IRAK4 inhibitor composition, its preparation method and use

Abstract

An IRAK4 inhibitor composition, its preparation method and use. The composition comprises (i) a compound of Formula I, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof, (ii) a diluent; (iii) a disintegrant; and (iv) a lubricant. The structure of Formula I is shown below: TIFF2025526471000025.tif42165

Description

[Technical Field]

[0001] This application claims priority to a prior application bearing patent application number 202210917341.X and entitled "IRAK4 inhibitor Composition and Preparation Method and Use Thereof," filed with the Intellectual Property Office of the People's Republic of China on August 1, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of medicine, and in particular to an IRAK4 inhibitor composition and its preparation method and use. [Background technology]

[0003] Interleukin-1 receptor-associated kinases (IRAKs) are a family of intracellular serine / threonine protein kinases. Four members, IRAK1, IRAK2, IRAK-M, and IRAK4, share a common characteristic of possessing a typical N-terminal death domain, which induces interaction with MyD88 family adaptor proteins and a central kinase domain. Of these, only IRAK1 and IRAK4 possess kinase activity. IRAK4 is a key downstream factor in the inflammatory signaling pathway induced by Toll-like receptors (TLRs) / interleukin-1 receptors (IL-1Rs). The extracellular domain of TLRs recognizes pathogen-specific molecules (e.g., lipopolysaccharides, polypeptides, and viral DNA). After binding to its ligand, the intracellular IL-1R recruits MyD88 and other receptors to form a complex, which activates the autophosphorylation of IRAK1, which then activates the downstream serine / threonine kinase TAK1, which activates the NF-κB and MAPK signaling pathways, subsequently producing pro-inflammatory cytokines, chemokines, and destructive enzymes, ultimately inducing an inflammatory response and inducing innate immunity. IL-1R is involved in host defense and hematopoiesis, and functions as a bridge between innate and adaptive immunity.

[0004] WO2021057785A1 discloses an IRAK inhibitor composition comprising a compound of formula I. Currently, there are no documents disclosing stable pharmaceutical formulations of the compound of formula I. [ka] [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2021 / 057785 Summary of the Invention [Means for solving the problem]

[0006] In order to solve the problems of the prior art, the object of the present invention is to provide a pharmaceutical composition with good solubility, low impurity content, and good stability.

[0007] Thus, the present invention relates in one aspect to a pharmaceutical composition comprising: (i) A compound of Formula I, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, wherein the structure of Formula I is as follows: [ka] (ii) diluents; (iii) disintegrants; (iv) Contains a lubricant.

[0008] According to one embodiment of the present invention, the composition may further optionally comprise at least one of (v) a fluidizing agent and (vi) a surfactant.

[0009] According to one embodiment of the present invention, the diluent is selected from at least one of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and lactose. Preferably, the diluent is selected from at least one of anhydrous calcium hydrogen phosphate and microcrystalline cellulose. In some embodiments, the diluent is a combination of anhydrous calcium hydrogen phosphate and microcrystalline cellulose. Preferably, the weight ratio of anhydrous calcium hydrogen phosphate to microcrystalline cellulose is 1:10 to 10:1, e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1; preferably, 2:1 to 6:1, more preferably, 3:1.

[0010] According to one embodiment of the present invention, the content of the diluent, based on the total weight of the composition, can be any value within the range of 18% to 90%, or any range formed by a combination of any values within this range, for example, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 12 %, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, etc.

[0011] According to one embodiment of the present invention, the fluidizing agent is selected from colloidal silicon dioxide. Based on the total weight of the composition, the content of the fluidizing agent can be in the range of 0.1% to 5%. Based on the total weight of the composition, the content of the fluidizing agent can be any value within the range of 0.1% to 5%, or any range formed by a combination of any values within the range, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, etc.

[0012] According to one embodiment of the present invention, the disintegrant is selected from at least one of cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked povidone, preferably at least one of cross-linked sodium carboxymethylcellulose and sodium carboxymethyl starch, more preferably sodium carboxymethyl starch. Based on the total weight of the composition, the content of the disintegrant may be any value within the range of 1% to 10%, or a range formed by combining any values within the range, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.

[0013] According to one embodiment of the present invention, the surfactant is selected from at least one of sodium dodecyl sulfate, Tween 80, poloxamer, and potassium oleate, preferably sodium dodecyl sulfate. Based on the total weight of the composition, the content of the surfactant may be any value within the range of 1% to 5%, or a range formed by combining any values within the range, such as 1%, 2%, 3%, 4%, 5%, etc.

