Composition of ATX inhibitor and preparation method thereof

Abstract

The invention relates to a composition of an ATX inhibitor and a preparation method thereof, and the pharmaceutical composition comprises a compound shown in an active ingredient formula (I) or a pharmaceutically acceptable salt thereof, and at least one of a filler, an adhesive, a disintegrating agent, a glidant or a lubricant. The pharmaceutical composition has the advantages of good dissolution rate, low impurity content, good stability and the like.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to a composition of an ATX inhibitor and a preparation method thereof. Background Art

[0002] Autotaxin (ATX), also known as ENPP2, is a secreted enzyme that is mainly highly expressed in cancer cells, bronchial epithelial cells in the lungs, and alveolar macrophages. ATX is the only ENPP enzyme with lysophospholipase D (lysoPLD) activity and mainly converts lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA). The ATX-LPA signaling pathway is involved in many physiological and pathological processes, leading to its important connection with many serious diseases, mainly including cancer, fibrotic diseases, pain, immune diseases, inflammatory nervous system, and cardiovascular diseases (Nicolas, D. et al. US8993590B2).

[0003] The ATX-LPA functional axis plays an important role in fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF). Inhibitors targeting this functional axis mainly include ATX inhibitors, LPA receptor inhibitors, and LPA monoclonal antibodies, etc. Compared with traditional kinase inhibitors, ATX inhibitors regulate the signal pathways related to cell proliferation, survival, apoptosis, and migration by inhibiting the formation of LPA, and can potentially be used for the treatment of various cancers. Moreover, since the LPA signaling pathway is closely related to the fibrosis of multiple organs, it is an important target for studying new fibrotic diseases.

[0004] Currently, WO2022007882A1 has disclosed a new class of heteroaromatic compounds, the specific structure of which is shown in formula (I) (hereinafter referred to as compound A), which is a compound of an ATX inhibitor and has a high inhibitory activity against ATX and can be used for the treatment of pulmonary fibrosis, renal fibrosis, or hepatic fibrosis. Patent WO2023185979A1 discloses the crystal form of compound A.

[0005]

[0006] However, currently, there is no report on the prescription process of a single active ingredient preparation of compound A. As an ATX inhibitor, it is necessary to rapidly reach an effective blood drug concentration in the body to exert its efficacy, and the development of its oral immediate-release preparation is particularly necessary.

[0007] Compound A has poor solubility, and its in vivo bioavailability can be effectively improved by controlling the particle size of Compound A within a smaller range. However, Compound A with a small particle size has a low density and poor fluidity. Therefore, it is necessary to provide a pharmaceutical composition containing Compound A, which can improve the particle density of Compound A and the particle fluidity through a granulation process to meet the requirements of capsule filling. Summary of the Invention

[0008] Problems to be Solved by the Invention

[0009] In view of the defects of the prior art, the present invention provides a pharmaceutical composition applicable to a granulation process, which contains an active ingredient of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof, and at least one of a filler, a binder, a disintegrant, a glidant or a lubricant. This pharmaceutical composition has the advantages of rapid dissolution, low impurity content, good stability, good fluidity, etc., and meets the requirements of capsule filling.

[0010] Solutions for Solving the Problems

[0011] The present invention provides a pharmaceutical composition, which contains an active ingredient of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof, and at least one of a filler, a binder, a disintegrant, a glidant or a lubricant.

[0012]

[0013] Preferably, the content of the active ingredient is 10-70% of the total weight of the pharmaceutical composition, preferably 30-70%, more preferably 35-68%, and most preferably 40-68%.

[0014] Preferably, the content of the active ingredient is at most 1200 mg (calculated as the free base), preferably at most 1000 mg, 500 mg, 200 mg, 100 mg, 25 mg or 5 mg, and more preferably at most 200 mg or 25 mg.

[0015] Preferably, the particle size distribution of the active ingredient is D 50 < 100 μm, preferably D 50 < 50 μm, more preferably D 50 < 10 μm.

[0016] Preferably, the filler is selected from at least one of cellulose, microcrystalline cellulose, lactose, and starch, preferably at least two of cellulose, microcrystalline cellulose, lactose, and starch, more preferably a combination of microcrystalline cellulose and lactose, and the weight ratio of the microcrystalline cellulose to the lactose is 0.1-5:1, preferably 1-4:1.

