Parenteral formulation containing uracil derivative

Abstract

The present invention pertains to a parenteral formulation containing a uracil derivative. The present invention also pertains to a sustained release type formulation containing a uracil derivative. Specifically, the present invention pertains to a parenteral formulation comprising a suspension in which a uracil derivative having coronavirus 3CL protease inhibitory activity is suspended. More specifically, the present invention pertains to a formulation for subcutaneous injection, intradermal injection, or intramuscular injection, the formulation comprising a suspension in which a uracil derivative having coronavirus 3CL protease inhibitory activity is suspended.

Description

Parenteral formulations containing uracil derivatives 【0001】 The present invention relates to a parenteral formulation containing a uracil derivative. The present invention relates to a sustained-release formulation containing a uracil derivative. More specifically, the present invention relates to a parenteral formulation comprising a suspension of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity. More specifically, the present invention relates to a formulation for subcutaneous, intradermal, or intramuscular injection comprising a suspension of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity. 【0002】 When coronavirus infects cells, it synthesizes two polyproteins. These two polyproteins contain a replication complex that makes up the viral genome, and two proteases. Proteases play an essential role in cleaving the polyproteins synthesized from the virus and enabling each protein to function. Of the two proteases, 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 1). Compounds having 3CL protease inhibitory activity are disclosed in Patent Documents 1-4 and Non-Patent Documents 2-12, but none of these documents describe or suggest the uracil derivative included in the formulation according to the present invention. Uracil derivatives included in the formulation according to the present invention, pharmaceutically acceptable salts thereof, or solvates thereof are described in Patent Documents 5 and 6. However, Patent Documents 5 and 6 do not describe specific formulations containing the uracil derivatives included in the formulation according to the present invention, pharmaceutically acceptable salts thereof, or solvates thereof. Patent Documents 7 and 8 disclose injectable formulations exhibiting sustained release, but do not describe parenteral formulations containing the uracil derivative according to the present invention. 【0003】 International Publication No. 2021 / 205298, International Publication No. 2021 / 250648, International Publication No. 2022 / 138987, International Publication No. 2022 / 138988, International Publication No. 2023 / 195529, International Publication No. 2023 / 195530, International Publication No. 2005 / 041937, International Publication No. 2012 / 037320 【0004】Science (2003), Vol. 300, pp. 1763-1767, “A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19,” Journal of Virology, 2021 Mar 10; 95(7), e01819-20. Cell Research (2020), Vol. 30, pp. 678-692. Science (2020), Vol. 368, pp. 409-412. ACS Central Science (2021), Vol. 7, No. 3, pp. 467-475. 261st Am Chem Soc (ACS) Natl Meet ・ 2021-04-05 / 2021-04-16 ・ Virtual, N / A ・ Abst 243Science (2021), Vol. 374, pp. 1586-1593, "Discovery and Development of PBI-0451", [online], March 24, 2022, 35th International Conference on Antiviral Research (ICAR), [Retrieved March 16, 2023], Internet <URL: https: / / ir.pardesbio.com / static-files / fc7c4f8c-e0bd-4b97-8c9c-eff09bafd4db> Molecules (2020), Vol. 25, pp. 3193 Molecules (2020), Vol. 25, pp. 3920 European Journal of Medicinal Chemistry (2020), Vol. 206, pp. 112711 Journal of the American Chemical Society (2022), Vol. 144, pp. 2905-2920 【0005】In the treatment of viral infections, there is a need for the development of sustained-release formulations from the perspective of improving quality of life (QOL) and pre-exposure prophylaxis for viral infections. While many compounds exhibiting coronavirus 3CL protease inhibitory activity are known for treating coronavirus infections, it remains unclear which of these compounds can be used in sustained-release formulations. In other words, there has been a need for a sustained-release formulation containing a compound exhibiting coronavirus 3CL protease inhibitory activity. The object of the present invention is to provide a parenteral formulation containing a uracil derivative. Preferably, the present invention provides a parenteral formulation comprising a suspension of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity. The present invention also aims to provide a sustained-release formulation comprising a suspension of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity. Furthermore, the object of the present invention is to provide a formulation for subcutaneous, intradermal, or intramuscular injection comprising a suspension of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity. 