[0014] According to one embodiment of the present invention, the lubricant is selected from at least one of magnesium stearate, talc, sodium stearyl fumarate, zinc stearate, sodium lauryl sulfate, and hydrogenated vegetable oil, and preferably magnesium stearate. Based on the total weight of the composition, the content of the lubricant may be any value within the range of 0.1% to 5%, or any range formed by any combination of values within the range, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, etc.

[0015] According to one embodiment of the present invention, the compound of formula I is selected from the following structures: [ka]

[0016] According to an embodiment of the present invention, the pharmaceutically acceptable salt may be, for example, an acid addition salt of a compound of the present invention having a nitrogen atom in a chain or ring and sufficient alkalinity; an acid addition salt that can be formed with the following inorganic acids: for example, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid or disulfate; or an acid addition salt that can be formed with the following organic acids: for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentylpropanoic acid, digluconic acid, 3-hydroxy-2- Naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0017] According to one embodiment of the present invention, a "solvate" refers to an associated complex formed by one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0018] According to one embodiment of the present invention, the compound of formula I may be in different crystalline forms, for example, any of the crystalline forms disclosed in CN202210267507.8 may be adopted.

[0019] In some embodiments, the compound of Formula I is in the form of crystalline Form III, which has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.15±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 24.32±0.20°, and 26.08±0.20° using Cu-Kα radiation.

[0020] According to one embodiment of the present invention, crystalline Form III is an anhydrate of Compound A.

[0021] Preferably, crystalline Form III has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 21.09±0.20°, 24.32±0.20°, and 26.08±0.20° using Cu-Kα radiation.

[0022] Preferably, crystalline Form III has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 18.74±0.20°, 21.09±0.20°, 23.51±0.20°, 24.32±0.20°, and 26.08±0.20° using Cu-Kα radiation.

[0023] Preferably, crystalline Form III has the X-ray powder diffraction shown in Table 1, expressed as 2θ angles, with an error range of ±0.20°, using Cu-Kα radiation. [Table 1] Preferably, crystalline Form III has an X-ray powder diffraction pattern substantially as shown in FIG.

[0024] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of crystalline Form III shows that a first endothermic peak appears when heated around a peak temperature of 188.81°C.

[0025] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of crystalline Form III shows little weight loss before 180°C.

[0026] Preferably, crystalline Form III has a DSC-TGA pattern substantially as shown in FIG.

[0027] According to one embodiment of the present invention, crystalline Form III is a crystal having an irregular morphology. Preferably, the particle size of crystalline Form III is less than 5 μm. Preferably, crystalline Form III has a PLM pattern substantially as shown in FIG.

[0028] In some embodiments, Compound A is in the form of crystalline Form VII, which has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.94±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, and 24.23±0.20° using Cu-Kα radiation.

[0029] According to one embodiment of the present invention, crystalline Form VII is an anhydrate of Compound A.

[0030] Preferably, crystalline Form VII has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, 22.54±0.20°, and 24.23±0.20° using Cu-Kα radiation.

[0031] Preferably, crystalline Form VII has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.11±0.20°, 21.75±0.20°, 22.54±0.20°, 24.23±0.20°, 26.62±0.20°, and 31.64±0.20° using Cu—Kα radiation.

[0032] Preferably, crystalline Form VII has the X-ray powder diffraction shown in Table 2, expressed as 2θ angles, with an error range of ±0.20°, using Cu-Kα radiation. [Table 2] Preferably, crystalline Form VII has an X-ray powder diffraction pattern substantially as shown in FIG.

[0033] According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of crystalline Form VII shows that a first endothermic peak appears when heated around a peak temperature of 201.07°C.

[0034] According to one embodiment of the present invention, thermogravimetric analysis (TGA) of crystalline Form VII shows little weight loss before 200°C, for example, little weight loss before 180°C.

[0035] Preferably, crystalline Form VII has a DSC-TGA pattern substantially as shown in FIG.

[0036] According to one embodiment of the present invention, crystalline Form VII is a crystal having an irregular morphology. Preferably, the particle size of crystalline Form VII is less than 5 μm. Preferably, crystalline Form VII has a PLM pattern substantially as shown in FIG.