[0017] Preferably, the content of the filler is 15-80% of the total weight of the pharmaceutical composition, preferably 20-60%, more preferably 25-55%.

[0018] Preferably, the binder is selected from at least one of hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose, preferably from hypromellose and / or hydroxypropyl cellulose, more preferably from hypromellose.

[0019] Preferably, the content of the binder is 2-5% of the total weight of the pharmaceutical composition, preferably 2-4%, more preferably 2.5-3.5%.

[0020] Preferably, the disintegrant is selected from at least one of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone, preferably from croscarmellose sodium and / or crospovidone, more preferably from croscarmellose sodium.

[0021] Preferably, the content of the disintegrant is 1-6% of the total weight of the pharmaceutical composition, preferably 2-6%, more preferably 3-6%.

[0022] Preferably, the glidant is selected from at least one of colloidal silicon dioxide, precipitated silica, light anhydrous silicic acid, microcrystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch, or magnesium aluminum metasilicate, preferably colloidal silicon dioxide and / or precipitated silica.

[0023] Preferably, the content of the glidant is 0.1-6% of the total weight of the pharmaceutical composition, preferably 0.1-4%, more preferably 0.1-1%.

[0024] Preferably, the lubricant is selected from at least one of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal silica, talc, and colloidal silicon dioxide, preferably from magnesium stearate and / or colloidal silicon dioxide.

[0025] Preferably, the content of the lubricant is 0.25-5% of the total weight of the pharmaceutical composition, preferably 0.25-1%, more preferably 0.3-0.8%.

[0026] Preferably, the pharmaceutical composition comprises: the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, microcrystalline cellulose, lactose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0027] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows:

[0028]

[0029] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows:

[0030]

[0031] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows:

[0032]

[0033] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows:

[0034]

[0035] Or,

[0036]

[0037] Preferably, the pharmaceutical composition is an oral preparation, preferably a tablet or a capsule, more preferably a capsule.

[0038] Preferably, the pharmaceutically acceptable salts of the compound shown in (I) are selected from hydrochloride, sulfate, phosphate, mesylate, benzenesulfonate and p-toluenesulfonate, preferably p-toluenesulfonate.

[0039] The present invention also provides a method for preparing the pharmaceutical composition according to any one of the above, comprising the step of mixing the compound shown in formula (I) or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipients.

[0040] Preferably, the method is selected from wet granulation, dry granulation or direct powder compression, preferably wet granulation.

[0041] The present invention also provides an application of the pharmaceutical composition according to any one of the above in the preparation of a drug for treating and / or preventing diseases related to ATX (autotaxin).

[0042] Preferably, the ATX-related diseases are fibrotic diseases, cancers, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, diseases related to abnormal angiogenesis or pain, preferably fibrotic diseases, cancers, dermatological diseases, preferably pulmonary fibrosis (such as idiopathic pulmonary fibrosis), liver fibrosis, scleroderma, renal cancer, pancreatic cancer or cholestatic pruritus.

[0043] Effects of the invention

[0044] Through creative research, it is found that the pharmaceutical composition of the present invention has rapid dissolution, low impurity content, good stability, as well as good safety and effectiveness. Meanwhile, it is easy to prepare and suitable for industrial production.

[0045] In addition, the drug granules obtained by using the pharmaceutical composition of the present invention in the granulation process can effectively increase the density of the product granules at a high proportion of the fine powder active ingredient, improve the fluidity of the active ingredient granules, and can meet the capsule filling requirements of products with different specifications. Description of the Drawings

[0046] Figure 1 It is the dissolution curve of the capsule of Prescription 1 of the present invention.

[0047] Figure 2 It is the dissolution curve of the capsules of Prescriptions 2 and 3 of the present invention.

[0048] Figure 3 It is the dissolution curve of the capsule of Prescription 4 of the present invention.