【0006】 The inventors have discovered that the compound represented by formula (I), its pharmaceutically acceptable salt, or its solvates have low solubility in water and are suitable as active ingredients for sustained-release formulations. They have also discovered that parenteral formulations comprising a suspension of the compound represented by formula (I), its pharmaceutically acceptable salt, or its solvates can be used as formulations for subcutaneous, intradermal, or intramuscular injection, thus completing the present invention. The present invention relates to the following: (1) Formula (I): (1) A preparation for subcutaneous, intradermal, or intramuscular injection comprising a suspension of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. (2) The preparation according to (1) above, comprising crystals of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. (3) The preparation according to (2) above, comprising crystals of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, having a solubility in water of 0.01 mg / mL or less. (4) The preparation according to (3) above, comprising anhydrous crystals of a compound represented by formula (I). (5) The preparation according to any one of (1) to (4) above, comprising a stabilizer in the suspension. (6) The preparation according to (5) above, wherein the stabilizer is a suspending agent. (7) The preparation according to (6) above, wherein the suspending agent is one or more selected from the group consisting of polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan esters of fatty acids, and poloxamers. (8) The preparation according to (7) above, wherein the suspending agent is polyoxyethylene sorbitan fatty acid ester. (9) The preparation according to (8) above, wherein the suspending agent is polysorbate 20. (10) The preparation according to (7) above, wherein the suspending agent is poloxamer. (11) The preparation according to (10) above, wherein the suspending agent is poloxamer 338. (12) The preparation according to any of (7) to (11) above, containing 0.1 to 4.0 w / v% of the suspending agent. (13) The preparation according to any of (7) to (11) above, containing 5.0 w / v% of the suspending agent. (14) The preparation according to (5) above, wherein the stabilizer is a dispersant. (15) The formulation according to (14) above, wherein the dispersant is one or more selected from the group consisting of polyethylene glycol, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, amorphous cellulose, polysaccharides, hyaluronic acid, polyvinyl alcohol, and polyvinylpyrrolidone. (16) The formulation according to (14) or (15) above, comprising 0.1 to 2.0 w / v% of the dispersant. (17) The formulation according to any one of (1) to (16) above, comprising a pH adjuster in the suspension. (18) The formulation according to (17) above, wherein the pH of the suspension is adjusted to 4.0 to 8.0.The preparation according to any one of (1) to (18) above, which is obtained by grinding the compound represented by formula (I), its pharmaceutically acceptable salt or their solvate in suspension. (20) The preparation according to (19) above, wherein the Z-average after grinding of the compound represented by formula (I), its pharmaceutically acceptable salt or their solvate is 0.1 to 3.0 μm. (21) The preparation according to (20) above, wherein the Z-average is 0.1 to 1.0 μm. (22) The preparation according to any one of (1) to (21) above, wherein the amount of the compound represented by formula (I), its pharmaceutically acceptable salt or their solvate is 10 to 500 mg per 1 mL of the suspension. (23) The preparation according to (22) above, wherein the amount of the compound represented by formula (I), its pharmaceutically acceptable salt or their solvate is 10 to 200 mg per 1 mL of the suspension. (24) The preparation according to any one of (1) to (21) above, wherein the amount of the compound represented by formula (I), its pharmaceutically acceptable salt or their solvate is 400 to 700 mg per 1 mL of the suspension. (25) The preparation according to any one of (1) to (24) above, wherein the blood concentration of the compound represented by formula (I) at 2 months after injection is 5 to 30 ng / mL. (26) The preparation according to any one of (1) to (25) above, which redisperses upon shaking. (27) The preparation according to any one of (1) to (26) above, which continuously releases the compound represented by formula (I) for 2 months or more after injection. (28) A method for producing a preparation for subcutaneous injection, intradermal injection or intramuscular injection, comprising a step of grinding the compound represented by formula (I), its pharmaceutically acceptable salt or their solvate in suspension, which consists of a suspension in which the compound represented by formula (I), its pharmaceutically acceptable salt or their solvate is suspended. 【0007】 The preparation according to the present invention has an inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic agent and / or prophylactic agent for coronavirus infections. Further, the preparation according to the present invention can maintain a blood concentration for a long period of time by parenteral administration. Furthermore, the preparation according to the present invention has excellent dispersibility and can be easily redispersed. Also, the anhydrous crystal of the compound represented by formula (I) contained in the preparation according to the present invention has high stability in the preparation and can be stored for a long period of time. 【0008】 The powder X-ray diffraction pattern of the anhydrous crystal of the compound represented by formula (I) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents Intensity. A peak list of the powder X-ray diffraction pattern in Figure 1 is shown. In the table, Position represents 2θ (°), and Intensity represents the intensity. The crystal structure (structure in the asymmetric unit) of the anhydrous crystal of the compound represented by formula (I) is shown. The differential scanning calorimetry (DSC) results of the anhydrous crystal of the compound represented by formula (I) are shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat (W / g). The differential thermal-thermogravimetric analysis (TG / DTA) results of the anhydrous crystal of the compound represented by formula (I) are shown. The vertical axis represents heat (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure means degrees Celsius (°C). The Raman spectrum of the anhydrous crystal of the compound