Solid pharmaceutical composition

Abstract

Provided is a solid pharmaceutical composition comprising a compound according to formula 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, wherein the compound according to formula 1 or a pharma- ceutically acceptable salt thereof constitutes about 30% to about 80% of the total weight of the solid pharmaceutical composition. JPEG2024544423000033.jpg86162

Description

【Technical Field】 【0001】 The present invention belongs to the technical field of medicine, and particularly relates to a novel selective EP4 antagonist, 4-{(1S)-1-[({3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]-4-1H-pyrazolyl}carbonyl)amino]ethyl}benzoic acid, and a solid pharmaceutical composition comprising the same and optionally at least one pharmaceutically acceptable carrier, and a method for preparing the same. 【Background Art】 【0002】 The most abundant types of immune cells infiltrating solid tumors include myeloid cells, mainly TAM and MDSC. Depletion of monocytes including TAM and MDSC in animal models significantly inhibits the tumor growth of established tumors (Zeisberger, et al., 2006; Srivastava, et al., 2012). The presence and accumulation of TAM and MDSC in tumors have been well documented in the literature, which is associated with poor prognosis in patients with breast cancer, pancreatic cancer, or other types of cancer (Joyce and Pollard, 2009; Ding, et al., 2009; Ganjoo, et al., 2011; Medrek, et al., 2012; Zhang, et al., 2012). 【0003】 Both TAM and MDSC are derived from immature monocyte precursors. EP4 is one of the four PGE2 receptors expressed on myeloid cells (Wang and DuBois, 2010), and plays an important role in promoting the differentiation of monocytes into TAM and MDSC in the tumor microenvironment (Lechner, et al., 2011; Mao, et al., 2014; Majumder, et al., 2014). Therefore, EP4 antagonism may be a potential anti-cancer therapy, and its mechanism of action is to weaken the formation and function of immunosuppressive TAM and MDSC. 【0004】 The structure of 4-{(1S)-1-[({3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]-4-1H-pyrazolyl}carbonyl)amino]ethyl}benzoic acid is shown in formula 1 and hereafter referred to as AN0025 in this application. It is a potent antagonist that exhibits antitumor activity by modulating the accumulation and function of prostaglandin E2 (PGE2) receptor 4 (EP4) (PG E2-EP4). Observation of immunosuppressive myeloid cells such as tumor-associated macrophages [TAMs] and myeloid-derived suppressor cells [MDSCs] in the tumor microenvironment. 【0005】 JPEG0007874176000001.jpg86162 Oral administration is a more convenient and safer route of administration than other routes of administration (such as intramuscular injection and intravenous injection), and is a preferred method of administration in the drug development process. 【0006】 The AN0025 capsule was developed for Phase I clinical research. It is prepared by combining AN0025 with a pharmaceutically acceptable carrier, and using dry granulation technology, granules containing the active ingredient AN0025 are prepared and filled into hypromellose hollow capsules. Further details of this capsule are described below as "Comparative Example 1". 【0007】 However, the intra-batch variation (RSD) of AN0025 capsule dissolution is relatively large (Figure 1), resulting in low reliability of dissolution test results and making it difficult to establish a good quality assessment method based on dissolution. It is also difficult to evaluate the impact of various material and process variables on product quality, and it is difficult to establish a good quality control method to ensure process robustness and quality consistency of AN0025 preparations across different batches. Therefore, in order to overcome the above-mentioned problem of large dissolution variability, it is necessary to develop an appropriate and robust solid pharmaceutical composition. 【0008】 Content of the invention The present invention relates to a quality-controllable solid dosage form and a method for preparing the same, comprising the compound 4-{(1S)-1-[({3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]-4-1H-pyrazolyl}carbonyl)amino]ethyl}benzoic acid (compound AN0025) and optionally at least one pharmaceutically acceptable carrier. AN0025 belongs to the Biopharmaceutical Classification System as a Class IV drug, i.e., a drug with low dissolution and low permeability. The inventors unexpectedly discovered in experiments that AN0025 tablets prepared by different processes could show better uniformity in in vitro dissolution tests, and that AN0025 tablets prepared with different API particle sizes had similar in vitro dissolution behavior and in vivo exposure levels. The bioavailability of the AN0025 tablets provided by this invention in Beagle dogs is equivalent to that of clinical capsules, but with less individual variability in in vivo exposure (AUC). These results indicate that AN0025 tablets offer better controllability in commercial production and superior efficacy and safety in clinical applications. 【0009】 JPEG0007874176000002.jpg86162 In one embodiment, the present invention provides a solid pharmaceutical composition comprising a compound according to Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the compound according to Formula 1 or a pharmaceutically acceptable salt thereof constitutes about 30% to about 80% of the total weight of the solid pharmaceutical composition, and the dosage form of the solid pharmaceutical composition is a tablet. 【0010】 In one embodiment, the compound of Formula 1 or a pharmaceutically acceptable salt thereof constitutes about 40% to about 60% of the total weight of the solid pharmaceutical composition. 【0011】 In one embodiment, the pharmaceutically acceptable carrier includes one or more selected from fillers, binders, lubricants, disintegrants, and flow enhancers. 【0012】 In one embodiment, pharmaceutically acceptable carriers include the following: a. Fillers that make up approximately 5% to 60% of the total weight of the solid pharmaceutical composition. b. Binders that make up approximately 0% to approximately 8% of the total weight of the solid pharmaceutical composition. c. Disintegrants that make up approximately 0% to approximately 30% of the total weight of the solid pharmaceutical composition. d. Lubricants constituting approximately 0.1% to 10% of the total weight of the solid pharmaceutical composition. e. A flow promoter comprising approximately 0% to 5% of the total weight of the solid pharmaceutical composition. 【0013】 In yet another embodiment, pharmaceutically acceptable carriers include: a. Fillers that make up approximately 10% to 50% of the total weight of the solid pharmaceutical composition. b. Binders that make up approximately 2% to 6% of the total weight of the solid pharmaceutical composition. c. Disintegrants that constitute approximately 0.1% to approximately 25% of the total weight of the solid pharmaceutical composition. d. Lubricants constituting approximately 0.5% to 8% of the total weight of the solid pharmaceutical composition. e. A flow promoter that constitutes approximately 0% to 3% of the total weight of the solid pharmaceutical composition. 【0014】 In preferred embodiments, pharmaceutically acceptable carriers include: a. Fillers that make up approximately 20% to 40% of the total weight of the solid pharmaceutical composition. b. A binder that constitutes approximately 3% to 5% of the total weight of the solid pharmaceutical composition. c. Disintegrants that constitute approximately 1% to 25% of the total weight of the solid pharmaceutical composition. d. Lubricants that constitute approximately 1% to 6% of the total weight of the solid pharmaceutical composition. e. A flow promoter that constitutes approximately 0% to 1% of the total weight of the solid pharmaceutical composition. 【0015】 In one embodiment, the filler is selected from the group comprising microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, starch, dextrin, pregelatinized starch, mannitol, sorbitol, lactose, dextran, sucrose, dextrose, and combinations thereof; the binder is selected from the group comprising cellulose ethers, povidone, copovidone, starch, corn syrup, and combinations thereof, where the class of cellulose ethers includes, but is not limited to, hypromellose, hydroxypropylcellulose, methylcellulose, and hydroxyethylcellulose; the disintegrant is selected from the group comprising sodium crosscarboxymethylcellulose, croscarmellose thulopovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and combinations thereof; the lubricant is selected from the group comprising magnesium stearate, sodium stearyl fumarate, macrogol, glycerin, behenate esters, talc, and combinations thereof. 