Relatively speaking, different types of polymers have different properties for solubilizing compound 1. Enteric materials HPMCP HP55 and HPMCAS LF showed similar solubilization properties, that is, the increase in polymer ratio inhibited the solubility of compound 1 under initial conditions, and the solubility of compound 1 gradually increased with the extension of dissolution time. PVP K30 had a higher solubility of compound 1 under initial conditions, and the solubility of compound 1 gradually decreased with time. After Kollidon VA64 and HPMC E5 solubilized compound 1, the solubility was relatively stable at different times.

As for the effect of the ratio of polymer to compound 1 on the solubilization effect, it can be seen from the above results that, except for the increase in the dosage of enteric materials HPMCP HP55 and HPMCAS LF to 1:10, which will lead 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 dosage of other polymers is in the range of 1:2 to 1:10.

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

Example 4: Investigation of the solubilization ability of surfactant on compound 1

Under the same conditions, a small amount of water or methanol was used to dissolve the surfactant, and 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. The results are shown in Table 4.

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

By 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.

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

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

From the results in Table 5, it can be seen that adding 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.

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

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

The results showed that at the same proportion of SDS dosage, the process of direct powder mixing was also beneficial to the solubilization of compound 1.

Example 5: Effect of dosage form on in vivo exposure of compound 1

Pharmacokinetic (PK) tests were conducted using three preparations: 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).

The PK test method is: use 1-3 years old beagle dogs, take a single oral dose of 50 mg of the preparation, and collect blood at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after taking the medicine to test the concentration of compound 1 in the blood. Plot the time and blood drug concentration to evaluate the changes of compound 1 in beagle dogs.

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

Table 8 Prescription composition of PK test compound 1 (common tablets containing solid dispersion of compound 1)

Table 9 Prescription composition of PK test compound 1 (enteric-coated tablets containing solid dispersion of compound 1)

In the above prescriptions 2 and 3, acetone is selected to dissolve copolyvidone and compound 1, and the dissolved materials are spray-dried under the conditions of an inlet air temperature of 100°C and an outlet air temperature of 50°C to prepare a solid dispersion of compound 1 and copolyvidone; thereafter, the solid dispersion is mixed with other excipients and pressed into tablets. In prescription 1, compound 1 is directly mixed with all the excipients and pressed into tablets.

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 prescriptions 2 and 3 prepared by solid dispersion technology is significantly higher than that of prescription 1 containing micronized compound 1 directly physically mixed. This shows that solid dispersion technology effectively increases the in vivo exposure of compound 1, making it easier for compound 1 to reach the concentration required for treating diseases. For prescriptions 2 and 3, the _Cmax of the blood drug concentration of prescription 2 is larger and the peak time ( _tmax ) is shorter, which can make the product exert its efficacy earlier after administration.

In summary, the preparations prepared using copolyvidone VA64 showed a smaller t _max and a larger C _max , which will be more conducive to the therapeutic effect of the product.

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

Example 6: Screening of fillers

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

Preparation process:

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

(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. The material was pressed into large pieces using a dry granulator at a main pressure of 40 to 45 kg/ ^cm2 , and the crushed large pieces were sieved with a 20-mesh screen to form granules.

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

(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 shall be detected.

The screening prescription design of fillers is shown in Table 10.

Table 10 Formulation design for filler screening


"Adding inside the granules" means adding in the dry granulation step (2); "adding outside the granules" means adding in the total mixing step (3). The same applies below.

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

Table 11 Effect of fillers on the stability of compound 1 formulation

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

Example 7: Screening of glidants

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

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 investigate the feasibility of the process. The process was the same as the preparation process of Example 6, and the results were shown in Table 13.

Table 12 Effect of the addition method of glidant on formulation design

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

The above results show that after removing the silicon dioxide added to the granules, the material tends to stick to the rollers during the dry granulation process due to the decrease in material fluidity, resulting in a decrease in the feasibility of continuous production. Therefore, in order to ensure the ease of industrial production, the role of the internal flow aid is clear.

The above granules were continued to be used for tableting process to investigate the effect of the added flow aid. The results are shown in Table 14.

Table 14 Effect of glidant addition method on dry granulation (tablet pressing)

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.

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.

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

Table 15 Effect of the amount of glidant on the formulation design

Table 16 Investigation of the effect of flow aid dosage on the preparation process

The above results show that the dosage of the glidant in the range of 0.3%-10% does not significantly affect the process of the preparation.

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

Example 8: Lubricant screening

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

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

Table 17 Effect of lubricant addition method on formulation design

Table 18 Study on the effect of lubricant dosage on formulation process

During the preparation production process, it was found that adding lubricants alone to the dry granulation or tableting process did not improve the feasibility of the preparation process. However, after adding lubricants to both processes, the process feasibility of the samples was good.

