Pharmaceutical compositions and their uses

Abstract

This invention relates to pharmaceutical compositions and their uses. Specifically, this invention relates to pharmaceutical compositions comprising compound I or a pharmaceutically acceptable salt, hydrate, or solvation thereof. The pharmaceutical compositions according to the invention can be administered orally for inhibiting kinases and / or for treating various diseases or conditions, such as autoimmune diseases.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 202310732310.1, filed on June 20, 2023, entitled "Pharmaceutical Composition and Use Thereof".

[0002] Cross-reference to related applications

[0003] This application claims priority to Chinese Patent Application No. CN202210700586.7, filed on June 20, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] This invention relates to pharmaceutical compositions and their uses. Specifically, this invention relates to pharmaceutical compositions comprising compound I or a pharmaceutically acceptable salt, hydrate, or solvation thereof. The pharmaceutical compositions according to the invention can be administered orally for inhibiting kinases and / or for treating various diseases or conditions, such as autoimmune diseases. Background Technology

[0005] The Janus kinase (JAK) family is a small family of receptor-associated tyrosine kinases that are crucial for signaling cascades downstream of type I and type II cytokine receptors. Type I and type II cytokine receptors—comprising a family of over 50 receptors for cytokines, interleukins, interferons (IFNs), colony-stimulating factors (CSFs), and hormones—share a unique intracellular signaling pathway mediated by JAKs. These receptors bind directly to the intracellular domains of type I and type II cytokine receptors, rather than to other classes of cytokine receptors. JAK-dependent cytokines are major contributors to immunopathology. JAK dependence on type I and type II cytokines has been established in various genetic models, from mutagenic cell lines and knockout mice to humans. Polymorphisms in JAK and signal transducer and activator of transcription (STAT) genes are associated with autoimmunity, and loss of function due to the inability of type I and type II cytokines to transmit signals through their receptors leads to immunodeficiency. The critical role of JAKs in type I and type II cytokine signaling suggests that interfering with the activity of these kinases could potentially lead to a new class of immunomodulatory drugs.

[0006] The present invention provides a pharmaceutical composition comprising a novel compound, which can be administered orally and is advantageous for inhibiting kinases and / or for treating various diseases or conditions, such as autoimmune diseases. Summary of the Invention

[0007] International application number PCT / CN2021 / 140271, filed on December 22, 2021 (the contents of which are incorporated herein by reference in their entirety), describes compound I of the following formula, which has the function of regulating IL-12, IL-23 and / or IFNα.

[0008]

[0009] The purpose of this invention is to solve the problem of uniform mixing of compound I in pharmaceutical formulations, especially for low doses of compound I as the active ingredient, and to improve the flowability of the final powder containing compound I and reduce the tendency to stick during tableting. Another purpose of this invention is to develop solid dosage forms containing compound I, such as tablets or capsules, with good in vitro dissolution rates and high in vivo bioavailability.

[0010] In one aspect, the present invention relates to a pharmaceutical composition comprising or consisting of the following components:

[0011] a) Compound I, with the following structural formula:

[0012]

[0013] Or its pharmaceutically acceptable salts, hydrates or solvates;

[0014] b) One or more acid regulators;

[0015] c) One or more fillers may be used;

[0016] d) One or more adhesives, optionally;

[0017] e) One or more surfactants may be selected;

[0018] f) One or more optional disintegrants; and

[0019] g) One or more lubricants may be selected.

[0020] In some embodiments, component a is substantially pure compound I, which is amorphous, crystalline, or any combination thereof.

[0021] In some embodiments, the acid regulator is selected from monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids; preferably dicarboxylic acids.

[0022] In some embodiments, the acidity regulator is selected from lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, and any combination thereof; preferably selected from citric acid, tartaric acid, maleic acid, mandelic acid, malic acid, and any combination thereof; more preferably selected from tartaric acid, maleic acid, and any combination thereof.

[0023] In some embodiments, the acid regulator has a pKa value of about 0 to about 7.0, preferably about 1.0 to about 5.0, and more preferably about 1.5 to about 3.0, when measured in water at 25°C.

[0024] In some embodiments, component c is a combination of an insoluble filler and a soluble filler, wherein the insoluble filler is, for example, microcrystalline cellulose, and the soluble filler is, for example, lactose monohydrate, dicalcium phosphate, mannitol, or any combination thereof, wherein the weight ratio of the insoluble filler to the soluble filler is at least about 1:9, at least about 2:8, at least about 3:7, at least about 4:6 and / or at most about 9:1, at most about 8:2, at most about 7:3, at most about 6:4, preferably about 1:1.

[0025] In some embodiments, the pharmaceutical composition comprises or consists of the following components:

[0026] a) about 0.5 to about 20% by weight, preferably about 1.0 to about 10% by weight, and more preferably about 2.5 to about 5% by weight of compound I;

[0027] b) about 1 to about 10% by weight, preferably about 2 to about 8% by weight, more preferably about 3 to about 5% by weight, of an acid modifier, which is maleic acid; or about 5 to about 40% by weight, preferably about 10 to about 35% by weight, and more preferably about 15 to about 30% by weight, of an acid modifier, which is tartaric acid.

[0028] c) about 20 to about 95% by weight, preferably about 30 to about 90% by weight and more preferably about 40 to about 85% by weight of a filler, which is a combination of an insoluble filler and a soluble filler, wherein the insoluble filler is microcrystalline cellulose and the soluble filler is lactose monohydrate and / or mannitol.

[0029] d) about 0.5 to about 10% by weight, preferably about 1.0 to about 8.0% by weight, and more preferably about 2.0 to about 6.0% by weight, of an adhesive which is hydroxypropyl methylcellulose;

[0030] e) about 0.2 to about 6.0% by weight, preferably about 0.6 to about 4.0% by weight, and more preferably about 1.0 to about 2.0% by weight of a surfactant, which is sodium dodecyl sulfate;

[0031] f) about 0.5 to about 40% by weight, preferably about 2.0 to about 20% by weight, and more preferably about 4.0 to about 10% by weight, of a disintegrant, which is croscarmellose sodium; and

[0032] (g) about 0.2 to about 6% by weight, preferably about 0.4 to about 4.0% by weight and more preferably about 0.6 to about 2.0% by weight of a lubricant, which is magnesium stearate;

[0033] The weight percentage is based on the total weight of the pharmaceutical composition.

[0034] In another aspect, the present invention relates to a pharmaceutical composition comprising or consisting of the following components:

[0035] a) Compound I, with the following structural formula:

[0036]

[0037] Or its pharmaceutically acceptable salts, hydrates or solvates;

[0038] b) One or more matrix polymers;

[0039] c) One or more fillers may be used;

[0040] d) One or more disintegrants may be selected;

[0041] e) One or more optional drowsiness aids; and

[0042] f) One or more lubricants may be used.

[0043] In some embodiments, component a is substantially pure compound I, which is amorphous.

[0044] In some embodiments, the matrix polymer is selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof; preferably selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and any combination thereof; more preferably selected from hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose phthalate.

[0045] In some embodiments, the weight ratio (a / b) of component a to component b is about 1:9 to about 4:6, preferably about 1.5:8.5 to about 3:7, and more preferably about 2:8.

[0046] In some embodiments, component a and component b form a solid dispersion, wherein the solid dispersion is obtained by spray drying.

[0047] In some embodiments, the pharmaceutical composition comprises or consists of the following components:

[0048] a) about 0.5 to about 20% by weight, preferably about 1.0 to about 10% by weight, and more preferably about 2.5 to about 5% by weight of compound I;

[0049] b) about 1.0 to about 40% by weight, preferably about 4.0 to about 25% by weight and more preferably about 8.0 to about 15% by weight of a matrix polymer selected from hydroxypropyl methylcellulose succinate and hydroxypropyl methylcellulose phthalate;

[0050] c) about 20 to about 95% by weight, preferably about 30 to about 90% by weight and more preferably about 40 to about 85% by weight of a filler, which is a combination of an insoluble filler and a soluble filler, wherein the insoluble filler is microcrystalline cellulose and the soluble filler is lactose monohydrate and / or mannitol.