【0016】 In one embodiment, the filler is selected from microcrystalline cellulose, lactose, mannitol, sorbitol and combinations thereof; the binder is selected from hydroxypropyl cellulose, hypromellose, polyvinyl cellulose, ketones, copovidone and combinations thereof; the disintegrant is selected from sodium crosscarboxymethylcellulose, crospovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose and combinations thereof; and the lubricant is selected from magnesium stearate, sodium stearyl fumarate and combinations thereof. 【0017】 In one embodiment, the solid pharmaceutical composition of the present invention comprises granules having an internal phase. In one embodiment, the solid pharmaceutical composition of the present invention further comprises an outer phase adjacent to the granules having an inner phase. 【0018】 In one embodiment, for the solid pharmaceutical composition provided by the present invention, AN0025 and other pharmaceutically acceptable carriers are prepared into granules having good fluidity and compressibility through a granulation process, and then compressed into tablets. All other pharmaceutically acceptable carriers in the solid pharmaceutical composition can be added internally to participate in the granulation process or partially added as an external phase. 【0019】 In one embodiment, the granules having an inner phase are prepared by a dry preparation process including the following steps: screening and weighing the compound AN0025 and various pharmaceutically acceptable carriers; blending the compound AN0025 and the pharmaceutically acceptable carriers and mixing for an appropriate time; rolling. Making the mixture into a ribbon and crushing the ribbon into granules; mixing the granules with an extragranular excipient for an appropriate time; compressing the mixture into tablets. 【0020】 In one embodiment, the granules having an inner phase are prepared by a wet preparation process including the following steps: screening and weighing the compound AN0025 and each pharmaceutically acceptable carrier; mixing the compound AN0025 and the pharmaceutically acceptable carriers simultaneously with a granulation fluid. Mixing at an appropriate mixing speed for an appropriate time and chopping the mixture into granules. The granulation fluid can be obtained by dispersing a binder in a solvent (water) or a wetting agent such as simply water, and drying the granules. Mixing the granules with an extragranular excipient for an appropriate time and compressing the mixture into tablets. 【0021】 In one embodiment, the solid pharmaceutical composition further comprises a coating. 【0022】 In one embodiment, the compound of formula 1 has a particle size D90 of less than about 200 microns. 【0023】 In a preferred embodiment, the compound of formula 1 has a particle size D90 of less than about 100 microns. 【0024】 In one embodiment, the solid pharmaceutical composition of the present invention contains about 50 mg to about 500 mg of the compound of formula 1. 【0025】 In a preferred embodiment, the solid pharmaceutical composition of the present invention contains about 100 mg to about 300 mg of the compound of Formula 1. 【0026】 In another aspect, the present invention provides the use of solid pharmaceutical compositions in the preparation of pharmaceuticals for the treatment of multiple sclerosis, rheumatoid arthritis, or cancer, the cancers of which include skin cancer, breast cancer, colorectal cancer, prostate cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, glioblastoma, lung cancer, head and neck cancer, medulloblastoma, and urethral cancer. 【0027】 [Brief explanation of the drawing] 【0028】 [Figure 1] Comparison of eluted RSD in Comparative Example 1, Example 1, and Example 2 [Figure 2] Comparison of dissolution curves between Comparative Examples 1, 2, and 3 and Examples 1 and 2 [Figure 3] Drug blood concentration-time curve (750 mg / dog) of capsule formulation (Comparative Example 1) AN0025 in Beagle dogs. [Figure 4] Drug blood concentration-time curve (750 mg / dog) of tablet AN0025 in Beagle dogs (Example 4) [Figure 5] Drug blood concentration-time curve (250 mg / dog) of capsule formulation (Comparative Example 1) AN0025 in Beagle dogs. [Figure 6] Drug blood concentration-time curve (250 mg / dog) for tablet AN0025 in Beagle dogs (Example 4) [Figure 7] Drug blood concentration-time curve (750 mg / dog) for tablet (Example 4a) AN0025 in Beagle dogs. [Modes for carrying out the invention] 【0029】 definition The present invention provides quality-controllable solid pharmaceutical compositions, solid pharmaceutical formulations, and processes for preparing the same, comprising the compound 4-{(1S)-1-[({3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]-4-1H-pyrazolyl}carbonyl)amino]ethyl}benzoic acid (AN0025) and a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier. 【0030】 As used herein, unless otherwise indicated, the following terms have the following meanings: The term “pharmaceutical composition” or “formulation” refers to a physical mixture of therapeutic compounds that affect an individual, administered to an individual (e.g., a human) for the prevention, treatment, or control of a particular disease or condition. For example, as used herein, the terms “pharmaceutical composition” or “formulation” also encompass tightly packed physical mixtures formed under high temperature and pressure. 【0031】 The term "pharmaceutically acceptable" means a compound, material, composition, carrier and / or dosage form that, within the bounds of sound medical judgment, is suitable for contact with individuals, particularly human tissues, without excessive toxicity, irritation, allergic reactions, or other problematic complications, and with a reasonable benefit / risk ratio. 【0032】 The term "pharmaceutically acceptable carrier" refers to any pharmaceutically acceptable inert material that is substantially inactive in terms of biological activity and constitutes a substantial part of a formulation. 【0033】 The term "therapeutic dose" refers to the amount or concentration that is effective in reducing, eliminating, treating, preventing, or controlling the symptoms of a disease or condition affecting an individual. The term "control" refers to all processes that can slow, interrupt, block, or stop the progression of a disease or condition affecting a mammal. However, "control" does not necessarily mean the complete elimination of all symptoms of the disease or condition. 【0034】 The term “treatment” includes not only slowing the progression of a disease or condition, but also preventive and / or therapeutic treatments. Preferably, the term “treatment” refers to therapeutic treatment as well as slowing the progression of a disease or condition. “Slowing progression” refers to the administration of a pharmaceutical composition to an individual in the early or early stages of the cancer being treated, for example, an individual diagnosed with the proplasia of the corresponding disease, or an individual in a situation where the corresponding disease is likely to develop. 【0035】 The term “oral dosage form” refers to a pharmaceutical composition prepared for administration to an individual via an oral route. Known examples of oral dosage forms include, but are not limited to, tablets, capsules, caplets, powders, pills, granules, solutions, suspensions, pre-solution concentrates, emulsions, and pre-emulsion concentrates. In some embodiments, powders, pills, granules, and tablets may be coated with suitable polymers or commonly used coating materials to achieve, for example, higher stability in the gastrointestinal tract or to achieve a desired release rate. Furthermore, capsules containing powders, pills, or granules may be further coated. Tablets may be scored to facilitate split administration. Alternatively, the dosage forms of the present invention may be unit dosage forms, where one unit dosage form is intended to deliver one therapeutic dose per administration, or where multiple unit dosage forms are intended to deliver a total therapeutic dose per administration. 【0036】 The term "administration" refers to the method by which a therapeutic compound is presented to an individual. 【0037】 The term "oral administration" refers to any method of administration by which a therapeutic compound can be delivered via the oral route, such as by swallowing, chewing, or inhaling an oral dosage form. Solid oral dosage forms are traditionally intended to substantially release and / or deliver the active drug in the oral cavity and / or the gastrointestinal tract behind the cheekbone. Examples of solid dosage forms include commonly used tablets, capsules, and caplets. 