[0049] Figure 4 It is the dissolution curve of the capsule of Prescription 5 of the present invention. Detailed Embodiments

[0050] To make the technical solutions and beneficial effects of the present invention more obvious and understandable, the following provides a detailed description by way of listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical and scientific fields to which this application belongs.

[0051] The inventor found that the powder of Compound A is fine and has poor fluidity. Therefore, a rapid-release preparation prescription containing this compound is provided. This preparation prescription is suitable for the granulation process and can obtain drug granules with high fluidity, good stability, and excellent rapid-release performance.

[0052] Terms and Definitions

[0053] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0054] In the present application, the compound of formula (I) includes its free base form and its pharmaceutically acceptable salt form. The "pharmaceutically acceptable salt" includes, but is not limited to, p-toluenesulfonate.

[0055] In the present application, the content of the compound of formula (I) in the pharmaceutical composition is calculated in its free base form.

[0056] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0057] The "filler" used in the present invention, also known as "diluent", refers to a class of excipients used to increase the volume and weight of the pharmaceutical composition product dosage form in a scientific context. Therefore, fillers can be conventionally used in the art, including but not limited to: calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, cellulose acetate, ethyl cellulose, fructose, lactose, lactitol, maltose, maltodextrin, maltitol, mannitol, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, corn starch, dextrin, sucrose, trehalose, and xylitol.

[0058] The "adhesive" used in the present invention refers to a class of excipients that impart increased cohesive force or tensile strength (e.g., hardness) to the pharmaceutical composition. Therefore, adhesives can be conventionally used in the art, including but not limited to: polyvinyl acetate resin, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose phthalate, sodium carboxymethyl cellulose, polyvinylpyrrolidone, povidone, pregelatinized starch, and starch.

[0059] The "disintegrant" used in the present invention refers to a class of excipients used to promote the breakup of the pharmaceutical composition product dosage form into smaller fragments in an aqueous environment in a scientific context. Therefore, disintegrants can be conventionally used in the art, including but not limited to: alginic acid, calcium alginate, calcium carboxymethyl cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, magnesium aluminum silicate, methyl cellulose, povidone, sodium alginate, sodium carboxymethyl cellulose, sodium starch glycolate, and starch.

[0060] The "glidant" used in the present invention refers to an excipient that imparts increased flow properties to the pharmaceutical composition. Therefore, glidants can be conventionally used in the art, including but not limited to: colloidal silicon dioxide, silica gel, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch, or magnesium aluminum metasilicate.

[0061] The "lubricant" used in the present invention refers to a type of excipient used to improve the processing of pharmaceutical composition product dosage forms under a scientific background. Therefore, the lubricant can be conventionally used in the art, including but not limited to: calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, hydrogenated vegetable oil, colloidal silicon dioxide, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micro powder silica gel and zinc stearate.

[0062] The preparation method of the pharmaceutical composition described in the present application can be carried out according to methods known in the art. The specific preparation method may include steps such as crushing, mixing, screening, granulation, filling, tableting, etc., and the required steps and methods or equipment for implementing the specific steps are selected according to the actual situation. For example, the crushing step can be carried out using a mortar, a ball mill, a roller press, an impact mill, a hammer mill and / or a jet mill; the mixing step can be carried out by stirring, grinding and / or sieving; the sieving step can be carried out by a shaking screen and / or an oscillating screen. Or refer to "Pharmaceutics" edited by Cui Fude et al. (6th or 7th edition, People's Medical Publishing House).

[0063] The term "externally added" means that during the preparation process of the pharmaceutical composition of the present invention, in order to further improve the powder fluidity and compressibility, promote the disintegration of the pharmaceutical composition, and improve the content uniformity, all or part of the prescribed amount of one or several additional pharmaceutical excipients in the prescription composition of the pharmaceutical composition is added after the granulation process, and the added pharmaceutical excipients are mixed with the granules obtained in the granulation process to obtain the total mixed powder of the pharmaceutical composition.