[0051] d) about 0.5 to about 40% by weight, preferably about 2.0 to about 20% by weight and more preferably about 4.0 to about 10% by weight of a disintegrant, which is croscarmellose sodium;

[0052] e) about 0.2 to about 10% by weight, preferably about 0.6 to about 4.0% by weight and more preferably about 1.0 to about 2.0% by weight of a flow aid, which is colloidal silica;

[0053] f) about 0.2 to about 6% by weight, preferably about 0.6 to about 4.0% by weight, and more preferably about 1.0 to about 2.0% by weight of a lubricant selected from magnesium stearate;

[0054] The weight percentage is based on the total weight of the pharmaceutical composition.

[0055] In another aspect, the present invention relates to a solid coated tablet comprising a tablet core and a coating film, wherein the tablet core is a pharmaceutical composition according to any one of the preceding claims, and wherein the coating film is formed of one or more coating agents selected from Opadry, polyvinyl alcohol, eutectic, gastric-soluble film coating premixes and any combination thereof, preferably Opadry.

[0056] In some embodiments, the weight gain percentage of the coating agent is about 1 to about 10% by weight, preferably about 2 to about 8% by weight, more preferably about 3 to about 6% by weight, and most preferably about 4% by weight, based on the weight of the core.

[0057] The pharmaceutical compositions described in this invention can be formulated for any suitable route of administration. In some embodiments, the pharmaceutical compositions can be formulated for oral administration. For example, in some embodiments, the pharmaceutical compositions may be tablets or capsules.

[0058] Some embodiments of the present invention relate to methods of using a pharmaceutical composition according to the present invention. For example, in some embodiments, the present invention provides a method of treating a subject with an autoimmune and / or inflammatory disease, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to the present invention. In some embodiments, the autoimmune and / or inflammatory disease is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and / or scleroderma.

[0059] The pharmaceutical compositions according to the invention can be used as monotherapy or combination therapy. For example, in some embodiments, the method according to the invention is used to treat autoimmune and / or inflammatory diseases in subjects in need, the method comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of the pharmaceutical composition according to the invention. In some embodiments, the method may further comprise treating the subject with additional autoimmune-enhancing and / or anti-inflammatory therapies.

[0060] It should be understood that the above overview and the following detailed description are merely exemplary and illustrative of the invention, and not restrictive. Attached Figure Description

[0061] Figure 1 The blood drug concentration-time curves in beagle dogs after administration of the formulations of Example 1 and Reference 1 and Reference 2 are shown.

[0062] Figure 2 The blood drug concentration-time curves in beagle dogs after administration of the formulations of Example 2 and Reference 1 are shown.

[0063] Figure 3 The blood concentration-time curves in beagle dogs after administration of 3 mg and 12 mg of the formulations of Examples 6 and 7, respectively, are shown.

[0064] Figure 4 The XRPD spectra of the compound I solid dispersion of Example 9 are shown initially and after being placed at 2-8°C for one month.

[0065] Figure 5 The XRPD spectra of the solid dispersion of Compound I in Example 10 are shown initially and after being placed at 2-8°C for one month.

[0066] Figure 6 The XRPD spectra of the compound I solid dispersion from Example 11 are shown initially and after one month of storage at 2-8°C.

[0067] Figure 7The blood concentration-time curves in beagle dogs after administration of the formulations of Example 13 and Reference 1 are shown. Detailed Implementation

[0068] Compound I

[0069] Compound I having the following formula is disclosed in international application number PCT / CN2021 / 140271 filed on December 22, 2021, the contents of which are incorporated herein by reference in their entirety.

[0070]

[0071] Compound I exhibited an IC50 of 2.5 nM in the HEK Blue IL23 bioactivity assay. 50 It has advantages in, for example, human liver microsomal stability, rat pharmacokinetics, and selectivity of TYK2 relative to JAK1, and therefore can be used to treat a variety of diseases or conditions, such as autoimmune and / or inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and / or scleroderma.

[0072] Compound I can be in any of a variety of forms, including free base form, crystalline form, its salt, its hydrate, its solvate, and amorphous form. Choosing a specific form of Compound I for use in the pharmaceutical compositions disclosed herein is within the capabilities of those skilled in the art.

[0073] In some embodiments, the pharmaceutical composition according to the invention comprises compound I or a pharmaceutically acceptable salt thereof or a hydrate or solvation thereof. In some embodiments, component a is typically substantially pure compound I, which may be amorphous, crystalline, or any combination thereof. In some embodiments, the purity of compound I may be greater than 70%, preferably greater than 90% (e.g., greater than 95%, greater than 97%, greater than 98%, or greater than 99%), by weight, by HPLC area, or both.

[0074] In some embodiments, compound I is in a crystalline form whose X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks at the following values: 7.0°, 9.7°, 14.1°, 14.5°, 17.2°, 18.2°, 19.6°, 21.3°, 24.1°, and 27.0° (2θ, ±0.2°). In some embodiments, compound I is in a crystalline form obtained by first slurrying compound I in tetrahydrofuran, and then slurrying it in ethanol and water. Preferably, the crystalline form is obtained by first slurrying compound I in tetrahydrofuran at 55-75°C for 0.5 to 5 hours, and then slurrying it in ethanol and water at 60-80°C for 6 to 48 hours.

[0075] In some embodiments, the pharmaceutical composition comprises at least about 0.5% by weight, at least about 0.7% by weight, at least about 1.0% by weight, at least about 1.5% by weight, at least about 2.0% by weight, at least about 2.5% by weight, and / or at most about 20% by weight, at most about 18% by weight, at most about 16% by weight, at most about 14% by weight, at most about 12% by weight, at most about 10% by weight, at most about 7.5% by weight, at most about 5.0% by weight, of compound I or a pharmaceutically acceptable salt, hydrate, or solvate thereof, based on the total weight of the pharmaceutical composition.

[0076] Acidity regulator

[0077] In this invention, the term "acid regulator" refers to a pharmaceutically usable acidic substance having a pKa value of about 0 to about 7.0, preferably about 1.0 to about 5.0, and more preferably about 1.5 to about 3.0 when measured in water at 25°C.

[0078] In some embodiments, the acid regulator according to the present invention is selected from monocarboxylic acids, dicarboxylic acids, tricarboxylic acids, or tetracarboxylic acids. Preferably, the acid regulator is selected from monocarboxylic acids, dicarboxylic acids, or tricarboxylic acids. More preferably, the acid regulator is one or more dicarboxylic acids.

[0079] In some embodiments, the acid modifier according to the invention is selected from lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, and any combination thereof; preferably selected from citric acid, tartaric acid, maleic acid, mandelic acid, malic acid, and any combination thereof; more preferably selected from tartaric acid, maleic acid, and any combination thereof. It has been found in this invention that the selection of the acid modifier will affect the stability of the pharmaceutical composition, the dissolution rate, and the sticking / flushing during tableting.

[0080] In some embodiments, the pharmaceutical composition according to the invention comprises at least about 0.5% by weight, at least about 1.0% by weight, at least about 2.0% by weight, at least about 3.0% by weight, at least about 4.0% by weight, at least about 5.0% by weight, at least about 6.0% by weight, and / or at most about 40% by weight, at most about 35% by weight, at most about 30% by weight, at most about 25% by weight, at most about 20% by weight, at most about 15% by weight, and at most about 10% by weight of an acidifier, based on the total weight of the pharmaceutical composition.