【0038】 The terms “individual” or “patient” are intended to include animals. Examples of individuals include mammals such as humans, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, an individual is a human, for example, a human who has cancer, is at risk of developing cancer, or is likely to develop cancer (including male and female subjects, and including neonates, infants, adolescents, young adults, adults, and elderly subjects). 【0039】 As used herein, unless otherwise specified, the terms “contains” and “includes” have an open and non-restrictive meaning. 【0040】 Unless otherwise indicated herein, or unless clearly inconsistent with the context, when describing the present invention, particularly in the context of the following claims, the terms "i," "the," and similar terms shall be interpreted as encompassing both singular and plural forms. 【0041】 As used herein, the terms “about” and “approximately” are used to give flexibility to the endpoint of a numerical range by specifying that a given value may be “slightly above” or “slightly below” the endpoint, taking into account the difference between different values, thereby explaining the visible difference in measurements between different instruments, samples, and sample preparations. The terms “about” or “approximately” generally mean within 10%, more preferably within 5%, and most preferably within 1% of a given value or range. 【0042】 For convenience, multiple items, structural elements, components, and / or materials used herein may be presented in lists. However, these lists should be considered as distinct and unique members, as each member of a list is individually identified. Therefore, individual members of a list should not be construed as substantially equivalent on the basis that they belong to a common group with other members of the same list, without implying otherwise. 【0043】 JPEG0007874176000003.jpg86162 Compound: A compound, a pharmaceutically acceptable salt or ester, and various forms thereof. 【0044】 Compound 4-{(1S)-1-[({3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]-4-1H-pyridine azolyl}carbonyl)amino]ethyl}benzoic acid (AN0025) and its pharmaceutically acceptable salts are intended for use in the pharmaceutical compositions of the present invention. This compound, its pharmaceutically acceptable salts, and the preparation thereof are disclosed in WO2012039972A, which is incorporated herein by reference in its entirety. 【0045】 The compounds of Formula 1 may be present in the pharmaceutical compositions of the present invention in the form of free acids or pharmaceutically acceptable salts. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the base or acidic functional group with appropriate organic or inorganic acids or bases, respectively. Examples of acid addition salts that can be used to form pharmaceutically acceptable salts include inorganic acids (hydrochloric acid, boric acid, nitric acid, sulfuric acid), organic acids (phosphoric acid, as well as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, methanesulfonic acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid), and acidic amino acids (e.g., aspartic acid, glutamic acid, etc.). Pharmaceutically acceptable base salts include, but are not limited to, alkali metal and alkaline earth metal-based cations such as sodium, lithium, potassium, calcium, magnesium, and aluminum salts, as well as non-toxic ammonium, quaternary ammonium, and ammonia cations, such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, hexahydropyrazine, pyridine, picoline, and triethanolamine; as well as basic amino acids such as arginine, lysine, and ornithine. 【0046】 According to the present invention, the compound of formula 1 or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical composition in amounts ranging from about 20% to about 90%, about 30% to about 80%, or about 35% to about 70% of the total weight of the composition. In one embodiment, the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount ranging from about 40% to about 60% of the total weight of the entire composition. Preferably, the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in amounts ranging from about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% of the total weight of the entire composition. 【0047】 In addition to the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the solid pharmaceutical composition of the present invention further comprises at least one pharmaceutically acceptable pharmaceutical carrier. Examples of these carriers include, but are not limited to, fillers (or diluents), disintegrants, flow enhancers, binders, stabilizers, colorants, flavor enhancers, preservatives, or combinations thereof. Those skilled in the art can select one or more of the aforementioned excipients by routine experimentation without undue burden to suit specific desired properties of the solid pharmaceutical composition. The amount of each carrier used may vary within the range commonly used in the art. 【0048】 The fillers suitable for use in the present invention are compatible with the components of the pharmaceutical composition, that is, they do not substantially reduce the chemical stability, physical stability, or biological activity of the pharmaceutical composition. Examples of pharmaceutically acceptable fillers include, but are not limited to, cellulose, modified cellulose (e.g., sodium carboxymethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, cellulose powder, calcium phosphate, calcium hydrogen phosphate, starch (corn starch, potato starch, etc.), dextrin, pregelatinized starch, sugars (mannitol, sorbitol, lactose, dextran, sucrose, dextrose, powdered sugar, compressed sugar, etc.), talc, or any combination thereof. In one embodiment of the present invention, the filler is preferably microcrystalline cellulose, mannitol, and / or lactose. In one embodiment of the present invention, the filler may be present in amounts of about 5% to about 60%, about 10% to about 50%, about 15% to about 45%, and about 20% to about 40% based on the total weight of the composition. In preferred embodiments of the present invention, the filler may be about 5%, about 10%, about 15%, about 20%, about 22%, about 25%, about 27.5%, about 30%, about 33%, about 34%, about 35%, about 37%, about 40%, about 42%, about 44%, about 46%, about 48%, about 50%, about 55%, or about 60% based on the total weight of the composition. 【0049】 Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starch, cellulose, calcium carboxymethylcellulose, alginates, rubber, sodium carboxymethyl starch, crosslinked polymers such as crosslinked polyvinylpyrrolidone or crospovidone, sodium crosscarboxymethylcellulose or sodium crosscarboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, soybean polysaccharides, sodium starch glycolate, and guar glue or combinations thereof. In one embodiment of the present invention, the disintegrant is preferably sodium crosscarboxymethylcellulose, low-substituted hydroxypropylcellulose, and / or crospovidone. In one embodiment of the present invention, the disintegrant may be present in amounts of about 0% to about 30%, about 0.1% to about 25%, about 1% to about 25%, about 1% to about 22.5%, and about 5% to about 20% based on the total weight of the composition. In preferred embodiments of the present invention, the disintegrant may be present in an amount of about 0.5%, about 1%, about 2.5%, about 5%, about 7.5%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 27.5%, or about 30% based on the total weight of the composition. 【0050】 Examples of pharmaceutically acceptable binders include, but are not limited to, starch, cellulose and microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose, hypromellose and its derivatives, sucrose, dextrose, corn syrup, polysaccharides, povidone, copovidone-neutralized gelatin, or combinations thereof. In one embodiment of the present invention, the binder is preferably hydroxypropylcellulose, hypromellose, povidone and / or copovidone. In one embodiment of the present invention, the binder may be present in amounts of about 0% to about 10%, about 0% to about 8%, about 2% to about 6%, about 3% to about 5%, or about 10%, based on the total weight of the composition. In preferred embodiments of the present invention, the binder may be present in amounts of about 0.5%, about 1%, about 2%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 7%, about 8%, about 9%, or about 10%, based on the total weight of the composition. 