represented by formula (I) is shown. The horizontal axis represents the Raman shift (cm). －１ The graph shows the C20 ｍａｘ The results for AUC, BA, and elimination rate constant kel are shown. In Test Example 7, when the compound represented by formula (I) was administered using the formulation of Example 3, the C ｍａｘ The results for AUC, BA, and elimination rate constant kel are shown. In Test Example 8, when the compound represented by formula (I) was administered using the formulation of Example 3, the C ｍａｘ The results for AUC, BA, and elimination rate constant kel are shown. In Test Example 9, when the compound represented by formula (I) was administered using the formulation of Example 3, the C ｍａｘ The results for AUC, BA, and elimination rate constant kel are shown. In Test Example 10, when the compound represented by formula (I) was administered using the formulation of Example 3, the C ｍａｘ, the results for AUC, BA, and elimination rate constant kel are shown. The appearance of the sample of Example 6-1 after standing for 3 days in a 5°C environment is shown. The state of the bottom surface when the container of the sample of Example 6-1 is tilted after standing for 3 days in a 5°C environment is shown. The state of the bottom surface after shaking the sample of Example 6-1 for 10 seconds after standing for 3 days in a 5°C environment is shown. In Test Example 14, C when the compound represented by formula (I) was administered with the formulations of Examples 8-1, 8-2, 9-1, and 9-2 ｍａｘ , the results for AUC, BA, and elimination rate constant kel are shown. In Test Example 15, C when the compound represented by formula (I) was administered with the formulations of Examples 8-1, 8-2, 9-1, and 9-2 ｍａｘ , the results for AUC, BA, and elimination rate constant kel are shown. In Test Example 17, C when the compound represented by formula (I) was administered with the formulations of Examples 14-1, 14-2, 15-1, and 9-2 ｍａｘ , the results for AUC, BA, and elimination rate constant kel are shown. The results for the sliding resistance of Example 16 when stored at 60°C for 2 weeks are shown. The results for the sliding resistance of Example 17 when stored at 60°C for 2 weeks are shown. 【0009】 The meanings of the terms used in this specification are explained below. The terms "comprising" and "including" mean not being limited to the constituent elements and not excluding elements not described. Hereinafter, the present invention will be described while showing embodiments. Throughout this specification, it should be understood that singular expressions include the concepts of their plural forms unless otherwise specified. Therefore, singular articles (for example, in English, "a", "an", "the", etc.) should be understood to include the concepts of their plural forms unless otherwise specified. Also, the terms used in this specification should be understood to be used in the meanings usually used in the above field unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as generally understood by those skilled in the art to which the present invention pertains. In case of contradiction, this specification (including the definitions) shall prevail. 【0010】Unless otherwise specified, the numerical values ​​described herein and in the claims are approximate. Variations in the values ​​are due to instrument calibration, instrument errors, purity of the material, crystal size, sample size, temperature, and other factors. 【0011】 The present invention relates to formula (I): The present invention relates to parenteral formulations containing the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and more particularly to sustained-release formulations. More specifically, the present invention relates to parenteral formulations comprising a suspension of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. More specifically, the present invention relates to formulations for subcutaneous, intradermal, or intramuscular injection comprising a suspension of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. 【0012】 The compound represented by formula (I) is compound (I-077) described in International Publication Nos. 2023 / 195529 and 2023 / 195530, and can be produced by the synthesis method of Examples 5-6 in those publications. Furthermore, it is described in those publications that the compound represented by formula (I) has coronavirus 3Cl protease inhibitory activity and inhibits coronavirus 3Cl protease. In this specification, the compound represented by formula (I) may also be referred to as compound (I). 【0013】 One or more hydrogen, carbon, and / or other atoms in the compound represented by formula (I) may be substituted with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes are, ２ H, ３ H, １１ C, １３ C, １４ C, １５ N, １８ O, １７ O, １８ F and ３６Like Cl, it includes hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine. Compounds represented by formula (I) also include compounds substituted with such isotopes (e.g., deuterium converters). Compounds substituted with such isotopes are also useful as pharmaceuticals. Compounds represented by formula (I) include all radiolabeled compounds substituted with radioisotopes contained in said isotope. The present invention also includes a "radiolabeling method" for producing said "radiolabeled compounds," and said "radiolabeled compounds" are useful as tools for metabolic pharmacokinetic studies, binding assays, and / or diagnostics. 【0014】 Radiolabeled compounds of the compound represented by formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds represented by formula (I) can be prepared by introducing tritium into a specific compound represented by formula (I) by a catalytic dehalogenation reaction using tritium. This method involves reacting a precursor of the compound represented by formula (I) that is appropriately halogen-substituted with tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, or a base. For other suitable methods for preparing tritium-labeled compounds, see "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". １４ C-labeled compounds are １４ It can be prepared by using a raw material containing carbon. 