[0081] filler

[0082] The pharmaceutical compositions of the present invention may further comprise one or more fillers. In some embodiments, the fillers according to the present invention are selected from powdered sugar, compressible sugar, dextrose, dextrin, glucose, lactose (preferably lactose monohydrate), mannitol, microcrystalline cellulose (e.g., MCC102, MCC105, MCC112, MCC200), powdered cellulose, sorbitol, sucrose, dicalcium phosphate, dicalcium hydrogen phosphate, starch, pregelatinized starch, and any combination thereof.

[0083] In some embodiments, the pharmaceutical composition according to the invention may contain two or more fillers, preferably two fillers. For example, the pharmaceutical composition may contain a combination of insoluble and soluble fillers. For example, the invention uses microcrystalline cellulose as an insoluble filler and lactose monohydrate, calcium hydrogen phosphate, or mannitol as a soluble filler, which is beneficial for improving the flowability and compressibility of the material.

[0084] In some embodiments, the amount of the one or more fillers may be at least about 20% by weight, at least about 25% by weight, at least about 30% by weight, at least about 35% by weight, at least about 40% by weight, at least about 45% by weight, at least about 50% by weight and / or at most about 95% by weight, at most about 93% by weight, at most about 90% by weight, at most about 87% by weight, at most about 85% by weight, based on the total weight of the pharmaceutical composition.

[0085] In the presence of a combination of insoluble and soluble fillers, the weight ratio of the insoluble filler to the soluble filler may be at least about 1:9, at least about 2:8, at least about 3:7, at least about 4:6 and / or at most about 9:1, at most about 8:2, at most about 7:3, at most about 6:4, preferably about 1:1.

[0086] adhesives

[0087] The pharmaceutical compositions of the present invention may further comprise one or more binders. In some embodiments, the binder according to the present invention is selected from hydroxypropyl methylcellulose, crosspovidone, povidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, nitrocellulose, polyethylene oxide, polyvinyl alcohol, polyethylene glycol, and any combination thereof; preferably selected from hydroxypropyl methylcellulose, hydroxypropylcellulose, crosspovidone, and povidone, and any combination thereof.

[0088] In the pharmaceutical compositions of the present invention, hydroxypropyl methylcellulose has been found to help the powder bind well and has lower hygroscopicity compared to other commonly used adhesives (such as povidone). Therefore, hydroxypropyl methylcellulose is preferably used as an adhesive in the pharmaceutical compositions of the present invention.

[0089] In some embodiments, the amount of the one or more matrix polymers may be at least about 0.5% by weight, at least about 1.0% by weight, at least about 2.0% by weight, at least about 3.0% by weight, at least about 3.0% by weight, at least about 4.0% by weight and / or at most about 10% by weight, at most about 8.0% by weight, at most about 6.0% by weight, at most about 5.0% by weight, at most about 4.5% by weight, based on the total weight of the pharmaceutical composition.

[0090] surfactants

[0091] The pharmaceutical compositions of the present invention may further comprise one or more surfactants. In some embodiments, the surfactants according to the present invention may be ionic surfactants, amphoteric surfactants, nonionic surfactants, or any combination thereof.

[0092] In some embodiments, the surfactant according to the invention is an ionic surfactant selected from ammonium dodecyl sulfate, sodium dodecyl sulfate, sodium dodecyl ether sulfate, sodium myristyl ether sulfate, sodium dioctyl sulfosuccinate, perfluorooctane sulfonate, perfluorobutane sulfonate, alkyl-aryl ether phosphate, alkyl ether phosphate, and any combination thereof; preferably selected from ammonium dodecyl sulfate, sodium dodecyl sulfate, sodium dodecyl ether sulfate, and any combination thereof; more preferably selected from sodium dodecyl sulfate.

[0093] In some embodiments, the amount of the one or more surfactants may be at least about 0.2% by weight, at least about 0.4% by weight, at least about 0.6% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 1.2% by weight, at least about 1.4% by weight and / or at most about 10% by weight, at most about 8.0% by weight, at most about 6.0% by weight, at most about 4.0% by weight, at most about 2.0% by weight, at most about 1.6% by weight, based on the total weight of the pharmaceutical composition.

[0094] Disintegrant

[0095] Disintegrants swell when moist, causing tablets to break, for example, at certain stages of the digestive process, releasing the active ingredient for absorption.

[0096] The pharmaceutical compositions of the present invention may further comprise one or more disintegrants. In some embodiments, the disintegrants according to the present invention may be selected from alginate, sodium alginate, calcium alginate, magnesium aluminum silicate, glycine, chitosan, calcium carboxymethyl cellulose, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium glycolate starch, and croscarmellose; preferably selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium glycolate starch, croscarmellose, and any combination thereof; more preferably selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, and any combination thereof.

[0097] Low-substituted hydroxypropyl cellulose is commercially available. Compared to hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose has only a small proportion of three free hydroxyl groups / glucose subunits converted to hydroxypropyl ethers. When dried at 105°C for 1 hour, low-substituted hydroxypropyl cellulose contains not less than 5.0% and not more than 16.0% hydroxypropoxy groups. The use of low-substituted hydroxypropyl cellulose is particularly advantageous for improving the solubility profiles of the pharmaceutical compositions according to the invention.

[0098] In the pharmaceutical composition of the present invention, it has been found that cross-linked sodium carboxymethyl cellulose can achieve good water absorption and swelling properties, thereby achieving good disintegration effect by means of capillary and swelling action.

[0099] In some embodiments, the amount of the one or more disintegrants may be at least about 0.5% by weight, at least about 1.0% by weight, at least about 2.0% by weight, at least about 3.0% by weight, at least about 4.0% by weight, at least about 5.0% by weight, at least about 6.0% by weight and / or at most about 40% by weight, at most about 35% by weight, at most about 30% by weight, at most about 25% by weight, at most about 20% by weight, at most about 15% by weight, at most about 10% by weight, based on the total weight of the pharmaceutical composition.

[0100] lubricant

[0101] Lubricants prevent ingredients from clumping together and adhering to tablet punches or capsule filling machines. Lubricants also ensure low friction between the solids and the die walls.

[0102] The pharmaceutical compositions of the present invention may further comprise one or more lubricants. In some embodiments, the lubricant according to the present invention is selected from magnesium stearate, aluminum stearate, calcium stearate, stearic acid, sodium stearate fumarate, talc, sodium benzoate, monoglyceride, polyethylene glycol, hydrogenated cottonseed oil, castor oil, sucrose ester, calcium silicate, silicon dioxide, and any combination thereof.

[0103] Magnesium stearate is a widely used lubricant. It possesses excellent hydrophilic and lipophilic properties, allowing for rapid distribution in blends. Furthermore, it exhibits a high surface area and good lubricity. In this invention, magnesium stearate is preferably used as the lubricant.

[0104] In some embodiments, the amount of the one or more lubricants may be at least about 0.2% by weight, at least about 0.4% by weight, at least about 0.6% by weight, at least about 0.8% by weight, at least about 1.0% by weight, and / or at most about 10% by weight, at most about 8.0% by weight, at most about 6.0% by weight, at most about 4.0% by weight, at most about 2.0% by weight, at most about 1.6% by weight, at most about 1.4% by weight, at most about 1.2% by weight, based on the total weight of the pharmaceutical composition.

[0105] matrix polymer

[0106] The pharmaceutical compositions of the present invention may comprise one or more matrix polymers. In some embodiments, the matrix polymer according to the present invention is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS MG), hydroxypropyl methylcellulose phthalate (HPMCP HP-50), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), and any combination thereof; preferably selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and any combination thereof; more preferably hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose phthalate.