[0064] The excipients used in this application can be specific models commonly used in the art. For example, microcrystalline cellulose that can be used includes but is not limited to PH101, PH102, PH103, or PH105. For example, hydroxypropyl methylcellulose that can be used includes but is not limited to E3, E5 or E6. For example, colloidal silicon dioxide (also known as colloidal silicon dioxide) that can be used includes but is not limited to Pharma200, AEROSIL 200, or AEROSIL 300. Those skilled in the art can select specific models as needed, and can also refer to the existing technologies such as "Handbook of Pharmaceutical Excipients" 6th edition by Raymond C Rowe et al. or "Compendium of Pharmaceutical Excipients" 2nd edition by Luo Mingsheng et al. for selection.

[0065] Those skilled in the art will understand that certain pharmaceutical excipients can be used in anhydrous form or in one or more hydrated forms. For example, lactose can be used as an anhydrous form or as a monohydrate form. Therefore, in the present invention, "lactose" includes lactose monohydrate, lactose in anhydrous form, and mixtures thereof.

[0066] The term "dissolution or dissolution rate" in this application is tested according to Method 2 of General Chapter 0931, Fourth Part of Chinese Pharmacopoeia 2020 Edition, paddle method (adding sedimentation blue). Using a pH 1.2 buffer solution containing 0.5% SDS as the dissolution medium (900 mL), and the dissolution test is determined at a paddle speed of 75 rpm at 37 ± 0.5 °C. The dissolution rate of the active drug within 60 minutes is greater than 70%, indicating good dissolution.

[0067] The term "Carr index" in this application is an index reflecting the flowability of powder particles. Carr index = (tapped density - bulk density) / tapped density. The term "bulk density" in this application is determined according to "fixed mass method" of General Chapter 0993, Fourth Part of Chinese Pharmacopoeia 2020 Edition; "tapped density" is determined according to "First Method" in "Determination of Tapped Density" of General Chapter 0993, Fourth Part of Chinese Pharmacopoeia 2020 Edition. The Carr index of the powder < 25% indicates that the flowability of the powder is acceptable, meeting the requirements of micro-filling process and capable of capsule filling.

[0068] The pharmaceutical composition of the present application

[0069] This application provides a pharmaceutical composition, which comprises a compound of formula (I) as the active ingredient or a pharmaceutically acceptable salt thereof, and at least one of a filler, a binder, a disintegrant, a glidant or a lubricant.

[0070]

[0071] In certain embodiments, the content of the active ingredient is 10 - 70% of the total weight of the pharmaceutical composition, such as 15%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, etc.

[0072] In certain embodiments, the content of the active ingredient is 30 - 70% of the total weight of the pharmaceutical composition.

[0073] In certain embodiments, the content of the active ingredient is 35 - 68% of the total weight of the pharmaceutical composition.

[0074] In certain embodiments, the content of the active ingredient is 40-68% of the total weight of the pharmaceutical composition.

[0075] In certain embodiments, the content of the active ingredient is 40.8% or 65.1% of the total weight of the pharmaceutical composition.

[0076] In certain embodiments, the content of the active ingredient is at most 1200 mg (in free base form).

[0077] In certain embodiments, the content of the active ingredient is at most 1000 mg, 500 mg, 200 mg, 100 mg, 25 mg or 5 mg (in free base form).

[0078] In certain embodiments, the content of the active ingredient is at most 200 mg or 25 mg (in free base form).

[0079] In certain embodiments, the content of the active ingredient is 200 mg or 25 mg (in free base form).

[0080] In certain embodiments, the particle size distribution of the active ingredient is D 50 < 100 μm.

[0081] In certain embodiments, the particle size distribution of the active ingredient is D 50 < 50 μm.

[0082] In certain embodiments, the particle size distribution of the active ingredient is D 50 < 10 μm.

[0083] In certain embodiments, the filler is selected from at least one of cellulose, microcrystalline cellulose, lactose, and starch.

[0084] In certain embodiments, the filler is selected from at least two of cellulose, microcrystalline cellulose, lactose, and starch.

[0085] In certain embodiments, the filler is selected from the combination of microcrystalline cellulose and lactose.

[0086] In certain embodiments, the weight ratio of the microcrystalline cellulose to the lactose is 0.1-5:1, such as 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, etc.

[0087] In certain embodiments, the weight ratio of the microcrystalline cellulose to the lactose is 1-4:1.

[0088] In certain embodiments, the weight ratio of the microcrystalline cellulose to the lactose is 1-3:1.