[0037] In some embodiments, the pharmaceutical composition comprises the following ingredients in weight percent: 5-15% of a compound of formula I Anhydrous calcium hydrogen phosphate 55-65% Microcrystalline cellulose 15-25% Sodium dodecyl sulfate 0.5~5% Colloidal silicon dioxide 0.5-2% Cross-linked sodium carboxymethylcellulose or sodium carboxymethyl starch 1-5% Magnesium stearate 0.5~5%

[0038] In some embodiments, the pharmaceutical composition comprises the following ingredients in weight percent: 8-12% of the compound of formula I Anhydrous calcium hydrogen phosphate 60-65% Microcrystalline cellulose 18-25% Sodium dodecyl sulfate 0.5~3% Colloidal silicon dioxide 0.5-1.5% Cross-linked sodium carboxymethylcellulose 2.5-3.5% Magnesium stearate 0.5~1.5%

[0039] In some embodiments, the pharmaceutical composition comprises the following ingredients in weight percent: Compound of Formula I 10% Anhydrous calcium hydrogen phosphate 63% Microcrystalline cellulose 21% Sodium dodecyl sulfate 1% Colloidal silicon dioxide 1% Cross-linked sodium carboxymethylcellulose 3% Magnesium stearate 1%

[0040] In some embodiments, the pharmaceutical composition comprises the following ingredients in weight percent: Compound of Formula I 8-12% Anhydrous calcium hydrogen phosphate 60-63% Microcrystalline cellulose 18-25% Sodium dodecyl sulfate 2.5~3.5% Colloidal silicon dioxide 0.5-1.5% Sodium carboxymethyl starch 2.5~3.5% Magnesium stearate 0.5~1.5%

[0041] In some embodiments, the pharmaceutical composition comprises the following ingredients in weight percent: 10% of the compound of formula I Anhydrous calcium hydrogen phosphate 61.5% Microcrystalline cellulose 20.5% Sodium dodecyl sulfate 3% Colloidal silicon dioxide 1% Sodium carboxymethyl starch 3% Magnesium stearate 1%

[0042] According to one embodiment of the present invention, the pharmaceutical composition may be an oral preparation selected from tablets, capsules, mini-tablets, or granules, preferably tablets.

[0043] In some embodiments, the pharmaceutical composition of the present invention is a tablet comprising a core and a coating agent, wherein the coating agent is selected from at least one of hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, polyacrylic acid resin, and Opadry. Preferably, the coating agent is Opadry (e.g., Opadry I and Opadry II). The weight of the coating accounts for 1-5%, preferably 1-4%, and more preferably 2% of the total weight of the tablet.

[0044] In another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising combining a compound of formula I with other ingredients and compressing into tablets.

[0045] According to one embodiment of the present invention, the preparation method further comprises a coating step.

[0046] According to one embodiment of the present invention, the preparation method further comprises the following coating step: (1) Passing a disintegrant, a lubricant, and a portion of a diluent through a 20 to 60 mesh sieve; (2) Passing the compound of formula I, or optionally the compound, together with a fluidizing agent and a surfactant through a 40-100 mesh sieve to obtain a premix material 1; then adding the remaining diluent and the premix material 1 to a hopper and mixing, and then passing the mixture through a 40-100 mesh sieve to obtain a premix material 2; (3) sequentially placing and mixing a disintegrant, a diluent, and a premix material 2 that have been passed through a 20 to 60 mesh sieve into a hopper mixer; (4) adding the lubricant passed through a 20 to 60 mesh sieve to the hopper mixer and mixing; (5) placing the entire powder blend into a tablet press for tableting.

[0047] According to one embodiment of the present invention, the preparation method includes the following steps: (1) weighing the compound of formula I, sodium dodecyl sulfate, colloidal silicon dioxide, sodium carboxymethyl starch, and magnesium stearate; dividing the microcrystalline cellulose into two portions and weighing them; dividing the anhydrous calcium hydrogen phosphate into two portions and weighing them, one portion being 1 / 3 of the formulation amount and the other portion being 2 / 3 of the formulation amount; (2) Passing 2 / 3 of the anhydrous calcium hydrogen phosphate, 1 / 2 of the microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate through a 40 mesh sieve; (3) mixing the compound of formula I, colloidal silicon dioxide, and sodium dodecyl sulfate, then passing the mixture through a 60-mesh sieve to obtain premix material 1, then adding 1 / 2 of microcrystalline cellulose, and then adding 1 / 3 of anhydrous calcium hydrogen phosphate and premix material 1 into a hopper, mixing, and passing the mixture through a 60-mesh sieve to obtain premix material 2; (4) sequentially adding 1 / 2 of the microcrystalline cellulose, premix material 2, sodium carboxymethyl starch, and 2 / 3 of the anhydrous calcium hydrogen phosphate to a hopper mixer and mixing; (5) adding magnesium stearate to the hopper mixer and kneading; (6) placing the entire powder blend into a tablet press for tableting.