[0107] In some embodiments, the amount of the one or more matrix polymers may be at least about 1.0 wt%, at least about 2.0 wt%, at least about 3.0 wt%, at least about 4.0 wt%, at least about 5.0 wt%, at least about 6.0 wt%, at least about 8.0 wt%, and / or at most about 40 wt%, at most about 35 wt%, at most about 30 wt%, at most about 25 wt%, at most about 20 wt%, at most about 15 wt%, based on the total weight of the pharmaceutical composition.

[0108] In some embodiments, the weight ratio of the compound I or its pharmaceutically acceptable salt, hydrate or solvate to the matrix polymer is from about 1:9 to about 4:6, preferably from about 1.5:8.5 to about 3:7, and more preferably from about 2:8.

[0109] In some embodiments, the compound I or a pharmaceutically acceptable salt, hydrate or solvate thereof forms a solid dispersion with the matrix polymer, wherein the solid dispersion is obtained by spray drying.

[0110] Flow aid

[0111] The pharmaceutical compositions of the present invention may further comprise one or more flow aids. In some embodiments, examples of flow aids according to the present invention include, but are not limited to, fumed silica, non-fumed silica, colloidal silica, hydrated silica, aggregated silicates, magnesium silicate, magnesium trisilicate, talc, etc. Preferably, the flow aid is selected from fumed silica, non-fumed silica, colloidal silica, and any combination thereof, more preferably colloidal silica.

[0112] In some embodiments, the amount of the one or more gliding agents may be at least about 0.2% by weight, at least about 0.4% by weight, at least about 0.6% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 1.2% by weight, at least about 1.4% by weight and / or at most about 10% by weight, at most about 8.0% by weight, at most about 6.0% by weight, at most about 4.0% by weight, at most about 2.0% by weight, at most about 1.6% by weight, based on the total weight of the pharmaceutical composition.

[0113] Pharmaceutical Composition

[0114] The pharmaceutical compositions according to the invention comprise compound I or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof, and optionally a pharmaceutically acceptable excipient. Suitable excipients, without limitation, include, for example, encapsulating materials or additives, such as absorption enhancers, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's *The Science and Practice of Pharmacy*, 21st edition, ARGennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2005; incorporated herein by reference), which discloses various excipients for formulating pharmaceutical compositions and known techniques for their preparation.

[0115] Typically, compound I, as the active ingredient, is provided in an effective amount in the pharmaceutical composition according to the invention. In some embodiments, the effective amount is a therapeutically effective amount (e.g., an effective amount for treating an autoimmune-related disease in a subject in need). As used herein, a therapeutically effective amount of the pharmaceutical composition or compound I according to the invention is an amount that effectively treats the disease or condition described herein, which may depend on the recipient of treatment, the disease or condition being treated and its severity, the composition comprising the compound, the time of administration, the route of administration, the duration of treatment, the efficacy of the compound, its clearance rate, and whether another drug is being taken concurrently.

[0116] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Typically, such preparation methods involve mixing the active ingredient, such as compound I of the present invention, with a carrier or excipient and / or one or more other auxiliary ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single-dose or multi-dose units.

[0117] Pharmaceutical compositions may be prepared, packaged, and / or sold as a single unit dose and / or as multiple single unit doses in batches. A “unit dose” is a pharmaceutical composition containing a discrete amount of a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient to be administered to a subject and / or a convenient fraction of that dose, such as half or one-third of the dose.

[0118] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any other components in the pharmaceutical compositions described herein may vary depending on the identity, size, and / or condition of the subject being treated, and further on the route by which the composition will be administered.

[0119] Coating agent

[0120] The pharmaceutical compositions of the present invention can be coated with one or more coating agents. In some embodiments, the coating agent according to the present invention is selected from Opadry, polyvinyl alcohol, eutectic, gastric-soluble film-coating premixes, and any combination thereof. In some embodiments, the coating agent is Opadry.

[0121] Opadry is a customizable, one-step dry powder mixing, fully formulated film coating system manufactured by Calexcom, containing the necessary polymers, plasticizers, and colorants.

[0122] Utec is a trade name for synthetic pharmaceutical excipients, which include methacrylic acid copolymers and methacrylate copolymers, and are widely used in the gastric coating of pharmaceutical preparations.

[0123] Gastric-soluble film-coating premixes generally contain titanium dioxide, talc, polyethylene glycol, hydroxypropyl methylcellulose, and a lake pigment. For example, the gastric-soluble film-coating premix is ​​a mixture of titanium dioxide, talc, polyethylene glycol 6000, hydroxypropyl methylcellulose, and tartrazine aluminum lake pigment.

[0124] In some embodiments, the weight gain percentage of one or more coating agents according to the invention is about 1 to about 10% by weight, preferably about 2 to about 8% by weight, more preferably about 3 to about 6% by weight, and most preferably 4% by weight, based on the weight of the pharmaceutical composition (tablet core) of the invention.

[0125] In this article, the weight gain percentage refers to the percentage of the difference between the average tablet weight after coating and before coating to the average tablet weight before coating. The calculation formula is: weight gain percentage = (average tablet weight after coating - average tablet weight before coating) / average tablet weight before coating * 100%.

[0126] definition

[0127] As used herein, the term "about" to modify quantities relating to the invention refers to possible variations in numerical quantities, such as those resulting from routine testing and processing; unintentional errors in such testing and processing; differences in the manufacture, origin, or purity of the ingredients used in the invention, etc. As used herein, "about" also includes a specific value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include equivalents of the listed quantities. In one embodiment, the term "about" means within 20%, 10%, or 5% of the reported value.

[0128] As used herein, the term "solid dispersion" refers to a dispersion of one or more active agents in a solid matrix polymer, which is prepared by a variety of methods, including spray drying, melting (melting), solvent, or melt-solvent methods.

[0129] As used herein, the term "treatment" means the elimination, reduction, or relief of a disease or condition and / or related symptoms. While not excluded, treating a disease or condition does not require the complete elimination of said disease, condition, or related symptoms. As used herein, the term "treatment" can include "preventive treatment," which refers to reducing the likelihood of the recurrence or previously controlled relapse of a disease or condition in a subject who is not currently ill but is at risk or prone to developing or experiencing a relapse. The term "treatment" and its synonyms are understood to mean administering a therapeutically effective amount of the pharmaceutical composition according to the invention to a subject who requires such treatment.

[0130] Example

[0131] Materials and equipment

[0132] The starting materials, reagents, solvents, etc., used in this invention are commercially available. The instruments and equipment used in this invention are also commercially available.

[0133] Compound I was prepared by the following method:

[0134]

[0135] Compound I-1 was prepared from 2-amino-5-chloropyridine via multiple synthetic steps following a known process described in International Application No. PCT / CN2021 / 140271, filed on December 22, 2021, the contents of which are incorporated herein by reference in their entirety.

[0136] Step 1: Under nitrogen atmosphere, compound I-1 (200 g), (2,4-dimethoxyphenyl)methylamine (290 g), and cesium fluoride (88 g) were added to N-methylpyrrolidone (1000 mL), and reacted at 120 °C for 3 hours. The reaction mixture was then cooled to room temperature, quenched with water, and filtered. The filter cake was washed with water and collected. The crude product was slurried at 65 °C with a mixed solvent of tetrahydrofuran and isopropanol (V / V, 1 / 1) to give compound I-2 (white solid, 251 g, yield 91%). LCMS: 478.1 [M+1] + .