[0089] In certain embodiments, the weight ratio of the microcrystalline cellulose to the lactose is 1.5 to 2.5:1.

[0090] In certain embodiments, the weight ratio of the microcrystalline cellulose to the lactose is 1.5 to 2.2:1.

[0091] In certain embodiments, the weight ratio of the microcrystalline cellulose to the lactose is 2:1.

[0092] In certain embodiments, the content of the filler is 15 to 80% of the total weight of the pharmaceutical composition, such as 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 60%, 65%, 70%, 75%, etc.

[0093] In certain embodiments, the content of the filler is 20 to 60% of the total weight of the pharmaceutical composition.

[0094] In certain embodiments, the content of the filler is 25 to 55% of the total weight of the pharmaceutical composition.

[0095] In certain embodiments, the content of the filler is 25 to 52% of the total weight of the pharmaceutical composition.

[0096] In certain embodiments, the binder is selected from at least one of hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose.

[0097] In certain embodiments, the binder is selected from hypromellose and / or hydroxypropyl cellulose.

[0098] In certain embodiments, the binder is selected from hypromellose.

[0099] In certain embodiments, the content of the binder is 2 to 5% of the total weight of the pharmaceutical composition, such as 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, etc.

[0100] In certain embodiments, the content of the binder is 2 to 4% of the total weight of the pharmaceutical composition.

[0101] In certain embodiments, the content of the binder is 2.5 to 3.5% of the total weight of the pharmaceutical composition.

[0102] In certain embodiments, the content of the binder is 3% of the total weight of the pharmaceutical composition.

[0103] In certain embodiments, the disintegrant is selected from at least one of sodium croscarmellose, starch, sodium carboxymethyl starch, and crospovidone.

[0104] In certain embodiments, the disintegrant is selected from sodium croscarmellose and / or crospovidone.

[0105] In certain embodiments, the disintegrant is selected from sodium croscarmellose.

[0106] In certain embodiments, the content of the disintegrant is 1-6% of the total weight of the pharmaceutical composition, such as 1.5%, 2.0%, 2.5%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%, 5.8%, etc.

[0107] In certain embodiments, the content of the disintegrant is 2-6% of the total weight of the pharmaceutical composition.

[0108] In certain embodiments, the content of the disintegrant is 3-6% of the total weight of the pharmaceutical composition.

[0109] In certain embodiments, the content of the disintegrant is 5% of the total weight of the pharmaceutical composition.

[0110] In certain embodiments, the glidant is selected from at least one of colloidal silicon dioxide, precipitated silica, light anhydrous silicic acid, microcrystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch, or magnesium aluminum metasilicate.

[0111] In certain embodiments, the glidant is selected from colloidal silicon dioxide and / or precipitated silica.

[0112] In certain embodiments, the glidant is selected from colloidal silicon dioxide.

[0113] In certain embodiments, the content of the glidant is 0.1-6% of the total weight of the pharmaceutical composition, such as 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%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, etc.

[0114] In certain embodiments, the content of the glidant is 0.1-4% of the total weight of the pharmaceutical composition.

[0115] In certain embodiments, the content of the glidant is 0.1-1% of the total weight of the pharmaceutical composition.

[0116] In certain embodiments, the content of the glidant is 0.5% of the total weight of the pharmaceutical composition.

[0117] In certain embodiments, the lubricant is selected from at least one of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal silicon dioxide, talc, and colloidal silica.

[0118] In certain embodiments, the lubricant is selected from magnesium stearate and / or colloidal silicon dioxide.

[0119] In certain embodiments, the lubricant is selected from magnesium stearate.

[0120] In certain embodiments, the content of the lubricant is 0.25-5% of the total weight of the pharmaceutical composition, such as 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%, 3.0%, 4.0%, 5.0%, etc.

[0121] In certain embodiments, the content of the lubricant is 0.25-2% of the total weight of the pharmaceutical composition.

[0122] In certain embodiments, the content of the lubricant is 0.25-1% of the total weight of the pharmaceutical composition.

[0123] In certain embodiments, the content of the lubricant is 0.3-0.8% of the total weight of the pharmaceutical composition.