[0048] According to one embodiment of the present invention, the preparation method includes adding Opadry to a film coating premix (gastro-soluble); preparing an Opadry coating powder suspension for coating at 12% solids.

[0049] In another aspect, the invention relates to the use of the pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of a disease or condition mediated by IRAK.

[0050] According to one embodiment of the present invention, the IRAK-mediated disease or condition is selected from diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, pyemia, inflammatory bowel disease, rheumatoid arthritis, asthma, and allergies.

[0051] In another aspect, the invention relates to the use of the pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of a disease or condition mediated by interleukin-1 receptor-associated kinase.

[0052] According to one embodiment of the present invention, the interleukin-1 receptor-linked kinase mediated disease or condition is selected from diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, rheumatoid arthritis, psoriasis, pyemia, autoimmune diseases and allergies.

[0053] In another aspect, the present invention relates to a method for preventing and / or treating an IRAK-mediated disease or condition, comprising administering a therapeutically effective amount of the pharmaceutical composition to an individual in need thereof.

[0054] In some embodiments, the IRAK is selected from IRAK4-related kinases.

[0055] In another aspect, the present invention relates to a method for preventing and / or treating an interleukin-1 receptor-associated kinase disease or condition, comprising administering a therapeutically effective amount of the pharmaceutical composition to an individual in need thereof.

[0056] Unless otherwise specified, numerical ranges set forth in this specification and claims should be understood to be equivalent to reciting at least each specific integer value in the specification, reciting the two endpoints of the range, each integer within the range, and each decimal point within the range.

[0057] Beneficial Effects of the Invention The inventors have found that the compound of formula I has strong adhesive properties and is prone to aggregation during the dissolution process, which does not promote dissolution. Therefore, experimental research has provided a pharmaceutical composition of an IRAK4 inhibitor with good dissolution performance, low impurity content, and good stability. [Brief explanation of the drawings]

[0058] [Figure 1] 1 is an XRPD pattern of crystalline forms II and III. [Figure 2] 1 is a DSC-TGA pattern of crystalline form III. [Figure 3] PLM pattern of crystalline form III (scale 2.5 μm). [Figure 4] 1 is an XRPD pattern of crystalline form VII. [Figure 5] 1 is a DSC-TGA pattern of crystalline form VII. [Figure 6] 1 is a PLM pattern of crystalline form VII (scale 5 μm). DETAILED DESCRIPTION OF THE INVENTION

[0059] The technical solutions of the present invention will be described in more detail below in conjunction with specific examples. It should be understood that the following examples are intended to illustrate and explain the present invention by way of example only, and should not be construed as limiting the scope of protection of the present invention. All technologies achieved based on the above content of the present invention are included in the scope of protection that the present invention aims to provide.

[0060] Unless otherwise specified, raw materials and reagents used in the following examples are either commercially available or can be prepared by known methods.

[0061] The active ingredient used in the examples is the following compound (chemical name: 2-((2-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide): [ka] The compound can be prepared by reference to WO2021057785A1, and the crystalline forms of the compound (including crystalline form III and crystalline form VII) can be obtained by reference to CN202210267507.8. [Example]

[0062] Example 1 Compositions were prepared according to the formulations shown in Table 1, and their dissolution rates were measured.