[0137] Step 2: Under nitrogen atmosphere, compound I-2 (200 g) and N,N-diisopropylethylamine (81 g) were added to tetrahydrofuran (1200 mL), and the mixture was heated to 65 °C. A solution of cyclopropaneformyl chloride (52.6 g) in THF (500 mL) was added dropwise, and the reaction was allowed to proceed for 2 hours. The reaction mixture was cooled to 25 °C, quenched with water, and extracted with dichloromethane. The organic phase was washed with water, concentrated under reduced pressure, and slurried with isopropanol at 80 °C for 1 hour to give compound I-3 (pale yellow solid, 196 g, yield 87%). LCMS: 546.2 [M+1] + . 1 H NMR: (400MHz, CDCl3); δ: 12.20 (s, 1H), 9.08 (s, 1H), 8.45 (s, 1H), 8.06, (d, 1H, J = 4.0Hz), 7.62 (d, 1H, J = 4.0Hz), 7.27 (d, 1H, J = 12.0Hz), 6.43 (dd, 1H, J=4.0,12.0Hz),6.36(d,1H,J=4.0Hz),5.24(s,2H),3.77(s,3H),3.62(s, 3H),2.55(s,3H),1.80-1.71(m,1H),1.20-1.16(m,2H),0.84-0.78(m,2H).

[0138] Step 3: Under nitrogen atmosphere, compound I-3 (160 g) was added to 1,4-dioxane (1600 mL). A solution of potassium peroxymonosulfate complex salt (325 g) in water (700 mL) was added at a temperature below 30 °C, and the reaction was carried out at 30 °C for 24 hours. The reaction mixture was filtered and washed with dichloromethane. The filtrate was washed with a 5% sodium sulfite aqueous solution and water, respectively. After concentrating the organic phase, methanol was added and the mixture was stirred at 65 °C for 1 hour to obtain compound I-4 (white solid, 121 g, yield 72%). 1 HNMR: (400MHz, DMSO-d6); δ: 12.25 (s, 1H), 9.45 (s, 1H), 8.75 (d, 1H, J = 4.8Hz), 8.58, (d, 1H, J = 2.4Hz), 8.25 (d, 1H, J = 2.4Hz), 7.10 (d, 1H, J =8.0Hz),6.48-6.44(m,2H),5.04(s,2H),3.72(s,3H),3.60(s,3H),3.41(s,3H),1.80-1.74(m,1H),0.96-0.91(m,2H),0.81-0.76(m,2H).

[0139] Step 4: Under nitrogen atmosphere, compound I-4 (105 g) was added to trifluoroacetic acid (TFA, 330 mL) and reacted at 35 °C for 6 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was added to anhydrous ethanol, stirred for 30 minutes, and then filtered. The filter cake was first slurried in tetrahydrofuran at 65 °C for 1 hour, and then slurried in ethanol and water at 70 °C for 12 hours to give compound I (white solid, 67 g, yield 86%). LCMS: 428.2 [M+1] + ; 1 H NMR: (400MHz, DMSO-d6); δ: 12.14(s,1H),11.44(s,1H),9.36(s,1H),9.19,(s,1H),8.65( d,1H,J=2.4Hz),8.23(d,1H,J=2.4Hz),3.38(s,3H),2.12-2.09(m,1H),0.86-0.84(m,4H).

[0140] The obtained compound I is in crystalline form, and the XRPD peak table for this crystalline form is as follows:

[0141]

[0142]

[0143] Reference ratio 1

[0144] Based on the absorption of compound I in animals, a preferred liquid formulation was selected, which is prepared as follows:

[0145] Weigh 350 mg of compound I into a 250 mL glass container, add 52.5 mL of polyethylene glycol 300 (PEG300) and 70 mL of propylene glycol (PG), heat in an oil bath to 85 °C and stir to dissolve into a clear solution, add 35 mL of vitamin E polyethylene glycol succinate (ETPGS), 8.75 mL of ethanol and 8.75 mL of water, stir to form a homogeneous solution, remove from the oil bath and slowly cool to room temperature.

[0146] Reference ratio 2

[0147] A solid tablet without an acid regulator was prepared as follows:

[0148] Compound I and mannitol were sieved separately. The sieved compounds I and mannitol, along with microcrystalline cellulose, hydroxypropyl methylcellulose, sodium dodecyl sulfate, and croscarmellose sodium, were placed in a wet granulator, and purified water was sprayed in for wet granulation. After drying and granulation, the resulting granules were mixed with croscarmellose sodium and magnesium stearate in a mixing hopper to obtain total mixed granules, which were then compressed into tablets. Table 1 below shows the tablet composition of Reference Example 2.

[0149] Table 1: Composition of solid tablets in Reference Example 2

[0150] Element Weight (mg / tablet) Weight percentage (%) Compound I 10.00 2.50 Mannitol 160.0 40.00 microcrystalline cellulose 180.0 45.00 Hydroxypropyl methylcellulose 16.00 4.00 Sodium dodecyl sulfate 6.000 1.50 Cross-linked carboxymethyl cellulose sodium (added internally) 12.00 3.00 Cross-linked sodium carboxymethyl cellulose (added externally) 12.00 3.00 magnesium stearate 4.000 1.00 total 400.0 100.00

[0151] Example 1

[0152] A solid tablet containing an acid regulator was prepared as follows:

[0153] Compound I and lactose monohydrate were sieved separately, and tartaric acid was pulverized and sieved. The sieved compound I and lactose monohydrate, along with microcrystalline cellulose, hydroxypropyl methylcellulose, sodium dodecyl sulfate, the sieved tartaric acid, and croscarmellose sodium, were placed in a wet granulator, and purified water was sprayed in for wet granulation. After drying and granulation, the resulting granules were mixed with croscarmellose sodium and magnesium stearate in a mixing hopper to obtain total mixed granules, which were then compressed into tablets. Table 2 below shows the tablet composition of Example 1.

[0154] Table 2: Composition of the solid tablets in Example 1

[0155]

[0156]

[0157] Pharmacokinetic studies of Example 1 and Reference Examples 1 and 2

[0158] Six beagle dogs were divided into three groups and administered compound I in three cycles of crossover dosing. Each beagle dog received a single oral dose of 10 mg of one of the three prescription formulations. Blood samples were collected before administration and at 0.0833, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, and 96 hours after administration. Plasma concentrations of compound I were determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated. Table 3 below provides the specific pharmacokinetic parameter values. Figure 1 The blood drug concentration-time curves in beagle dogs after administration of the formulations of Example 1 and Reference 1 and Reference 2 are shown.

[0159] Table 3: Pharmacokinetic parameters in beagle dogs after oral administration of the formulations of Example 1, Reference 1, and Reference 2 (n=6)

[0160]

[0161] From Table 3 and Figure 1 It can be seen that the in vivo absorption of the solid tablets without acid modifiers (Reference 2) is much lower than that of the optimized liquid formulation (Reference 1). Compared with the solid tablets without acid modifiers (Reference 2), the solid tablets with tartaric acid as an acid modifier (Example 1) have lower C... max The value increased significantly, indicating a significant increase in drug absorption in the body. Compared to the optimized liquid formulation (Reference 1), the solid tablets with tartaric acid added as an acidity regulator (Example 1) showed a significant increase in C. max The values ​​were basically the same, and the difference in drug absorption in vivo was not significant. Therefore, it is evident that adding an acid modifier to solid tablets can significantly improve the in vivo bioavailability of compound I.

[0162] Example 2

[0163] Solid tablets were prepared using a method similar to that of Example 1, and Table 4 below shows the tablet composition of Example 2.

[0164] Table 4: Composition of the solid tablets in Example 2

[0165]

[0166]

[0167] Pharmacokinetic studies of Example 2 and Reference Example 1

[0168] Six beagle dogs were divided into crossover groups and administered different prescription formulations orally in a single dose of 10 mg each. Blood samples were collected before administration and at 0.0833, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, and 96 hours after administration. The plasma concentration of compound I was determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated. Table 5 below shows the specific pharmacokinetic parameter values. Figure 2 The blood drug concentration-time curves in beagle dogs after administration of the formulations of Example 2 and Reference Example 1 are shown.