【0051】 Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, glyceryl behenate, and combinations thereof. In one embodiment of the present invention, the lubricant is magnesium stearate and / or sodium stearyl fumarate. In one embodiment of the present invention, the lubricant may be present in an amount of about 0.1% to about 10%, about 0.5% to about 8%, or about 1% to about 6% based on the total weight of the composition. In preferred embodiments of the present invention, the lubricant is present in an amount of about 0.5%, about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% based on the total weight of the composition. 【0052】 A pharmaceutically acceptable flow promoter refers to a pharmaceutically acceptable excipient whose primary function is to improve the flowability of a product by reducing intergranular friction. The flow promoter can be selected from silicon-containing materials such as fumed pulverized silica gel, pyrolysis silica gel, sodium aluminosilicate hydrate, and talc. Preferably, the pharmaceutical composition of the present invention contains a flow promoter, preferably colloidal silicon dioxide. In one embodiment of the present invention, the flow promoter may be about 0% to about 5%, about 0% to about 3%, or about 0% to about 1%, based on the total weight of the composition. In a preferred embodiment of the present invention, there is no flow promoter. In another preferred embodiment, the flow promoter is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5%. 【0053】 In one embodiment, the solid pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier selected from the group consisting of: a filler present in an amount of about 5% to about 60% by weight relative to the weight of the composition; a disintegrant present in an amount of about 0% to about 30% by weight relative to the weight of the composition; a binder present in an amount of about 0% to about 8% relative to the weight of the composition; a lubricant present in an amount of about 0.1% to about 10% by weight relative to the weight of the composition; a flow promoter present in an amount of about 0% to about 5% relative to the weight of the composition; or a combination thereof. The flow promoter may be colloidal silicon dioxide. 【0054】 In one embodiment, the solid pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier selected from the group consisting of: a filler present in an amount of about 10% to about 50% by weight relative to the weight of the composition; a disintegrant present in an amount of about 0.1% to about 25% by weight relative to the weight of the composition; a binder present in an amount of about 2% to about 6% by weight relative to the weight of the composition; a lubricant present in an amount of about 0.5% to about 8% by weight relative to the weight of the composition; a flow promoter present in an amount of about 0% to about 3% by weight relative to the weight of the composition; or a combination thereof. The flow promoter may be colloidal silicon dioxide. 【0055】 Preferably, the filler is selected from microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, starch, dextrin, pregelatinized starch, mannitol, sorbitol, lactose, dextran, sucrose, dextrose, or a combination thereof; the binder is selected from cellulose ether, povidone, copovidone, starch, corn syrup, or a combination thereof, with cellulose ethers including but not limited to hypromellose, hydroxypropylcellulose, methylcellulose, and hydroxyethylcellulose; the disintegrant is selected from sodium crosscarboxymethylcellulose, crospovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropyl, or a combination thereof; the lubricant is selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, glycerin, behenate ester, talc, or a combination thereof. More preferably, the filler is selected from microcrystalline cellulose, lactose, mannitol, sorbitol or a combination thereof; the binder is selected from hydroxypropylcellulose, hypromellose, povidone, copovidone or a combination thereof; the disintegrant is selected from sodium croscarboxymethylcellulose, crospovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose or a combination thereof; and the lubricant is selected from magnesium stearate, sodium stearyl fumarate or a combination thereof. Preferably, the elution RSD of the solid pharmaceutical composition at any point in time from 5 to 60 minutes is less than 20%. More preferably, the elution RSD of the solid pharmaceutical composition at any point in time from 5 to 60 minutes is less than 10%. 【0056】 In another embodiment, the solid pharmaceutical composition of the present invention comprises granules having an internal phase produced by a granulation unit and an external phase adjacent to the granules produced by an external additive unit. The components of the granules and the external phase, and the content of each component, may be the same or different. The respective proportions of the granules and the external phase to the total weight of the solid pharmaceutical composition can be appropriately adjusted by researchers according to selected auxiliary materials and process requirements. 【0057】 This invention relates to a manufacturing process for solid pharmaceutical compositions. 【0058】 In one embodiment, the pharmaceutical composition of the present invention is prepared by a dry granulation process. According to the present invention, the pharmaceutical composition can be prepared by a method comprising the steps of grinding a granular fraction containing compound 1 or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, and grinding a plurality of granules having an internal phase, the granules being mixed with an external additive, and the final mixture being optionally compressed into a tablet. For compaction, an apparatus is used that utilizes two rollers that rotate essentially toward each other. The ground granules, fed into the roller compactor by a screw conveyor system, are subjected to a compressive force. 【0059】 In the present invention, unless otherwise specified, "granulation section" refers to the raw material section used to prepare granules having an internal phase, and "external additive section" refers to the auxiliary material section used to produce a solid pharmaceutical preparation by mixing with the granules having an internal phase produced from the granulation section, and constitutes the external phase of the solid pharmaceutical preparation adjacent to the granules having an internal phase. 【0060】 Various methods of granulation, sieving, and mixing are known in the art, including free-fall or tumbling mixing, compression into tablets using a single-punch or rotary tablet press, or compression using a roller compression device. 【0061】 The sieving or screening step can be achieved using any suitable means, such as a vibrating sieve, a manual / vibrating sieve, or a commercially available screening mill fitted with a screen of appropriate size. Those skilled in the art will have experience and knowledge of how to determine and select a screen of appropriate size for use in the sieving or screening step. For example, the sieving or screening step can be carried out using a screening mill with a screen of appropriate size. 【0062】 The compaction step is achieved using a roller compactor having a compressive force in the range of approximately 3.6 MPa to approximately 19.4 MPa, preferably approximately 4.0 MkPa to 10.0 MPa, and most preferably approximately 7.0 MPa. The device used is preferably a roller compactor. The screw speed of the device is appropriately adjusted to ensure proper quality of the compacted material. The roll speed is appropriately adjusted to ensure proper quality of the compacted material. 【0063】 The grinding / screening step can be achieved using any suitable means. Typically, the ground material (forming granules with an internal phase) is passed through a screening mill or vibrating sieve / mill with a mesh size of at least 0.5 mm, e.g., 0.6 mm, 0.8 mm, 1.2 mm, or 2 mm. This grinding / screening step produces multiple granules. 【0064】 The step of mixing the granules and external additives can be performed using a hopper mixer. The solid tablet dosage form can then be compressed to the desired target tablet weight using a suitable rotary press. 