[0063] Preparation method: The active ingredient, sodium dodecyl sulfate, colloidal silicon dioxide, sodium carboxymethyl starch, magnesium stearate, and film-coating premix (gastrosoluble) Opadry were weighed; microcrystalline cellulose was divided into two portions and weighed; for Formulation 1, lactose was divided into two portions and weighed; for Formulation 2, anhydrous calcium hydrogen phosphate was divided into two portions, one portion being 1 / 3 of the formulation volume and the other being 2 / 3 of the formulation volume. Two-thirds of the anhydrous calcium hydrogen phosphate, one-half of the microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate were each passed through a 40-mesh sieve for later use. The active ingredient, colloidal silicon dioxide, and sodium dodecyl sulfate were mixed, and the mixture was then passed through a 60-mesh sieve to obtain Premix Material 1. Next, 1 / 2 of the microcrystalline cellulose, 1 / 3 of the anhydrous calcium hydrogen phosphate, and Premix Material 1 were added to a hopper, mixed, and passed through a 60-mesh sieve to obtain Premix Material 2. 1 / 2 of the microcrystalline cellulose, Premix Material 2, sodium carboxymethyl starch, and 2 / 3 of the anhydrous calcium hydrogen phosphate were sequentially added to the hopper mixer and mixed. Magnesium stearate was added to the hopper mixer and mixed for 3 minutes. The entire mixed powder was placed in a tablet press for tableting. [Table 3] [Table 4] From Tables 1 and 2, it can be seen that anhydrous calcium hydrogen phosphate promotes the dispersion of the compound of formula I during the dissolution process, and anhydrous calcium hydrogen phosphate and microcrystalline cellulose act as diluents, thereby improving the dissolution efficiency of the formulation.

[0064] Example 2 Formulations 3 and 4 were prepared according to the preparation method for formulation 2. The formula ratios for formulations 3 and 4 are shown in Table 3. [Table 5] [Table 6] From Tables 3 and 4, it can be seen that formulation 3 has better dissolution effect.

[0065] Example 3 Formulations 5, 6, and 7 were prepared according to the method for preparing formulation 2. The formula ratios for formulations 5, 6, and 7 are shown in Table 5. [Table 7] [Table 8] As can be seen from Table 6, when sodium dodecyl sulfate is added to the formulation, the dissolution effect is always good.

[0066] Example 4 Formulations 8 and 9 were prepared according to the method for preparing Formulation 2. The formula ratios for Formulations 8 and 9 are shown in Table 7. [Table 9] [Table 10] As shown in Table 8, adding sodium carboxymethyl starch as a disintegrant to the formulation achieves a better dissolution effect.

[0067] Example 5 Formulations 10 and 11 were prepared according to the preparation method for Formulation 2. [Table 11] [Table 12] As can be seen from Table 10, when the coating agent is either Opadry I or II, the dissolution effect is good.

[0068] Example 6 The stability factors of Formulation 11 are tested under various conditions as shown in Table 11. [Table 13] As can be seen from Table 11, the dissolution of the composition does not change significantly under various conditions, and therefore the composition is very stable under all conditions.

[0069] Example 7 The total impurity content of Formulation 11 under various conditions is tested as shown in Table 12. [Table 14] From Table 12, it can be seen that under the accelerated conditions of 40°C / 75%RH, the impurities do not increase under the conditions of open, closed, and closed with desiccant. Therefore, the composition has good stability.

[0070] Example 8 The dissolution results of uncoated tablets of Formulation 11 with different hardness are shown in Table 13. [Table 15] As can be seen from Table 13, the hardness of the composition is in the range of 40 to 70 N, and the dissolution is good.

[0071] Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for illustrating the principles of the present invention. Those skilled in the art can make various insubstantial modifications and improvements to the present invention without departing from the concept of the present invention, all of which fall within the scope of protection claimed by the present invention.

Claims

1. (i) A compound of Formula I, a stereoisomer, solvate, or a pharmaceutically acceptable salt thereof, wherein the structure of Formula I is as follows: 【Chemical 1】 (ii) a diluent; (iii) a disintegrant; and (iv) A pharmaceutical composition comprising a lubricant.

2. 10. The pharmaceutical composition of claim 1, wherein the composition may optionally further comprise at least one of: (v) a fluidizing agent; and (vi) a surfactant.

3. 3. The pharmaceutical composition according to claim 1, wherein the diluent is selected from at least one of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and lactose; preferably, the diluent is selected from at least one of anhydrous calcium hydrogen phosphate and microcrystalline cellulose; more preferably, the diluent is a combination of anhydrous calcium hydrogen phosphate and microcrystalline cellulose, and even more preferably, the mass ratio of anhydrous calcium hydrogen phosphate to microcrystalline cellulose is 1:10 to 10:1; preferably, the content of the diluent is in the range of 18% to 90% based on the total weight of the composition.