[0124] In certain embodiments, the content of the lubricant is 0.5% of the total weight of the pharmaceutical composition.

[0125] In certain embodiments, the pharmaceutical composition comprises: a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, microcrystalline cellulose, lactose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0126] In certain embodiments, the components of the pharmaceutical composition and their weight percentages are:

[0127]

[0128] In certain embodiments, the components of the pharmaceutical composition and their weight percentages are:

[0129]

[0130] In certain embodiments, the components of the pharmaceutical composition and their weight percentages are as follows:

[0131]

[0132]

[0133] In certain embodiments, the components of the pharmaceutical composition and their weight percentages are as follows:

[0134]

[0135] In certain embodiments, the components of the pharmaceutical composition and their weight percentages are as follows:

[0136]

[0137] In certain embodiments, the active ingredient is the p-toluenesulfonate salt of the compound of formula (I) (Compound A).

[0138] In certain embodiments, the pharmaceutical composition is an oral preparation.

[0139] In certain embodiments, the pharmaceutical composition is a tablet or a capsule.

[0140] In certain embodiments, the pharmaceutical composition is a capsule.

[0141] In certain embodiments, the pharmaceutically acceptable salts of the compound of formula (I) are selected from hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0142] In certain embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is p-toluenesulfonate.

[0143] The present invention has screened the types and dosage ratios of various excipients, and finally obtained a pharmaceutical composition with the characteristics of rapid dissolution and good stability. Under the conditions of a pH 1.2 buffer medium containing 0.5% SDS, the dissolution rate (%) of the active ingredient in the pharmaceutical composition reaches 70% or higher at 60 min.

[0144] Preparation method

[0145] The present invention also provides a method for preparing the pharmaceutical composition according to any one of the above, comprising the step of mixing the compound of formula (I) or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipients.

[0146] In certain embodiments, the method is selected from wet granulation, dry granulation, or direct powder compression.

[0147] In certain embodiments, the method is selected from wet granulation.

[0148] In certain embodiments, the dry granulation comprises the following steps: sieving the active substance and a part of the glidant respectively, mixing the sieved active substance, a part of the glidant with the filler, the binder, the disintegrant, and a part of the lubricant to obtain a premix; dry granulating the obtained premix and then sieving to obtain dry granules, mixing the obtained dry granules with the remaining lubricant and glidant to obtain a total mixed powder, and filling into capsules.

[0149] In certain embodiments, the wet granulation comprises the following steps: mixing the active substance with the filler, the binder, the disintegrant, a part of the glidant and a part of the lubricant to obtain a premix; wet granulating the obtained premix and then sieving to obtain wet granules, drying the obtained wet granules to obtain dry granules; sizing the obtained dry granules; mixing the sized dry granules with the remaining lubricant and the remaining glidant to obtain a total mixed powder, and filling into capsules.

[0150] The pharmaceutical composition of the present invention obtained by dry granulation or wet granulation shows advantages such as a fast dissolution rate, excellent particle fluidity, and a low dissolution RSD. At the same time, the preparation process of the pharmaceutical composition provided by the present invention is simple, more suitable for large-scale industrial production, especially suitable for the scale-up production of the wet granulation process.

[0151] The compound of formula (I) and its pharmaceutically acceptable salts according to the present invention can be obtained by the methods described in WO2022007882A1 or WO2023185979A1, the disclosure of which is incorporated herein by reference. All the pharmaceutical excipients used in the present invention can be purchased through commercial channels, such as hydroxypropyl methylcellulose, etc.

[0152] Application

[0153] The present invention also provides the use of the pharmaceutical composition according to any one of the above in the preparation of a drug for treating and / or preventing diseases related to ATX (autotaxin).

[0154] In certain embodiments, the ATX-related diseases are fibrotic diseases, cancers, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, diseases related to abnormal angiogenesis, or pain.

[0155] In certain embodiments, the ATX-related disease is a fibrotic disease, cancer, dermatological disease, preferably pulmonary fibrosis, liver fibrosis, scleroderma, renal cancer, pancreatic cancer or cholestatic pruritus.