【0065】 In preferred embodiments, the present invention relates to a solid oral dosage form coated with a coating comprising the pharmaceutical composition of the present invention. Suitable coatings are known in the art, commercially available, or can be manufactured according to known methods. Typically, the coating material is a hydrophilic polymer such as polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethylcellulose, or hypromellose. Components of the coating composition may include typical amounts of plasticizers such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, or glycerin, opacifiers such as titanium dioxide, and / or colorants such as iron oxide or aluminum lake. Typically, the coating material is applied in an amount that provides a coating ranging from about 1% to about 6% of the total solid oral dosage form. These products are dry premixes of individually prepared film-forming polymers, opacifiers, colorants, and plasticizers, which are further processed into aqueous coating suspensions. Preferably, the coating is applied to achieve a weight increase of about 1% to 10%, preferably about 2% to 6%, of the total composition of the solid oral dosage form. In one embodiment of the present invention, the coating material is Opadry®, and the coating weight constitutes approximately 3% to 4% of the total weight of the solid oral dosage form. 【0066】 In another embodiment, the present invention relates to a process for producing a solid pharmaceutical composition, and includes the following steps: 【0067】 (a) Mix compound 1 or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier and mix them uniformly; 【0068】 (b) Compress the sieved or screened material to form a compressed material; 【0069】 (c) Crushing the compressed material to form multiple granules; 【0070】 (d) Mix the granules with the external additive to form a final mixture; and 【0071】 (e) If necessary, compress the final mixture into tablets. 【0072】 In one embodiment, the present invention may also include a process for producing coated tablets, further comprising the step of compressing the final mixture into tablets according to the steps described above, and optionally coating the tablets. 【0073】 In another embodiment, the pharmaceutical composition of the present invention is prepared by a wet granulation process. According to the present invention, the pharmaceutical composition can be produced by a method comprising the following steps: screening and weighing compound AN0025 and each pharmaceutically acceptable carrier; mixing compound AN0025 and the pharmaceutically acceptable carrier at an appropriate mixing rate for an appropriate time, while adding a granulation fluid with or without a binder; and pulverizing the mixture into granules, where the granulation fluid may be a binder solution prepared by dispersing a binder in a solvent (water), or simply a wetting agent such as water; drying the granules; mixing the granules with an appropriate amount of an external excipient for an appropriate time; and then compressing them into tablets in a solid dosage form of a desired target tablet weight using a suitable rotary press. 【0074】 In another embodiment, the present invention relates to a process for producing a solid pharmaceutical composition, and includes the following steps: 【0075】 (a) Mix compound 1 or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier and mix them uniformly; (b) Mix compound AN0025 and a pharmaceutically acceptable carrier at an appropriate mixing rate for an appropriate time while adding a granulating fluid to pulverize the mixture into granules; (c) Dry the granules; (d) Obtain dried granules of the target particle size by sieving; (e) Mix the granules with the external additive to form a final mixture; and (f) If necessary, the final mixture is compressed into tablets. 【0076】 In one embodiment, the particle size of the compound of formula 1 in the solid pharmaceutical composition tablet of the present invention has a D90 of less than about 200 microns. In another embodiment, the particle size of the compound of formula 1 in the solid pharmaceutical composition tablet of the present invention has a D90 of less than about 100 microns. In a preferred embodiment, the particle size of the compound of formula 1 in the solid pharmaceutical composition tablet of the present invention has a D90 of about 10 microns to about 80 microns. 【0077】 In one embodiment, the present invention may also include a process for producing coated tablets, further comprising the step of compressing the final mixture into tablets according to the process described above, and optionally coating the tablets. 【0078】 In one embodiment, the solid pharmaceutical composition tablet of the present invention contains about 50 mg to about 500 mg of the compound of formula 1, and in another embodiment, the solid pharmaceutical composition tablet of the present invention contains about 100 mg to about 300 mg of the compound of formula 1. Preferably, the solid pharmaceutical composition tablet of the present invention contains about 125 mg to about 250 mg of the compound of formula 1. 【0079】 The tablet-based pharmaceutical compositions of the present invention, obtained by dry granulation or wet granulation, exhibit the following advantages: 【0080】 (1) Pharmaceutical formulations have a fast dissolution rate. (2) The formulation of the pharmaceutical composition has a lower dissolution RSD. (3) The pharmaceutical composition formulation is suitable for APIs of different particle sizes. (4) There is little individual variation in the in vivo exposure levels of pharmaceutical composition formulations. The pharmaceutical compositions of the present invention and their solid dosage forms can be used to treat cancers, particularly multiple sclerosis, rheumatoid arthritis, or cancers that can be beneficially treated by inhibiting EP4. Examples of cancers suitable for treatment with the solid pharmaceutical compositions of the present invention include, but are not limited to, skin cancer, breast cancer, colorectal cancer, prostate cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, glioblastoma, lung cancer, head and neck cancer, medulloblastoma, and urethral cancer. Other diseases that can be treated with the solid pharmaceutical compositions of the present invention are disclosed in International Publication No. 2012039972, which is incorporated herein by reference in its entirety. 【0081】 In one embodiment, the present invention provides a solid pharmaceutical composition for use in the treatment of cancer. In one embodiment, the present invention provides the use of the solid pharmaceutical composition of the present invention in the manufacture of a drug for treating cancer. 【0082】 In one embodiment, the present invention provides a method for treating cancer, comprising administering a solid composition of the present invention, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a patient suffering from cancer. 【0083】 Details of one or more embodiments of the present invention are described in the appendix above. Similar or equivalent methods and materials to those described herein may be used in carrying out or testing the present invention, but preferred methods and materials are described herein. Other features, purposes, and advantages of the present invention will become apparent from the specification and claims. In this specification and the appendix claims, unless the context makes otherwise clear, the singular nouns refer to multiple subjects. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. All patents and publications referenced in this specification are incorporated by reference. The following examples are presented to better illustrate preferred embodiments of the present invention. These examples should not be construed as limiting the scope of the disclosed patent as defined by the appendix claims. 【0084】 Examples 1. Dissolution test method: Dissolution parameters Equipment: United States Pharmacopeia and Chinese Pharmacopoeia Apparatus II (Paddle Method) Speed: 50 rpm Elution solvent: pH 6.8 phosphate buffer Elution volume: 900mL Temperature: 37±0.5℃ 【0085】 HPLC detection conditions Detection wavelength: 234nm Chromatography column: YMC-Triart C 18 75 × 4.6 mm, 3 μm Column temperature: 40℃ Solvent A: Water / 70% perchloric acid (1000 / 1, v / v) Solvent B: Acetonitrile / 70% perchloric acid (1000 / 1, v / v) 【0086】 Dissolution gradient: JPEG0007874176000004.jpg55170 【0087】 Pharmacokinetic parameter testing methods In the present invention, the pharmacokinetic parameters of the comparative examples and examples were measured by chromatography and mass spectrometry, and the details of the test conditions are described in Tables 1a and 1b. 【0088】 Table 1a, Chromatography conditions JPEG0007874176000005.jpg152170 【0089】 Table 1b, mass spectrometry conditions JPEG0007874176000006.jpg133170 【0090】 2. Comparative Example 1 The capsule formulation of Comparative Example 1 was prepared according to the ingredients and quantities listed in Table 2a. 