[0169] Table 5: Pharmacokinetic parameters in beagle dogs after oral administration of the formulations of Example 2 and Reference 1 (n=6)

[0170]

[0171] From Table 5 and Figure 2 It can be seen that, compared with the optimized liquid formulation (Reference Example 1), the solid tablets with maleic acid added as an acid regulator (Example 2) have a lower C content. max The values ​​are basically the same, AUC last The values ​​are basically the same, meaning that the absorption of the two in the beagle's body is basically the same, and much higher than that of the solid tablets without added acid regulators (see ratio 2).

[0172] Example 3

[0173] Solid tablets were prepared using a method similar to that of Example 1, and Table 6 below shows the tablet composition of Example 3.

[0174] Table 6: Composition of the solid tablets in Example 3

[0175] Element Weight (mg / tablet) Weight percentage (%) Compound I 10.00 2.50 Mannitol 160.0 40.00 microcrystalline cellulose 168.0 42.00 Hydroxypropyl methylcellulose 16.00 4.00 Sodium dodecyl sulfate 6.000 1.50 Maleic acid 12.00 3.00 Cross-linked carboxymethyl cellulose sodium (added internally) 12.00 3.00 Cross-linked sodium carboxymethyl cellulose (added externally) 12.00 3.00 magnesium stearate 4.000 1.00 total 400.0 100.00

[0176] Example 4

[0177] Solid tablets were prepared using a method similar to that of Example 1, and Table 7 below shows the tablet composition of Example 4.

[0178] Table 7: Composition of the solid tablets in Example 4

[0179]

[0180]

[0181] Example 5

[0182] Solid tablets were prepared using a method similar to that of Example 1, and Table 8 below shows the tablet composition of Example 5.

[0183] Table 8: Composition of the solid tablets in Example 5

[0184] Element Weight (mg / tablet) Weight percentage (%) Compound I 5.000 5.00 Lactose monohydrate 32.50 32.50 microcrystalline cellulose 35.00 35.00 Hydroxypropyl methylcellulose 4.000 4.00 Sodium dodecyl sulfate 1.500 1.50 tartaric acid 15.00 15.00 Cross-linked carboxymethyl cellulose sodium (added internally) 3.000 3.00 Cross-linked sodium carboxymethyl cellulose (added externally) 3.000 3.00 magnesium stearate 1.000 1.00 total 100.0 100.00

[0185] Example 6

[0186] Solid tablets were prepared using a method similar to that of Example 1, and these tablets were then coated with Opadry amb II film, resulting in a 4% weight gain. Table 9 below shows the composition of the coated tablets from Example 6.

[0187] Table 9: Composition of the coated tablets of Example 6

[0188]

[0189]

[0190] Example 7

[0191] Solid tablets were prepared using a method similar to that of Example 1, and these tablets were then coated with an Opadry film, resulting in a 4% weight gain. Table 10 below shows the composition of the coated tablets of Example 7.

[0192] Table 10: Composition of the coated tablets of Example 7

[0193]

[0194] Dissolution test

[0195] A 900 mL hydrochloric acid aqueous solution (pH 2.0) containing 0.5% sodium dodecyl sulfate (SDS) was added to each dissolution vessel as the dissolution medium. The medium temperature was maintained at 37 ± 0.5 °C, and the paddle rotation speed was kept at 75 rpm. The coated tablets obtained in Example 7 were added to the dissolution vessels, and samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, and 75 min (the limiting speed was 250 rpm from 60 min to 75 min) using the paddle rotation speed. The samples were filtered through a 0.45 μm microporous membrane, and the filtrate was used to determine the dissolution amount by HPLC. The results are shown in Table 11 below.

[0196] Table 11: Dissolution amount (wt%) of the coated tablets of Example 7 at different time points

[0197]

[0198] Stability test experiment

[0199] The stability of the coated tablets of Example 7 was investigated under high temperature (60°C or 50°C), accelerated test (40°C / 75% RH), and long-term test (25°C / 60% RH) conditions. The results are shown in Table 12 below.

[0200] Table 12: Stability test results of the coated tablets in Example 7

[0201]

[0202] Example 8

[0203] Pharmacokinetic studies in Examples 6 and 7

[0204] Six beagle dogs were divided into four groups and crossover-administered with different formulations (coated tablets from Example 6 or Example 7) via single oral dose. The dosage for beagle dogs was either 3 mg (1 tablet) or 12 mg (4 tablets). Blood samples were collected before administration and at 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, and 96 hours after administration. The plasma concentration of compound I was determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated. Table 13 below provides the specific pharmacokinetic parameter values. Figure 3 The blood drug concentration-time curves in beagle dogs after administration of the formulations of Example 6 and Example 7 are shown.

[0205] Table 13: Pharmacokinetic parameters in beagle dogs after oral administration of 3 mg and 12 mg of the formulations from Examples 6 and 7 (n=6)

[0206]

[0207] From Table 13 and Figure 3 It can be seen that, at the same dosage of 3 mg and 12 mg, the pharmacokinetic parameters and in vivo absorption of the coated tablets of Examples 6 and 7 in dogs are basically the same. At similar dosages, the absorption of the solid tablets of Examples 6 and 7 (3 mg × 4 tablets) and Reference Example 1 (10 mg) in beagle dogs is also similar.

[0208] Preparation of solid dispersions

[0209] To increase the absorption of the solid composition of compound I in vivo after oral administration, compound I can also be prepared into a solid dispersion with one or more polymeric materials, mixed with other excipients, granulated, compressed into tablets, or directly filled into capsules.

[0210] The solid dispersion of compound I was prepared as follows:

[0211] (1) Solution preparation

[0212] Tetrahydrofuran and purified water were added to a mixing tank and stirred. Then, compound I was slowly added to the prepared mixed solvent (tetrahydrofuran:pure water = 95:5, v / v), and stirred continuously for approximately 1 hour until completely dissolved. Next, the matrix polymer was slowly added to the solution containing compound I, and stirred for approximately 3 hours to obtain the drug solution. Before use, the drug solution was passed through a 200-mesh sieve, transferred to another mixing tank, and stirred continuously until ready for use.

[0213] (2) Spray drying

[0214] First, install the spray drying equipment and preheat it after testing and ensuring it is running normally. Then, set the spray drying parameters and spray in a blank solvent to allow the equipment to equilibrate for at least 20 minutes. Once the system is stable, begin spraying the drug solution for spray drying.

[0215] (3) Vacuum drying

[0216] After spray drying, the solid dispersion collected from the spray drying equipment is evenly spread on a stainless steel tray, which is then placed in the tray of a vacuum drying oven. The drying temperature and vacuum level are set to dry the sample. During the drying process, the sample needs to be turned over periodically with a stainless steel shovel to ensure uniform drying. Drying is stopped when the solvent residue in the solid dispersion sample is below 720 ppm, and the resulting compound I solid dispersion is collected.

[0217] Example 9

[0218] A solid dispersion of compound I was prepared using hydroxypropyl methylcellulose succinate (HPMCAS-MG) as the matrix polymer according to the method described above. Table 14 below shows the composition of the solid dispersion of Example 9.

[0219] Table 14: Composition of the solid dispersion in Example 9

[0220] Element Percentage % (w / w) Prescription dosage (g) Compound I 20 120.0 HPMCAS-MG 80 480.0 Tetrahydrofuran (THF) N / A 25365 Purified water N / A 1500

[0221] Example 10

[0222] A solid dispersion of compound I was prepared using hydroxypropyl methylcellulose phthalate (HPMCP HP-50) as the matrix polymer according to the method described above. Table 15 below shows the composition of the solid dispersion of Example 10.

[0223] Table 15: Composition of the solid dispersion in Example 10

[0224] Element Percentage % (w / w) Prescription dosage (g) Compound I 20 120.0 HPMCP HP-50 80 480.0 Tetrahydrofuran (THF) N / A 25365 Purified water N / A 1500

[0225] Example 11

[0226] A solid dispersion of compound I was prepared according to the method described above, using polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) as the matrix polymer. Table 16 below shows the composition of the solid dispersion of Example 11.