[0156] In certain embodiments, the ATX-related disease is idiopathic pulmonary fibrosis.

[0157] The present invention will be further described below through specific examples. Unless otherwise specified herein, "%" represents mass percentage. The materials and reagents in the following examples, unless otherwise specified, are commonly used materials or reagents in the art, and can all be obtained commercially or synthesized by known methods. The experimental methods without specified conditions in the following examples are usually carried out according to conventional experimental conditions or the conditions recommended by the manufacturers of relevant reagents (kits).

[0158] Example 1

[0159] The p-toluenesulfonate of the active ingredient (hereinafter referred to as Compound B) and colloidal silica were passed through a 30-mesh sieve, added to other materials for two-dimensional mixing, magnesium stearate was added, dry granulation was carried out, external materials were added, and manual capsule filling was carried out with a capsule filling module. The specific prescription is shown in Table 1.

[0160] Table 1

[0161]

[0162] As can be seen from Table 1, the particles obtained by dry granulation from the prescription of Example 1 have good flowability.

[0163] Figure 1 The dissolution curve of the capsule of Example 1 is shown. The results show that the capsule of Example 1 has excellent dissolution performance, especially can achieve rapid release of the active ingredient.

[0164] The dry granulation process does not introduce a humid and hot environment, which is beneficial to the chemical stability of the preparation product. However, due to the certain viscosity of Compound B and its relatively high proportion in the prescription, there is a certain degree of adhesion to the rollers of the dry granulator in the dry granulation process of the pharmaceutical composition of Prescription 1.

[0165] Example 2

[0166] After mixing the respective internal components according to Prescriptions 2 and 3 respectively, spraying liquid, supplementary spraying, kneading, wet granulation, wet screening, fluidized bed drying, dry screening, adding external materials, and manual capsule filling with a capsule filling module. The specific prescription is shown in Table 2.

[0167] Table 2

[0168]

[0169]

[0170] As can be seen from Table 2, the particle fluidity obtained by wet granulation from Formulations 2 and 3 of Example 2 is good.

[0171] Figure 2 The dissolution curves of the capsules of Formulations 2 and 3 are shown. The results show that the capsules of Formulations 2 and 3 have excellent dissolution performance, and in particular, can achieve rapid release of the active ingredient. The disintegrant can cause the granules of the capsule contents to disintegrate through different action mechanisms, which is beneficial to the dissolution and absorption of the main drug. Increasing the amount of the disintegrant is beneficial to improving the dissolution rate.

[0172] Example 3

[0173] After mixing the respective internal addition components according to Formulations 4 and 5 respectively, spraying liquid, supplementary spraying, kneading, wet granulation, wet sizing, fluidized bed drying, dry sizing, adding external materials, and manually filling capsules in the capsule filling module. The specific formulations are shown in Table 3.

[0174] Table 3

[0175]

[0176] As can be seen from Table 3, the particle fluidity obtained by wet granulation from Formulations 4 and 5 of Example 3 is good.

[0177] Figure 3 and Figure 4 The dissolution curves of the capsules of Formulations 4 and 5 are shown respectively. The results show that the capsules of Formulations 4 and 5 have excellent dissolution performance, and in particular, can achieve rapid release of the active ingredient.

[0178] It should be understood that the above embodiments are all exemplary and do not cover all possible implementation manners included in the claims. Without departing from the scope of the present disclosure, various deformations and changes can also be made on the basis of the above embodiments. Similarly, the various technical features of the above embodiments can also be arbitrarily combined to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only represent several implementation manners of the present invention and do not limit the protection scope of the present invention patent.

Claims

1. A pharmaceutical composition comprising a compound of formula (I) as the active ingredient or a pharmaceutically acceptable salt thereof, and at least one of a filler, a binder, a disintegrant, a glidant or a lubricant, 2. The pharmaceutical composition according to claim 1, wherein The content of the active ingredient is 10-70% by weight of the total weight of the pharmaceutical composition, preferably 30-70%, more preferably 35-68%, and most preferably 40-68%.

3. The pharmaceutical composition according to claim 2, characterized in that, The content of the active ingredient is at most 1200 mg (calculated as the free base), preferably at most 1000 mg, 500 mg, 200 mg, 100 mg, 25 mg or 5 mg, more preferably at most 200 mg or 25 mg.