【0015】The compound represented by formula (I) may form a prodrug, and the compound represented by formula (I) included in the formulation according to the present invention also includes various such prodrugs. A prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound represented by formula (I) by enzymatic oxidation, reduction, hydrolysis, etc., under physiological conditions in the body, and compounds that are converted to the compound represented by formula (I) by hydrolysis by gastric acid, etc. Methods for selecting and producing a suitable prodrug derivative are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may be active themselves. 【0016】 As used herein, the “compound represented by formula (I)” may form salts, cocrystals, or solvates thereof. As used herein, the “compound represented by formula (I), its pharmaceutically acceptable salts, or solvates thereof” also include such various salts, cocrystals, and solvates thereof. 【0017】 As used herein, "salt" means, for example, a compound represented by formula (I) and a counter molecule arranged regularly within the same crystal lattice, and may contain any number of counter molecules. It refers to a compound and a counter molecule that form an ionic bond through proton transfer within the crystal lattice. 【0018】 As used herein, "cocrystal" means that counter molecules are regularly arranged within the same crystal lattice, and may contain any number of counter molecules. Furthermore, a cocrystal is defined as one in which the intermolecular interactions between a compound and counter molecules are mediated by non-covalent and non-ionic chemical interactions such as hydrogen bonds and van der Waals forces. 【0019】Generally, salts are considered to involve proton transfer between the compound and the counter molecule; however, it is known that in some cases, proton transfer may not be complete. This state is not a true salt and is sometimes called a cocrystal. It is also known that proton transfer may change continuously with temperature. Therefore, as used herein, "a pharmaceutically acceptable salt of the compound represented by formula (I)" includes cocrystals and refers to a pharmaceutically acceptable salt or cocrystal of the compound represented by formula (I). 【0020】 One embodiment of this specification is a pharmaceutically acceptable salt or cocrystal of the compound represented by formula (I) with hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric acid, methanesulfonic acid sulfate, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethylbenzenesulfonic acid, chlorobenzenesulfonic acid, methoxybenzenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malonic acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphate, tartaric acid, benzoic acid, glutamic acid, aspartic acid, 2-naphthalenesulfonic acid, hexanoic acid, acetylsalicylic acid, etc. 【0021】 The study of salt formation and cocrystal formation provides a means of altering the physicochemical and biological properties of a drug without changing its chemical structure. Salt formation and cocrystal formation can dramatically affect the properties of a drug. Hygroscopicity, stability, solubility, and processing properties are also important considerations in the selection of an appropriate salt or cocrystal. The solubility of a salt or cocrystal can affect its suitability for use as a drug. If aqueous solubility is low, the dissolution rate in in vivo administration may be limited by the absorption process, resulting in low bioavailability. Furthermore, low water solubility may make administration by injection difficult, limiting the selection of an appropriate route of administration. 【0022】The compound represented by formula (I) can form a solvate (i.e., a hydrate) with water or a solvate with a common organic solvent. A pharmaceutically acceptable salt of the compound represented by formula (I) can form a solvate (i.e., a hydrate) with water or a solvate with a common organic solvent. 【0023】As used herein, "solvate" refers to a compound, for example, represented by formula (I), in which any number of solvent molecules are regularly arranged. Examples of solvent molecules include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, and Examples include pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, xylene, and t-butanol. Preferably, examples include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methylisopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid. Most preferably, ethyl acetate is used. Furthermore, when the compound represented by formula (I) is left in the atmosphere, it may absorb moisture, resulting in adsorbed water adhering to it or the formation of hydrates. 【0024】The compound represented by formula (I), its pharmaceutically acceptable salts, or solvates thereof have low solubility in water, making them useful in producing parenteral formulations consisting of suspensions containing an active ingredient exhibiting coronavirus 3Cl protease inhibitory activity. By using this parenteral formulation for subcutaneous, intradermal, or intramuscular injection, the active ingredient can be released continuously. 【0025】 The suspension of the present invention refers to a suspension in which a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is suspended. In this suspension, the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is dispersed. Furthermore, in the suspension of the present invention, the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof can be easily redispersed. For example, in the case of a vial filled with the suspension, the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof can be redispersed in the vial by shaking the vial up and down for about 10 seconds. 