[0227] Table 16: Composition of the solid dispersion in Example 11

[0228] Element Percentage % (w / w) Prescription dosage (g) Compound I 20 120.0 Soluplus 80 480.0 Tetrahydrofuran (THF) N / A 25365 Purified water N / A 1500

[0229] Characterization experiments of solid dispersion of compound I

[0230] The solid dispersions of Compound I prepared by spray drying were subjected to tests for appearance, X-ray powder diffraction (XRPD), mDSC, THF solvent residue, and content. Table 17 below shows the characterization results of the solid dispersions of Compound I in Examples 9-11.

[0231] Table 17: Characterization results of the solid dispersions of Compound I in Examples 9-11

[0232]

[0233] Dynamic solubility detection of compound I solid dispersion

[0234] To evaluate the in vivo solubility of the prepared solid dispersions, FaSSIF-V2 (pH = 6.5 ± 0.05) was selected as the medium, and the dynamic solubility of the solid dispersions of Examples 9-11 and Compound I itself was tested. First, an appropriate amount of solid sample was added to a glass vial, followed by the addition of FaSSIF-V2 medium (preheated to 37°C) to prepare a solution with a concentration of 1 mg / mL. The vial was then placed on a magnetic heater with temperature control at 37°C and stirred to ensure complete dissolution. Samples were taken at 15 min, 30 min, 60 min, and 120 min, and insoluble matter was separated using a centrifuge. The supernatant was diluted with a diluent and the drug content was determined by HPLC. Table 18 below shows the solubility of the solid dispersions of Examples 9-11 and Compound I itself in FaSSIF-V2 at different time points.

[0235] Table 18: Solubility of the solid dispersions of Examples 9-11 and Compound I itself in FaSSIF-V2 at different times

[0236]

[0237] As can be seen from Table 18, preparing compound I into the solid dispersion significantly improves the solubility of the drug. Solid dispersions prepared using HPMCP HP-50 and HPMCAS MG as matrix polymers exhibit higher solubility and can maintain a supersaturated state for a longer period compared to solid dispersions prepared using other matrix polymers.

[0238] Stability determination experiment of compound I solid dispersion

[0239] Take appropriate amounts of the solid dispersions of Compound I from Examples 9-11 and place them into clean glass bottles, seal them with plastic wrap, and then place the sample vials into aluminum foil bags and seal them. Place the samples in a refrigerator at 2-8°C for one month to examine the stability of the solid dispersions. Table 19 below shows the experimental results of the stability of the solid dispersions of Compound I from Examples 9-11. Figure 4-6 The XRPD spectra of the solid dispersions of Compound I in Examples 9-11 are shown initially and after being placed at 2-8°C for one month.

[0240] Table 19: Stability test results of Compound I solid dispersions in Examples 9-11

[0241]

[0242] As can be seen from Table 19, the solid dispersions of Compound I in Examples 9-11 can maintain an amorphous state after being placed at 2-8°C for one month, and there are no significant changes in appearance, content and total impurities.

[0243] Example 12

[0244] Solid tablets of compound I were prepared using solid dispersion technology. The preparation method is as follows:

[0245] (1) Weighing

[0246] Compound I solid dispersion was prepared according to the preparation process of Example 9. Then, the prescribed amounts of compound I solid dispersion, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium (added internally), colloidal silica and magnesium stearate (added internally) were weighed out respectively.

[0247] (2) Mixing

[0248] Premix: Add the weighed lactose monohydrate, compound I solid dispersion, microcrystalline cellulose, croscarmellose sodium (added internally), and colloidal silica into the hopper, and mix at the set mixing speed.

[0249] Sieving: The premixed material is sieved through a granulator.

[0250] Lubrication: Add the sieved material back into the hopper, then add magnesium stearate (internal addition), and set the mixing speed and time for mixing.

[0251] (3) Dry granulation

[0252] Using a dry granulator, the mixed materials are pressed into thin sheets of uniform thickness by setting the dry granulation parameters. Then, the sheets are broken up through granulation to prepare drug granules.

[0253] (4) Total Mixing

[0254] Add the drug granules to the mixing hopper. First, add the externally added cross-linked carboxymethyl cellulose sodium through a 30-mesh sieve and mix it with the drug granules. Then, add the externally added magnesium stearate through a 30-mesh sieve and continue mixing.

[0255] (5) Tableting

[0256] The total mixture was compressed into 10mg round tablets using a tablet press. The parameters were adjusted as required to ensure that the weight, hardness, disintegration and friability of the tablets met the requirements.

[0257] (6) Inner packaging

[0258] Pack the unsold flakes into a high-density polyethylene bottle, add a desiccant, tighten the cap, and heat-seal.

[0259] Table 20 below shows the composition of the solid tablets of Example 12.

[0260] Table 20: Composition of the solid tablets in Example 12

[0261]

[0262]

[0263] Dissolution test

[0264] A 900 mL phosphate aqueous solution (pH 6.8) containing 1.0% sodium dodecyl sulfate (SDS) was added to each dissolution vessel as the dissolution medium. The medium temperature was maintained at 37 ± 0.5 °C, and the paddle rotation speed was kept at 75 rpm. The solid tablets obtained in Example 12 were added to the dissolution vessels, and samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, and 75 min (the limiting speed was 250 rpm from 60 min to 75 min) using the paddle rotation speed. The samples were filtered through a 0.45 μm microporous membrane, and the filtrate was used to determine the dissolution amount by HPLC. The results are shown in Table 21 below.

[0265] Table 21: Dissolution rate (wt%) of the coated tablets of Example 12 at different time points

[0266]

[0267] Stability test experiment

[0268] The stability of the solid tablets from Example 12 was investigated under high temperature (50°C) and accelerated testing (40°C / 75% RH) conditions. The results are shown in Table 22 below.

[0269] Table 22: Stability test results of solid tablets in Example 12

[0270]

[0271] As can be seen from Table 22, after the solid tablets of Example 12 were placed under high temperature and accelerated conditions for one month, there were no significant changes in content, moisture, total impurities and dissolution, indicating good product stability.

[0272] Example 13

[0273] Solid tablets of compound I were prepared using a method similar to that used in Example 12. Table 23 below shows the composition of the solid tablets of Example 13.

[0274] Table 23: Composition of the solid tablets in Example 13

[0275]

[0276]

[0277] Pharmacokinetic studies

[0278] Pharmacokinetic studies were conducted on the solid tablets of Example 13 in beagle dogs to investigate their absorption. Table 24 below provides the specific pharmacokinetic parameters. Figure 7 The blood drug concentration-time curves in beagle dogs after administration of the formulations of Example 13 and Reference 1 are shown.

[0279] Table 24: Pharmacokinetic parameters in beagle dogs after oral administration of the formulations of Example 13 and Reference 1 (n=6)

[0280]

[0281] From Table 24 and Figure 7 It can be seen that the C of compound I solid tablets prepared using solid dispersion in beagle dogs... max and AUC lastThe results were significantly higher than those of the optimized liquid formulation (Reference 1), indicating that preparing compound I into a solid dispersion significantly increases its absorption and bioavailability in beagle dogs.

[0282] Stability test experiment

[0283] The stability of the solid tablets from Example 13 was investigated under accelerated testing conditions (40°C / 75% RH). The results are shown in Table 25 below.

[0284] Table 25: Stability test results of the solid tablets in Example 13

[0285]

[0286] As can be seen from Table 25, the solid tablets of Example 13 showed no significant change in content and total impurities after being placed under accelerated conditions (40°C / 75%RH) for 4 weeks, indicating good product stability.