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

Table 19 Effect of lubricant dosage on formulation design

The results of the investigation on the effect of lubricant dosage on the dissolution of the preparation are shown in Figure 6. It can be seen that within the range of 0.05%-2%, as the amount of lubricant increases, the dissolution rate of the preparation tends to decrease. Therefore, the amount of glidant should be controlled and should not exceed the above range to avoid the over-lubrication of the lubricant affecting the quality of the preparation.

Example 9: Screening of disintegrants

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

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

Table 20 Formulation design for disintegrant screening

The results of the effect of different disintegrant dosages on the dissolution curve of compound 1 are shown in Figure 7. It can be seen that when the dosage of disintegrant is small (≤5%), the dissolution rate of the preparation is slow. When the dosage of disintegrant is large (≥15%), the dissolution rate of the preparation will not continue to increase with the increase of disintegrant.

Example 10: Study on surfactants in complete formulation

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

Table 21 Prescription design of surfactant investigation

*Solid dispersion does not contain surfactant SDS. Solid dispersion is prepared into tablets together with surfactant SDS and other excipients.

The effect of surfactant SDS on the dissolution of compound 1 is shown in Figure 8. It can be seen that the dissolution rate of compound 1 gradually increases with the increase in the amount of SDS, until the amount of SDS reaches 5%, the growth rate of the dissolution rate decreases. Therefore, the amount of SDS should be appropriately increased under the condition of guaranteed clinical safety to ensure faster dissolution of the product.

Example 11: Screening of Preparation Hardness

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

Table 22 Prescription design for preparation hardness study

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.

Example 12: Study on formulation specifications

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 dosage form and specifications of the product, the solid dispersion can be directly prepared into a separate product, such as powder, granules, capsules, tablets, etc., by an appropriate process. It is also possible to add other excipients to the solid dispersion and then prepare it into a 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 to test the stability. The results are shown in Table 25.

Table 23 Example of selection of dosage form strength (1)

Table 24 Example of selection of dosage form strength (2)

Table 25 Stability test results of preparations

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

Example 13: Study on the Effect of Coating on Preparation

The product of the present invention can be coated as needed. The coating material can be a non-functional ordinary film coating material used to increase recognition and distinguish product specifications, etc.; it can also be a coating material with specific functions, such as using a functional coating material to make the product have the characteristics of fixed-point, fixed-time or fixed-speed release. Coating can also increase the stability of the tablet core, such as reducing the impact of light, moisture, etc. on the tablet core.

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.

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

The coating process is as follows: the coating powder is mixed with purified water to form a coating solution with a solid content of 10%, and the tablet core is coated until the average coating weight gain reaches the theoretical amount. After the coating is completed, the moisture content of the product should be controlled to be no higher than 5%.

Table 26 Effect of coating on formulation design

The stability results are shown in Table 27.

Table 27 Effect of coating on formulation stability

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

From the above results, it can be seen that the coating does not significantly affect the stability and dissolution of the product.

Example 14: Effect of solid dispersion preparation process on product

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.

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

The hot melt extrusion process is as follows:

Compound 1 and copolyvidone VA64 are mixed evenly at a weight ratio of 1:9, and the materials are melt-extruded at 180°C using a twin-screw hot melt extruder (such as Pharma 11 twin-screw extruder), cooled and crushed to less than 40 mesh. Then, the mixture is mixed evenly with the remaining materials, and granules are prepared according to the dry granulation process shown in Example 6, and the materials are prepared into tablets according to the subsequent process.

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

Table 28 Prescription composition of process investigation samples

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

Table 30 Effect of process on formulation stability

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.

Example 15: Composition study of different dosage forms

As mentioned above, compound 1 will produce multiple intermediate products in the process of being made into tablets, and these intermediate products can be made into a new dosage form through appropriate processes to meet the needs of different patient groups and different indications. The compositions of various products are studied below.

Using the prescription composition of Table 31, a solid dispersion containing Compound 1 was prepared using the spray drying process shown in Example 6. The following excipients were added to the solid dispersion, mixed evenly, and packed into a double-layer aluminum-plastic composite film bag (to reduce the effect of humidity on the product) to obtain a powder that can be used by patients.

Table 31 Powder prescription composition

Using the formulation composition of Table 32, a solid dispersion containing Compound 1 was prepared using the spray drying process shown in Example 6. The following excipients including a suspending agent were added to the solid dispersion, mixed evenly, and packed into a double-layer aluminum-plastic composite film bag (to reduce the effect of humidity on the product) to obtain a dry suspension that can be used by patients.