【0091】 Table 2a Formulation composition of Comparative Example 1 JPEG0007874176000007.jpg107170 【0092】 The manufacturing process for the AN0025 capsules in Comparative Example 1 consisted of six steps: mixing, lubrication, granulation, sizing, capsule filling, and weight sorting. AN0025 API, mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose calcium, and microcrystalline cellulose were thoroughly mixed in a high-shear mixer or hopper mixer. Magnesium stearate was then added to the mixture for lubrication. The mixture was compressed into long strips using a roller compactor. The strips were sieved (sieve opening was 1.5 mm) to sizing. The sizing granules were filled into hypromellose (HPMC) capsules using a capsule filling machine, and overweight and underfilled capsules were removed using a weighing machine. 【0093】 Table 2b Mean values ​​of dissolution curves in the stability study of 125 mg capsules (Comparative Example 1) JPEG0007874176000008.jpg121170 【0094】 Table 2b shows the average dissolution curves during the stability study of the 125 mg capsules of Comparative Example 1. Under different storage conditions (25°C / 60% relative humidity for long-term stability and 40°C / 75% relative humidity for accelerated stability), there were significant differences in the results measured at different time points from 1 to 36 months. This difference fluctuated up and down rather than showing a trend, indicating that even the average dissolution value does not reflect the true dissolution state of the drug. 【0095】 Table 2C shows the dissolution curve measurement results for another batch of Comparative Example 1. Here, SD is the standard deviation and RSD is the relative standard deviation. Unless otherwise specified, the SD and RSD recorded in this article have the same definitions and calculation methods as in Table 2c. Figure 2c shows that the detection results for different capsule samples at the same time point differed significantly, with relatively large RSDs. The generally accepted standard for measuring dissolution curves by industry technicians is that the RSD of the dissolution measurement at the first time point is 20% or less, and the RSD of the dissolution measurement at other time points is 10% or less. 【0096】 Table 2C, Dissolution curve of Comparative Example 1 JPEG0007874176000009.jpg114170 The results above indicated that the capsule dissolution had a relatively large RSD, and that there was considerable variability in test results between different batches or between the same batch at different time points. 【0097】 3. Comparative Example 2 The capsule formulation for Comparative Example 2 was prepared according to the ingredients and quantities listed in Table 3. Comparative Example 2 used the same ingredients and quantities as Comparative Example 1, but was filled into different hollow capsules. 【0098】 Table 3a Formulation composition of Comparative Example 2 JPEG0007874176000010.jpg99170 【0099】 The manufacturing process for the AN0025 capsules in Comparative Example 2 consisted of six steps: mixing, lubrication, granulation, sizing, capsule filling, and weight sorting. AN0025 API, mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose calcium, and microcrystalline cellulose were mixed in a high-shear mixer. Magnesium stearate was mixed with the mixture using the high-shear mixer. The mixture was compressed into long strips using a roller compactor. The strips were sieved (sieve opening was 1.5 mm) to sizing. The entire granules were filled into gelatin hollow capsules using a capsule filling machine, and overweight and underfilled capsules were removed using a weighing machine. 【0100】 Table 3b Dissolution behavior in the stability analysis of Comparative Example 2 JPEG0007874176000011.jpg53170 Table 3b shows that Comparative Example 2, using gelatin capsules, dissolved faster and its dissolution RSD was significantly improved compared to Comparative Example 1, using HPMC capsules, although the 5-minute RSD was still above 20%. Furthermore, during accelerated stability testing at 40°C / 75% relative humidity, the capsules of Comparative Example 2 showed a relatively clear decrease in dissolution. 4. Comparative Example 3 To improve the relatively high RSD of Comparative Example 1, the inventors prepared capsules of Comparative Example 3 using different preparation processes according to the components and contents listed in Table 4a. 【0101】 Table 4a Formulation composition of Comparative Example 3 The preparation process for JPEG0007874176000012.jpg87170 is as follows: 【0102】 Step 1: Mixing The weighed compound AN0025, lactose monohydrate, hydroxypropyl cellulose, and microcrystalline cellulose were added to a high-shear granulator at 300 rpm and mixed for 2 minutes. 【0103】 Step 2: Granulation The parameters of the high-shear granulator were set to a stirring speed of 200 rpm and a shearing speed of 800 rpm. Purified water was slowly added as a wetting agent to prepare a soft material. After adding all the wetting agent, the machine was operated for 2 to 3 minutes at the same stirring and shearing speeds, and then discharged. This soft material was passed through a sieve with a mesh size of 2.0 mm to obtain wet granules. 【0104】 Step 3 Drying The moist granules obtained in the above process were dried to remove moisture. 【0105】 Step 4: Grain Sorting The granules obtained after drying were sieved again to obtain granules with an internal phase. 【0106】 Step 5 Mixing II The granules prepared above were uniformly mixed with low-substituted hydroxypropyl cellulose. 【0107】 Step 6 Lubrication II The mixture prepared above was uniformly mixed with magnesium stearate. 【0108】 Step 7: Capsule Filling The lubricant was filled into hypromellose (HPMC) capsules according to the target weight, completing the product. 【0109】 However, as shown in Table 4b, capsules prepared by the wet granulation process still had a high RSD. 【0110】 Table 4b Elution Profile of Comparative Example 3 JPEG0007874176000013.jpg106170 To fundamentally resolve the high RSD problem of compound AN0025 formulations, the inventors implemented the following specific examples. 【0111】 5. Example 1 of the present invention The tablets of Example 1 of the present invention were prepared according to the ingredients and content listed in Table 5a. 【0112】 Table 5a Formulation composition of Example 1 JPEG0007874176000014.jpg113170 The preparation process is as follows: 【0113】 Step 1: Mixing The weighed compound AN0025, mannitol, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, carboxymethylcellulose calcium, and crystalline cellulose were homogeneously mixed. Step 2: Lubrication I The magnesium stearate from the granulation section was added to the mixture from step 1 and mixed uniformly. 【0114】 Step 3: Granulation The mixture was pressed into strips using a roller compactor, with the following compression parameters: compression force 10 MPa, roll speed 4 rpm, and gap width 1.5 mm. 【0115】 Step 4: Grain Sorting Long strips were sieved using a coarse sieve (mesh opening 2.0 mm) and a fine sieve (mesh opening 0.6 mm) to obtain granules with a defined internal structure. 【0116】 Step 5 Lubrication II The granules prepared above were mixed with magnesium stearate from the external additive. 【0117】 Step 6: Tablet With a desired target tablet weight of 250 mg, tablets of the appropriate shape were compressed using a tablet press. 【0118】 The formulation of Example 1 was the same as that of Comparative Examples 1 and 2, differing only in that it was prepared in a different dosage form. The dissolution data is shown in Table 5b, and the dissolution RSD at all time points was 10% or less, which was a significant improvement compared to Comparative Examples 1 and 2. Furthermore, Figure 2 shows that the drug dissolution rate of the tablets in Example 1 was higher than that of the capsules in Comparative Example 1. 【0119】 Table 5b Elution curve of Example 1 JPEG0007874176000015.jpg115170 6. Example 2 of the present invention The tablets of Example 2 of the present invention were prepared according to the ingredients and content listed in Table 6a. 【0120】 Table 6a Formulation composition of Example 2 JPEG0007874176000016.jpg120170 The preparation process is as follows: 【0121】 Step 1: Mixing The weighed compound AN0025, lactose monohydrate, hydroxypropyl cellulose, and microcrystalline cellulose were added to a high-shear granulator and mixed at 300 rpm for 2 minutes. Step 2: Granulation The parameters of the high-shear granulator were set to a stirring speed of 200 rpm and a shearing speed of 800 rpm. Purified water was slowly added as a wetting agent to prepare a soft material. After adding all the wetting agent, the machine was operated for 2 to 3 minutes at the same stirring and shearing speeds, and then discharged. This soft material was passed through a sieve with a mesh size of 2.0 mm to obtain wet granules. 【0122】 Step 3: Drying The moist granules obtained in the above process were dried to remove moisture. 