4. 4. The pharmaceutical composition according to claim 1, wherein the glidant is selected from colloidal silicon dioxide; preferably, the content of the glidant is in the range of 0.1% to 5%, based on the total weight of the composition.

5. 5. The pharmaceutical composition according to claim 1, wherein the disintegrant is selected from at least one of cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked povidone, preferably at least one of cross-linked sodium carboxymethylcellulose and sodium carboxymethyl starch, more preferably sodium carboxymethyl starch; preferably, the content of the disintegrant is in the range of 1% to 10%, based on the total weight of the composition.

6. 6. The pharmaceutical composition according to claim 1, wherein the surfactant is selected from at least one of sodium dodecyl sulfate, Tween 80, poloxamer, and potassium oleate, and preferably sodium dodecyl sulfate; preferably, the content of the surfactant is in the range of 1% to 5% based on the total weight of the composition.

7. 7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that the lubricant is selected from at least one of magnesium stearate, talc, sodium stearyl fumarate, zinc stearate, sodium lauryl sulfate, and hydrogenated vegetable oil, preferably magnesium stearate; preferably, the content of the lubricant is in the range of 0.1% to 5%, based on the total weight of the composition.

8. The compound of formula I is characterized in that it is selected from the following structures: 【Chemistry 2】 Preferably, the compound of formula I is in the form of crystalline Form III, said crystalline Form III having an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.15±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 24.32±0.20° and 26.08±0.20° using Cu—Kα radiation; Preferably, the crystalline Form III has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 21.09±0.20°, 24.32±0.20°, and 26.08±0.20° using Cu—Kα radiation; Preferably, the crystalline Form III has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.15±0.20°, 15.04±0.20°, 15.98±0.20°, 16.62±0.20°, 17.14±0.20°, 18.74±0.20°, 21.09±0.20°, 23.51±0.20°, 24.32±0.20°, and 26.08±0.20° using Cu—Kα radiation; Preferably, said crystalline Form III has the X-ray powder diffraction shown in Table 1, expressed as 2-theta angles, with an error range of ±0.20°, using Cu-Kα radiation: 【Table 1】 Preferably, said crystalline Form III has an X-ray powder diffraction pattern substantially as shown in Figure 1; Preferably, differential scanning calorimetry (DSC) analysis of said crystalline Form III shows that a first endothermic peak appears when heated around a peak temperature of 188.81°C; Preferably, thermogravimetric analysis (TGA) of said crystalline Form III shows little weight loss before 180°C; Preferably, said crystalline Form III has a DSC-TGA pattern substantially as shown in Figure 2; Preferably, the compound of formula I is in the form of crystalline form VII, said crystalline form VII having an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.94±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, and 24.23±0.20° using Cu—Kα radiation; Preferably, the crystalline Form VII has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.75±0.20°, 22.54±0.20°, and 24.23±0.20° using Cu—Kα radiation; Preferably, the crystalline Form VII has an X-ray powder diffraction, expressed as 2θ angles, with characteristic peaks at 12.94±0.20°, 13.18±0.20°, 14.41±0.20°, 15.64±0.20°, 17.25±0.20°, 21.11±0.20°, 21.75±0.20°, 22.54±0.20°, 24.23±0.20°, 26.62±0.20°, and 31.64±0.20° using Cu—Kα radiation; Preferably, the crystalline Form VII has the X-ray powder diffraction shown in Table 2, expressed as 2θ angles, with an error range of ±0.20°, using Cu-Kα radiation: 【Table 2】 Preferably, the crystalline Form VII has an X-ray powder diffraction pattern substantially as shown in Figure 4; According to one embodiment of the present invention, differential scanning calorimetry (DSC) analysis of crystalline Form VII shows that an endothermic peak appears when heated around a peak temperature of 201.07°C; According to one embodiment of the present invention, thermogravimetric analysis (TGA) of crystalline Form VII shows little weight loss before 200°C, e.g., little weight loss before 180°C; Preferably, the crystalline Form VII has a DSC-TGA pattern substantially as shown in Figure 5.

9. The pharmaceutical composition is characterized in that it comprises the following ingredients in weight percent: 5-15% of a compound of formula I Anhydrous calcium hydrogen phosphate 55-65% Microcrystalline cellulose 15-25% Sodium dodecyl sulfate 0.5-5% Colloidal silicon dioxide 0.5-2% Cross-linked sodium carboxymethyl cellulose or sodium carboxymethyl starch 1-5% Magnesium stearate 0.5-5%. The pharmaceutical composition according to any one of claims 1 to 8.