Table 32 Dry suspension formulation composition

Using the prescription composition of Table 33, a solid dispersion containing Compound 1 was prepared using the spray drying process shown in Example 6. The solid dispersion was evenly mixed with the following excipients, and granules were prepared using the dry granulation process shown in Example 6. The granules were packed into a double-layer aluminum-plastic composite film bag (to reduce the effect of humidity on the product), and the granules were ready for use by patients.

Table 33 Granules prescription composition

Using the prescription composition of Table 34, a solid dispersion containing Compound 1 was prepared using the spray drying process shown in Example 6. The solid dispersion was evenly mixed with the following excipients, and granules were prepared using the dry granulation process shown in Example 6. The granules were loaded into capsule shells to form capsules. The capsules can also be packaged in double aluminum blisters (to reduce the impact of humidity on the product) to facilitate patient use and storage.

Table 34 Capsule prescription composition

Professional and technical personnel 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.

Example 16: Study on the stability of the preparation

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

Table 35 Prescription composition of stability test samples

Table 36 Test results of stability samples

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

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 in the prevention and treatment of diseases, etc., and ensures a good market application prospect for the product.

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

Claims (19)

A solid dispersion comprising: 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
a pharmaceutically acceptable polymer carrier, and Surfactants; 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; the surfactant is preferably sodium lauryl sulfate. The solid dispersion according to claim 1, wherein 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), and hydroxypropyl methylcellulose (HPMC); more preferably, the polymer carrier is copovidone. The solid dispersion according to claim 1, wherein 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. A pharmaceutical composition comprising: 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
a pharmaceutically acceptable polymer carrier, Surfactants; and Other pharmaceutically acceptable excipients; 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; the surfactant is preferably sodium lauryl sulfate; The active ingredient, the polymer carrier and optionally at least a portion of the surfactant are present in the form of a solid dispersion. The pharmaceutical composition according to claim 4, wherein 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), and hydroxypropyl methylcellulose (HPMC); more preferably, the polymer carrier is copovidone. The pharmaceutical composition according to claim 4, wherein, 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; the weight ratio of the active ingredient: the surfactant is 1:0.001 to 1:0.5. The pharmaceutical composition according to claim 4, wherein, based on the total weight of the pharmaceutical composition, The active ingredient accounts for 0.1wt% to 30wt%; The polymer carrier accounts for 1.0wt% to 90.0wt%; The surfactant accounts for 0.1wt% to 10.0wt%; The total weight of other pharmaceutically acceptable excipients accounts for 10 wt% to 98 wt%. The pharmaceutical composition according to claim 4, wherein other pharmaceutically acceptable excipients include one or more of a filler, a disintegrant, a glidant, a lubricant and a binder. The pharmaceutical composition according to claim 8, wherein 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. 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. The pharmaceutical composition according to claim 8, wherein the disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, polyvinyl pyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hypromellose and hydroxypropyl cellulose; preferably, the disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, polyvinyl pyrrolidone and microcrystalline cellulose. The pharmaceutical composition according to claim 8, wherein the disintegrant is cross-linked carboxymethyl cellulose sodium; When present, the amount of croscarmellose sodium is 0.5 wt% to 20.0 wt%, based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 8, wherein the glidant is selected from one or both of silicon dioxide and talc, preferably, the glidant is silicon dioxide; When present, the amount of silicon dioxide is 0.1 wt% to 10.0 wt%, based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 8, wherein 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. 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. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises the following components based on the total weight of the pharmaceutical composition: 0.1 wt% to 30.0 wt% of active ingredient; 1.0wt% to 90.0wt% of copolyvidone; 0wt% to 99.0wt% of mannitol; 0wt% to 99.0wt% of microcrystalline cellulose; 0.5wt% to 20.0wt% of cross-linked sodium carboxymethyl cellulose; 0.1wt% to 10.0wt% of sodium lauryl sulfate; 0.1 wt% to 10.0 wt% of silicon dioxide; 0.05wt% to 2.0wt% of magnesium stearate; The active ingredient, copovidone and optionally at least a portion of sodium lauryl sulfate are present in the form of a solid dispersion. The pharmaceutical composition according to any one of claims 4 to 16, wherein the solid dispersion is prepared by spray drying or hot melt extrusion; preferably, the solid dispersion is prepared by spray drying. The pharmaceutical composition according to any one of claims 4 to 16, wherein the pharmaceutical composition is an oral solid preparation, including tablets, granules, powders, dry suspensions or capsules. The pharmaceutical composition according to any one of claims 4 to 16, wherein the pharmaceutical composition is a tablet.