4. The pharmaceutical composition according to claim 1, characterized in that, The particle size distribution of the active ingredient is D 50 <100 μm, preferably D 50 <50 μm, more preferably D 50 <10 μm.

5. The pharmaceutical composition according to claim 1, wherein The filler is selected from at least one of cellulose, microcrystalline cellulose, lactose, starch, preferably at least two of cellulose, microcrystalline cellulose, lactose, starch, more preferably a combination of microcrystalline cellulose and lactose, and the weight ratio of the microcrystalline cellulose to the lactose is 0.1-5:1, preferably 1-4:1; and / or, The content of the filler is 15-80% by weight of the total weight of the pharmaceutical composition, preferably 20-60%, more preferably 25-55%.

6. The pharmaceutical composition according to claim 1, wherein The binder is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, methylcellulose, preferably hydroxypropyl methylcellulose and / or hydroxypropyl cellulose, more preferably hydroxypropyl methylcellulose; and / or, The content of the binder is 2-5% by weight of the total weight of the pharmaceutical composition, preferably 2-4%, more preferably 2.5-3.5%.

7. The pharmaceutical composition according to claim 1, wherein The disintegrant is selected from at least one of croscarmellose sodium, starch, sodium carboxymethyl starch and crospovidone, preferably croscarmellose sodium and / or crospovidone, more preferably croscarmellose sodium; and / or, The content of the disintegrant is 1-6% by weight of the total weight of the pharmaceutical composition, preferably 2-6%, more preferably 3-6%.

8. The pharmaceutical composition according to claim 1, wherein, The glidant is selected from at least one of colloidal silicon dioxide, precipitated silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch or magnesium aluminum metasilicate, preferably colloidal silicon dioxide and / or precipitated silicon dioxide; and / or, The content of the glidant is 0.1-6% by weight of the total weight of the pharmaceutical composition, preferably 0.1-4%, more preferably 0.1-1%.

9. The pharmaceutical composition according to claim 1, characterized in that, The lubricant is selected from at least one of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, microcrystalline silica, talc, colloidal silicon dioxide, preferably magnesium stearate and / or colloidal silicon dioxide; and / or, The content of the lubricant is 0.25-5% by weight of the total weight of the pharmaceutical composition, preferably 0.25-1%, more preferably 0.3-0.8%.

10. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition comprises: a compound of formula (I) as the active ingredient or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

11. The pharmaceutical composition according to claim 10, wherein The components of the pharmaceutical composition and their weight percentages are:

12. The pharmaceutical composition according to claim 11, wherein The components of the pharmaceutical composition and their weight percentages are:

13. The pharmaceutical composition according to claim 11, characterized in that, The components and their weight percentages of the pharmaceutical composition are as follows:

14. The pharmaceutical composition according to claim 13, characterized in that, The components and their weight percentages of the pharmaceutical composition are as follows: Or, 15. The pharmaceutical composition according to any one of claims 1 to 14, characterized in that, The pharmaceutical composition is an oral preparation, preferably a tablet or a capsule, more preferably a capsule; And / or, the pharmaceutically acceptable salts of the compound shown in (I) are selected from hydrochloride, sulfate, phosphate, mesylate, benzenesulfonate and p-toluenesulfonate, preferably selected from p-toluenesulfonate.

16. A method for preparing the pharmaceutical composition according to any one of claims 1 to 15, comprising the step of mixing the compound shown in formula (I) or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipients; Preferably, the method is selected from wet granulation, dry granulation or direct powder compression, preferably wet granulation.

17. Use of a pharmaceutical composition according to any one of claims 1 to 15 in the preparation of a medicament for the treatment and / or prevention of diseases related to ATX (autotaxin).

18. The use according to claim 17, wherein the ATX-related diseases are fibrotic diseases, cancers, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, diseases related to abnormal angiogenesis or pain, preferably fibrotic diseases, cancers, dermatological diseases, preferably pulmonary fibrosis, liver fibrosis, scleroderma, renal cancer, pancreatic cancer or cholestatic pruritus.

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