[0287] Example 14

[0288] Solid tablets of compound I were prepared using a method similar to that used in Example 12. Table 26 below shows the composition of the solid tablets from Example 14.

[0289] Table 26: Composition of the solid tablets in Example 14

[0290]

[0291]

[0292] Example 15

[0293] Solid tablets of compound I were prepared using a method similar to that used in Example 12. Table 27 below shows the composition of the solid tablets from Example 15.

[0294] Table 27: Composition of the solid tablets in Example 15

[0295] Element Prescription dosage (mg / tablet) Percentage % (w / w) Compound I 10.0 3.33 HPMCAS MG 40.0 13.34 Mannitol 135.00 45.00 microcrystalline cellulose 88.00 29.33 Cross-linked carboxymethyl cellulose sodium (added internally) 9.00 3.00 colloidal silica 4.50 1.50 Magnesium stearate (added internally) 2.25 0.75 Cross-linked sodium carboxymethyl cellulose (added externally) 9.00 3.00 Magnesium stearate (added) 2.25 0.75 total 300.0 100.0

[0296] Dissolution test

[0297] A two-stage dissolution method was employed, using 250 mL of simulated gastric juice (SGF) and 500 mL of phosphate buffer (pH 6.8) containing 0.1% sodium dodecyl sulfate (SDS) as the dissolution medium. First, the solid tablets from Examples 13-15 were dissolved in 250 mL of SGF medium for 30 minutes, followed by dissolution in 500 mL of phosphate buffer (pH 6.8) containing 0.1% sodium dodecyl sulfate (SDS) for another 60 minutes. During dissolution, the medium temperature was maintained at 37 ± 0.5 °C, and the paddle rotation speed was kept at 75 rpm. Samples were taken at 15 min, 30 min, 35 min, 45 min, 60 min, 75 min, and 90 min (the maximum rotation speed from 75 min to 90 min was 250 rpm). The samples were filtered through a 0.45 μm microporous membrane, and the filtrate was analyzed by HPLC to determine the dissolution amount. The results are shown in Table 28 below.

[0298] Table 28: Dissolution results of solid tablets in Examples 13-15

[0299]

[0300] As can be seen from Table 28, the solid tablets of Examples 14 and 15 showed comparable dissolution in the two-stage dissolution experiment, and were basically consistent with the dissolution of Example 13.

[0301] It should be understood that the above description may illustrate one or more, but not all, exemplary embodiments of the present invention, and the scope of the present invention should not be limited to any of the above exemplary embodiments.

[0302] If aspects of the invention are described as “comprising” or “including” features, embodiments “consisting of” or “substantially consisting of” are also conceivable.

[0303] All the various aspects, implementation schemes, options, and numerical ranges described in this article can be combined in any and all variations.

[0304] The foregoing description of specific embodiments so fully reveals the general nature of the invention that others can readily modify and / or adapt various applications of such specific embodiments by applying knowledge of the art without departing from the general concept of the invention, without excessive experimentation. Therefore, such adaptations and modifications are also included within the meaning and scope of equivalents of the disclosed embodiments, based on the teachings and guidance set forth herein. It should be understood that the wording or terminology used herein is for descriptive purposes and not for limitation, and therefore the terminology or terminology of this specification will be interpreted by those skilled in the art based on the teachings and guidance.

[0305] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent, or patent application were expressly and individually indicated to be incorporated by reference. If any meaning or definition of a term herein conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term herein shall prevail.

Claims

1. A pharmaceutical composition comprising or consisting of the following components: a) Compound I, with the following structural formula: ， Or its pharmaceutically acceptable salt; b) One or more matrix polymers; c) One or more fillers (optional); d) One or more disintegrants may be used; e) One or more optional drowsiness aids; and f) One or more lubricants may be used; The matrix polymer is selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, or a combination thereof; Component a and component b form a solid dispersion.

2. The pharmaceutical composition according to claim 1, wherein component a is pure compound I, which is amorphous.

3. The pharmaceutical composition according to claim 1 or 2, wherein the matrix polymer is hydroxypropyl methylcellulose succinate or hydroxypropyl methylcellulose phthalate.

4. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of component a to component b is from 1:9 to 4:

6.

5. The pharmaceutical composition according to claim 1, wherein the solid dispersion is obtained by spray drying.

6. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprises or consists of the following components: a) 0.5 to 20% by weight of compound I; b) 1.0 to 40% by weight of a matrix polymer selected from hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate; c) 20 to 95% by weight of filler, which is a combination of insoluble and soluble filler, wherein the insoluble filler is microcrystalline cellulose and the soluble filler is lactose monohydrate and / or mannitol. d) 0.5 to 40% by weight of a disintegrant, which is croscarmellose sodium; e) 0.2 to 10% by weight of a flow aid, which is colloidal silica; f) 0.2 to 6% by weight of a lubricant selected from magnesium stearate; The weight percentage is based on the total weight of the pharmaceutical composition.

7. A pharmaceutical composition comprising or consisting of the following components: a) Compound I, with the following structural formula: ， Or its pharmaceutically acceptable salt; b) One or more acid regulators; c) One or more fillers (optional); d) Optional one or more adhesives; e) One or more surfactants, optionally; f) One or more optional disintegrants; and g) One or more lubricants may be used; The acid regulator mentioned therein is tartaric acid, maleic acid, or a combination thereof.

8. The pharmaceutical composition according to claim 7, wherein component a is pure compound I, which is amorphous, crystalline, or a combination thereof.

9. The pharmaceutical composition according to claim 7 or 8, wherein the acidity regulator is tartaric acid or maleic acid.

10. The pharmaceutical composition according to claim 7 or 8, wherein component c is a combination of an insoluble filler and a soluble filler, wherein the insoluble filler is microcrystalline cellulose, and the soluble filler is lactose monohydrate, calcium hydrogen phosphate, mannitol, or any combination thereof.

11. The pharmaceutical composition according to claim 7 or 8, wherein the weight ratio of the insoluble filler to the soluble filler is at least 1:9 and at most 9:

1.

12. The pharmaceutical composition of claim 11, wherein the weight ratio of the insoluble filler to the soluble filler is at least 2:8 and at most 8:

2.

13. The pharmaceutical composition of claim 11, wherein the weight ratio of the insoluble filler to the soluble filler is at least 3:7 and at most 7:

3.

14. The pharmaceutical composition of claim 11, wherein the weight ratio of the insoluble filler to the soluble filler is at least 4:6 and at most 6:

4.

15. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition comprises or consists of the following components: a) 0.5 to 20% by weight of compound I; b) 1 to 10% by weight of an acid regulator, which is maleic acid; or 5 to 40% by weight of an acid regulator, which is tartaric acid; c) 20 to 95% by weight of filler, which is a combination of insoluble and soluble filler, wherein the insoluble filler is microcrystalline cellulose and the soluble filler is lactose monohydrate and / or mannitol. d) 0.5 to 10% by weight of an adhesive, which is hydroxypropyl methylcellulose; e) 0.2 to 6.0% by weight of a surfactant, which is sodium dodecyl sulfate; f) 0.5 to 40% by weight of a disintegrant, which is croscarmellose sodium; and g) 0.2 to 6% by weight of a lubricant, which is magnesium stearate; The weight percentage is based on the total weight of the pharmaceutical composition.

16. A solid coated tablet comprising a tablet core and a coating film, wherein the tablet core is prepared from a pharmaceutical composition according to any one of claims 1 to 15, and wherein the coating film is formed from one or more coating agents, the coating agent being a gastric-soluble film-coating premix.

17. The solid coated tablet of claim 16, wherein the coating agent is selected from Opadry, Eutrapeptide, and combinations thereof.

18. The solid coated tablet of claim 16 or 17, wherein the weight gain percentage of the coating agent is 1 to 10% by weight, based on the weight of the tablet core.

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