【0123】 Step 4: Grain Sorting The granules obtained after drying were sieved again to obtain granules with an internal structure. 【0124】 Step 5 Mixing II The granules prepared above were uniformly mixed with low-substituted hydroxypropyl cellulose. 【0125】 Step 6 Lubrication II The mixture prepared above was uniformly mixed with magnesium stearate. 【0126】 Step 7: Tablet Depending on the target tablet weight, the tablets were compressed to the appropriate shape using a tablet press. 【0127】 The elution data is shown in Table 6b, and the eluted RSD did not exceed 10% at any point in time. 【0128】 Table 6b Elution curve of Example 2 JPEG0007874176000017.jpg115170 【0129】 Table 6c Elution behavior during stability study of Example 2 JPEG0007874176000018.jpg46170 Example 2 and Comparative Example 3 have the same formulation ingredients and preparation process, but differ in that they are prepared in different dosage forms. A comparison of the dissolution curves for Example 2 is shown in Figure 2 of the specification. Similar to the experimental results for Example 1, the drug dissolution rate of the tablets in Example 2 is higher than that of the capsules in Comparative Example 3. 【0130】 As shown in Table 6c, Example 2 was relatively stable with no significant decrease during the stability analysis. However, as shown in Table 3b, the dissolution rate of Comparative Example 2 decreased significantly during the stability analysis. This result demonstrated the advantage of the tablet from a stability standpoint. 【0131】 Examples 1 and 2 demonstrated that the tablets of the present invention can significantly improve the high RSD problem of capsules, regardless of whether they are dry or wet granulated, and that this improvement is unrelated to the preparation process. 【0132】 7. Example 3 of the present invention The ratio of each component in the formulation was changed, and tablets of Example 3 of the present invention were manufactured according to the components and content listed in Table 7a. 【0133】 Table 7a Formulation composition of Example 3 JPEG0007874176000019.jpg139170 【0134】 The preparation process is as follows: Step 1: Mixing The weighed compound AN0025, mannitol, hydroxypropylcellulose, carboxymethylcellulose calcium, and microcrystalline cellulose were added to a hopper mixer and mixed uniformly. Step 2: Lubrication I Using a hopper mixer, the granular portion of magnesium stearate and the mixture from Step 1 were mixed until uniform. 【0135】 Step 3: Granulation The mixture was compressed into long strips using a roller compactor. The compression parameters were a compressive strength of 7 MPa, a roll speed of 2 rpm, and a gap width of 1.5 mm. 【0136】 Step 4: Grain Sorting After the long strips were crushed, the granules were sieved through a 0.8 mm screen to sizing them, resulting in granules with a defined internal structure. 【0137】 Step 5 Lubrication II The granules prepared above were mixed with magnesium stearate from the external additive. 【0138】 Step 6: Tablet Tablets of the appropriate shape were compressed using a tablet press to the desired target tablet weight of 500 mg. 【0139】 Step 7 Coating The coating solution was prepared by thoroughly dispersing OpaDry in purified water, and film coating was performed using a coating machine, with a target coating weight increase rate of 4%. 【0140】 Dissolution data is shown in Table 7b. However, the elution RSD at the first time point is slightly high (but less than 20%), while the elution RSD at other time points is less than 10%. 【0141】 Table 7b Elution Profile of Example 3 JPEG0007874176000020.jpg128170 【0142】 8. Example 4 The coated tablets of Example 4 were prepared according to the ingredients and quantities listed in Table 8a. 【0143】 Table 8a Formulation components of Example 4 JPEG0007874176000021.jpg147170 The preparation process is as follows: 【0144】 Step 1: Mixing The weighed compound AN0025, mannitol, hydroxypropylcellulose, crosscarboxymethylcellulose sodium, and microcrystalline cellulose were added to a hopper mixer and mixed uniformly. Step 2 Lubrication I Using a hopper mixer, the magnesium stearate from the granulation section was uniformly mixed with the mixture from step 1. 【0145】 Step 3: Granulation The mixture was pressed into long strips using a roller compactor, with the following compaction parameters: compression force of 7 MPa, roll speed of 2 rpm, and gap width of 1.5 mm. 【0146】 Step 4: Grain Sorting After crushing the strips, they were sizing through a 0.8 mm screen to obtain granules with an internal phase. 【0147】 Step 5 Lubrication II The granules prepared above were mixed with magnesium stearate from the external additive. 【0148】 Step 6: Tablet Once the desired target tablet weight of 500 mg was reached, the tablets were compressed into the appropriate shape using a tablet press. 【0149】 Step 7 Coating The coating solution was prepared by thoroughly dispersing OpaDry in purified water, and film coating was performed using a coating machine. The target coating weight increase rate was 4%. 【0150】 The elution data is shown in Table 8b, and the elution RSD did not exceed 10% at any time point. 【0151】 Table 8b Elution Profile of Example 4 JPEG0007874176000022.jpg139170 As shown in Table 8c, the elution rate did not change significantly even after being left for one month under conditions of 40°C / 75% relative humidity. 【0152】 Table 8c: Elution behavior in the stability analysis of Example 4 JPEG0007874176000023.jpg38170 【0153】 The tablets from Comparative Example 1, Example 3, and Example 4 were used in animal experiments. Table 8d shows a comparison of the pharmacokinetic parameters of various formulations in beagle dogs when the dosage is 750 mg / dog. Here, AUC 0-t AUC represents the area under the drug blood concentration-time curve from 0 to the last selected time point. 0-t_dose This represents the ratio of the area under the drug blood concentration-time curve from 0 to the last selected time point to the dose. Unless otherwise specified, AUC is as described herein.0-t and AUC 0-t_dose The definitions and calculation methods are the same as those in Table 8d. Compared to Comparative Example 1, the in vivo exposure (AUC) of the tablets in Example 3 and Example 4 were comparable, but the inter-individual variability (SD) was smaller, which was more consistent with the in vitro dissolution data, suggesting that the tablets had superior clinical efficacy and safety. The in vivo drug blood concentration-time curves for Beagle dogs under a dose of 750 mg / dog for Comparative Example 1 and Example 4 are shown in Figures 3 and 4, respectively. 【0154】 Table 8d Comparison of pharmacokinetic parameters of various formulations in Beagle dogs at a 750 mg dose. JPEG0007874176000024.jpg97170 【0155】 Table 8e shows a comparison of the pharmacokinetic parameters of different formulations in beagle dogs when the dose is 250 mg / dog. Compared to the capsule formulation of Comparative Example 1, the in vivo exposure (AUC) of the tablet formulation of Example 4 was equivalent, but the inter-individual variability (SD) was smaller, which was more consistent with the in vitro dissolution data, suggesting that the tablet formulation had superior clinical efficacy and safety. Figures 5 and 6 show the in vivo drug blood concentration-time curves for beagle dogs at a dose of 250 mg / dog for Comparative Example 1 and Example 4, respectively. 【0156】 Table 8e Comparison of pharmacokinetic parameters of various formulations in Beagle dogs at a 250 mg dose. JPEG0007874176000025.jpg79170 【0157】 The results above show that the tablets of the present invention have similar in vivo exposure levels to capsules, but with significantly reduced inter-individual variability and a decrease in RSD, and that this improvement is not affected by the dose. 【0158】 9. Example 4a The formulation components and preparation process of Example 4a were the same as in Example 4, but APIs of different particle sizes were used. The differences in particle sizes of the APIs used in Example 4 and Example 4a are shown in Table 9a. Here, D 50 represents the corresponding particle size when the cumulative particle size distribution percentage of one sample reaches 50%, i.e., the particle size when 50% of the granules are smaller than that. D 90 represents the corresponding particle size when the cumulative particle size distribution percentage of one sample reaches 90%, i.e., the particle size when 90% of the granules are smaller than that. Unless otherwise specified, D50 and D90 as described herein have the same definitions as in this example. 