10. The pharmaceutical composition is characterized in that it comprises the following ingredients in weight percent: Compound of Formula I 8-12% Anhydrous calcium hydrogen phosphate 60-65% Microcrystalline cellulose 18-25% Sodium dodecyl sulfate 0.5-3% Colloidal silicon dioxide 0.5-1.5% Cross-linked sodium carboxymethylcellulose 2.5-3.5% The pharmaceutical composition according to any one of claims 1 to 9, wherein the magnesium stearate is 0.5 to 1.5%.

11. The pharmaceutical composition is characterized in that it comprises the following ingredients in weight percent: Compound of Formula I 8-12% Anhydrous calcium hydrogen phosphate 60-63% Microcrystalline cellulose 18-25% Sodium dodecyl sulfate 2.5-3.5% Colloidal silicon dioxide 0.5-1.5% Sodium carboxymethyl starch 2.5-3.5% The pharmaceutical composition according to any one of claims 1 to 9, wherein the magnesium stearate is 0.5 to 1.5%.

12. The pharmaceutical composition is characterized in that it comprises the following ingredients in weight percent: Compound of formula I 10% Anhydrous calcium hydrogen phosphate 63% Microcrystalline cellulose 21% Sodium dodecyl sulfate 1% Colloidal silicon dioxide 1% Cross-linked sodium carboxymethylcellulose 3% 11. The pharmaceutical composition of claim 10, wherein magnesium stearate is 1%.

13. The pharmaceutical composition is characterized in that it comprises the following ingredients in weight percent: Compound of formula I 10% Anhydrous calcium hydrogen phosphate 61.5% Microcrystalline cellulose 20.5% Sodium dodecyl sulfate 3% Colloidal silicon dioxide 1% Sodium carboxymethyl starch 3% 12. The pharmaceutical composition of claim 11, wherein magnesium stearate is 1%.

14. 14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the oral formulation is selected from tablets, capsules, mini-tablets, or granules, preferably tablets; preferably, the tablet comprises a core and a coating agent, and the coating agent is selected from at least one of hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, polyacrylic acid resin, and Opadry, more preferably Opadry (e.g., Opadry I and Opadry II); preferably, the mass of the coating accounts for 1-5%, preferably 1-4%, more preferably 2% of the total mass of the tablet.

15. 15. A process for preparing a pharmaceutical composition according to any one of claims 1 to 14, characterized in that the process comprises mixing the compound of formula I with other ingredients and compressing into tablets; preferably, the preparation process further comprises a coating step.

16. The preparation method is characterized in that it comprises the following steps: (1) Passing a disintegrant, a lubricant, and a portion of a diluent through a 20 to 60 mesh sieve; (2) Passing the compound of formula I, or optionally the compound, together with a fluidizing agent and a surfactant through a 40-100 mesh sieve to obtain a premix material 1; then adding the remaining diluent and the premix material 1 to a hopper and mixing, and passing the mixture through a 40-100 mesh sieve to obtain a premix material 2; (3) sequentially placing the disintegrant, the diluent, and the premix material 2, which have been passed through a 20 to 60 mesh sieve, into a hopper mixer and mixing them; (4) adding a lubricant passed through a 20 to 60 mesh sieve to the hopper mixer and mixing; 16. A method for preparing the pharmaceutical composition of claim 15, comprising the step of: (5) placing the entire powder blend into a tablet press for compression.

17. Use of the pharmaceutical composition of any one of claims 1 to 14 in the preparation of a medicament for the prevention and / or treatment of an IRAK-mediated disease or condition, preferably wherein the IRAK-mediated disease or condition is selected from diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, pyemia, inflammatory bowel disease, rheumatoid arthritis, asthma, and allergies.

18. 15. Use of the pharmaceutical composition according to any one of claims 1 to 14 in the preparation of a medicament for the prevention and / or treatment of an interleukin-1 receptor-linked kinase mediated disease or condition, preferably wherein the interleukin-1 receptor-linked kinase mediated disease or condition is selected from diseases such as tumor, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, rheumatoid arthritis, psoriasis, pyemia, autoimmune diseases and allergies.

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