【0159】 Table 9a API particle size information for Example 4 and Example 4a JPEG0007874176000026.jpg46170 【0160】 Table 9b Elution Profile of Example 4a JPEG0007874176000027.jpg116170 【0161】 Generally, for poorly soluble drugs, the particle size of the API is often an important factor to consider in formulation development. Drugs with different particle sizes often exhibit faster in vitro elution and better in vivo absorption behavior due to differences in specific surface area, with smaller particle sizes being more common. However, surprisingly, Examples 4 and 4a showed similar elution behavior, and their in vitro elution similarity coefficient f² was 52 (if f² is greater than 50, the elution is considered similar). The elution curve for Example 4a is shown in detail in Table 9b. 【0162】 Table 9c, Comparison of pharmacokinetic parameters of different particle size APIs in Beagle dogs at a 250 mg dose. JPEG0007874176000028.jpg88170 The in vivo pharmacokinetic data from beagle dogs led to similar conclusions. Different particle sizes of AN0025 API did not affect product quality. The tablets provided by the present invention have good durability against raw materials of different particle sizes. A comparison of in vivo pharmacokinetic parameters between Example 4 and Example 4a is shown in Table 9C. In Example 4a, the in vivo drug blood concentration-time curve for beagle dogs at a dose of 750 mg / dog is shown in Figure 7. 【0163】 10. Example 5 of the present invention The tablets of Example 5 of the present invention were prepared according to the ingredients and content listed in Table 10a. 【0164】 Table 10a Formulation composition of Example 5 JPEG0007874176000029.jpg154170 【0165】 The preparation process is as follows: Step 1: Mixing The weighed compound AN0025, mannitol, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, carboxymethylcellulose calcium, and microcrystalline cellulose were added to a hopper mixer and mixed uniformly. Step 2 Lubrication I Using a hopper mixer, the sodium stearyl fumarate from the granulation section was uniformly mixed with the mixture from step 1. 【0166】 Step 3: Granulation The mixture was compressed into long strips using a roller compactor. The compression parameters were a compression force of 7 MPa, a roll speed of 2 rpm, and a gap width of 1.5 mm. 【0167】 Step 4: Grain Sorting After crushing the strips, they were passed through a 0.8 mm sieve to sizing and obtain granules with an internal structure. 【0168】 Step 5 Lubrication II The granules prepared above were mixed with stearyl fumarate, an external additive. 【0169】 Step 6: Tablet Once the desired target tablet weight of 500 mg was reached, the tablets were compressed into the appropriate shape using a tablet press. 【0170】 Step 7 Coating The coating solution was prepared by thoroughly dispersing OpaDry in purified water, and film coating was performed using a coating machine. The target coating weight increase rate was 4%. 【0171】 The elution data is shown in Table 10b, and the eluted RSD did not exceed 10% at any point in time. Table 10b Elution curve for implementation example 5 JPEG0007874176000030.jpg140170

Claims

[Claim 1] The solid pharmaceutical composition comprises the compound described in Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound described in Formula 1 or a pharmaceutically acceptable salt thereof constitutes about 30% to about 80% of the total weight of the solid pharmaceutical composition, and the dosage form of the solid pharmaceutical composition is a tablet. The pharmaceutically acceptable carrier includes the following: a. Fillers that constitute approximately 5% to 60% of the total weight of the solid pharmaceutical composition. b. A binder that constitutes approximately 0% to approximately 8% of the total weight of the solid pharmaceutical composition. c. Disintegrants that constitute approximately 0% to approximately 30% of the total weight of the solid pharmaceutical composition. d. Lubricants constituting approximately 0.1% to approximately 10% of the total weight of the solid pharmaceutical composition. e. Flow promoters that constitute approximately 0% to approximately 5% of the total weight of the solid pharmaceutical composition. The filler is selected from the group comprising microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, starch, dextrin, pregelatinized starch, mannitol, sorbitol, lactose, dextran, sucrose, dextrose, and combinations thereof. The binder is selected from the group including cellulose ether, povidone, copovidone, starch, corn syrup, and combinations thereof, where cellulose ether includes, but is not limited to, hypromellose, hydroxypropylcellulose, methylcellulose, and hydroxyethylcellulose. The disintegrant is selected from the group comprising sodium crosscarboxymethylcellulose, crospovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and combinations thereof. The lubricant is selected from the group comprising magnesium stearate, sodium stearyl fumarate, polyethylene glycol, glycerin, behenate esters, talc, and combinations thereof. A solid pharmaceutical composition characterized by the following features. [Claim 2] The solid pharmaceutical composition according to claim 1, wherein the compound described in Formula 1 or a pharmaceutically acceptable salt thereof constitutes about 40% to about 60% of the total weight of the solid pharmaceutical composition. [Claim 3] The solid pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier comprises the following: a. Fillers that constitute approximately 10% to 50% of the total weight of the solid pharmaceutical composition. b. A binder that constitutes approximately 2% to 6% of the total weight of the solid pharmaceutical composition. c. Disintegrants that constitute approximately 0.1% to approximately 25% of the total weight of the solid pharmaceutical composition. d. Lubricants constituting approximately 0.5% to approximately 8% of the total weight of the solid pharmaceutical composition. e. A flow promoter that constitutes approximately 0% to approximately 3% of the total weight of the solid pharmaceutical composition. [Claim 4] The solid pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable carrier comprises the following: a. Fillers that constitute approximately 20% to 40% of the total weight of the solid pharmaceutical composition. b. A binder that constitutes approximately 3% to 5% of the total weight of the solid pharmaceutical composition. c. Disintegrants that constitute approximately 1% to approximately 25% of the total weight of the solid pharmaceutical composition. d. Lubricants constituting approximately 1% to 6% of the total weight of the solid pharmaceutical composition. e. A flow promoter that constitutes approximately 0% to approximately 1% of the total weight of the solid pharmaceutical composition. [Claim 5] The fillers are selected from microcrystalline cellulose, lactose, mannitol, sorbitol, and combinations thereof. The binder is selected from hydroxypropylcellulose, hypromellose, povidone, copovidone, and combinations thereof. The disintegrants are selected from sodium crosscarboxymethylcellulose, crospovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and combinations thereof. The lubricant is selected from magnesium stearate, sodium stearyl fumarate, and combinations thereof. The solid pharmaceutical composition according to any one of claims 1-4. [Claim 6] A solid pharmaceutical composition according to any one of claims 1 to 4, comprising granules having an internal phase. [Claim 7] The solid pharmaceutical composition according to claim 6, further comprising an external phase adjacent to granules having an internal phase. [Claim 8] The solid pharmaceutical composition according to any one of claims 1 to 4, wherein the particle size of the compound of formula 1 has a D90 of less than approximately 200 microns. [Claim 9] The solid pharmaceutical composition according to claim 8, wherein the particle size of the compound of formula 1 has a D90 of less than approximately 100 microns. [Claim 10] A solid pharmaceutical composition according to any one of claims 1 to 4, further comprising a coating. [Claim 11] A solid pharmaceutical composition according to any one of claims 1 to 4, comprising approximately 50 mg to approximately 500 mg of the compound of formula 1. [Claim 12] The solid pharmaceutical composition according to claim 11, comprising approximately 100 mg to approximately 300 mg of the compound of formula 1. [Claim 13] Use of the solid pharmaceutical composition according to claim 1 for preparing a pharmaceutical for the treatment of multiple sclerosis, rheumatoid arthritis, or cancer. [Claim 14] The use according to claim 13, wherein the cancers include skin cancer, breast cancer, colorectal cancer, prostate cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, glioblastoma, lung cancer, head and neck cancer, medulloblastoma, and urinary tract cancer.

Images