【0026】 The compound represented by formula (I) contained in the formulation according to the present invention has coronavirus 3CL protease inhibitory activity, and therefore the formulation according to the present invention is useful as a therapeutic and / or prophylactic agent for diseases involving coronavirus 3CL protease. In the present invention, "therapeutic and / or prophylactic agent" also includes symptom-improving agents. Diseases involving coronavirus 3CL protease include viral infections, and coronavirus infections are preferred. 【0027】 Examples of coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, and particularly preferably, infections caused by SARS-CoV-2. Among coronavirus infections, particularly preferably, is COVID-19. 【0028】The formulation of the present invention has at least one of the following characteristics: (1) Excellent dispersibility of the active ingredient. (2) Less prone to sedimentation of the active ingredient. (3) Excellent redispersibility of the active ingredient. (4) Good stability of the active ingredient against heat, humidity, light, etc. (5) Excellent storage stability as a formulation. (6) Capable of sustained release of the active ingredient. (7) Simple administration method. 【0029】One aspect of the present invention is a formulation comprising crystals of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. More specifically, it is a formulation comprising crystals of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof that is sparingly soluble in water. More specifically, it is a formulation comprising crystals of a compound represented by formula (I) or a solvate thereof. In one aspect, the solubility in water of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is 0.1 mg / mL or less, preferably 0.01 mg / mL or less, and more preferably 0.001 mg / mL or less. The solubility in water can be measured at 20 ± 5°C. In particular, crystals of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof that have a solubility in water of 0.1 mg / mL or less, preferably 0.01 mg / mL or less, and more preferably 0.001 mg / mL or less, as measured at 25°C, are preferred. Another aspect of the present invention is a formulation comprising anhydrous crystals of the compound represented by formula (I). The solubility of the anhydrous crystals of the compound represented by formula (I) in water at 25°C is 0.0004 mg / mL, and the solubility of the ethyl acetate crystalline form of the compound represented by formula (I) in water at 25°C is 0.002 mg / mL. Furthermore, the solubility of the anhydrous crystals of the compound represented by formula (I) in water at 37°C is 0.0007 mg / mL. Here, in the 18th edition of the Japanese Pharmacopoeia, solubility is defined as "the degree to which a drug dissolves within 30 minutes when, in the case of a solid, it is powdered, placed in a solvent, and shaken vigorously for 30 seconds every 5 minutes at 20±5°C, unless otherwise specified." The term "almost insoluble" is used when the amount of solvent required to dissolve 1 g or 1 mL of solute is 10,000 mL or more. Therefore, if the solubility in water is 0.1 mg / mL or less, it can be said to be "almost insoluble." Furthermore, the compound represented by formula (I), its pharmaceutically acceptable salts, or solvates thereof are suitable as active ingredients in sustained-release formulations.As described above, not only is it low solubility in water, but it is also suitable as an active ingredient in sustained-release formulations administered by subcutaneous, intradermal, or intramuscular injection in terms of molecular weight, CLogP, lipophilicity, particle size at administration, dissolution rate in the body, adverse effects at the injection site, blood protein binding rate, and stability. 【0030】 In this specification, "crystal" refers to a solid in which the constituent atoms, ions, molecules, etc., are arranged regularly in three dimensions, and is distinguished from amorphous solids that do not have such a regular internal structure. The crystals used in this specification may be single crystals, twins, polycrystalline, etc. Furthermore, "crystals" may have "crystal polymorphs" in which the composition is the same but the arrangement within the crystal differs, and these are collectively referred to as "crystal forms." "The compound represented by formula (I), its pharmaceutically acceptable salts, or solvates thereof" encompass their crystal polymorphs. The crystals used in this specification may be deuterium converters. The crystals used in this specification are isotopes (e.g., ３ H, １４ C, ３５ S, １２５ It may be labeled with (I, etc.). The crystal morphology and / or degree of crystallinity can be confirmed by spectroscopic methods such as X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, and solid-state NMR. Furthermore, the physical properties of the crystal can be confirmed by many techniques such as differential scanning calorimetry, water adsorption / desorption measurement, and solubility properties. 【0031】 One embodiment described herein is an anhydrous crystal of the compound represented by formula (I). In this specification, "anhydrous" is synonymous with "solvate," "nonsolvate," "anhydrous," and "nonhydrate." The anhydrous crystals of the compound represented by formula (I) have a theoretical water content of 0% by weight. However, in the analysis of water and / or solvent content, the water content may be higher than the theoretical water content due to the influence of adhering water and / or solvent on the crystal surface. The anhydrous crystals of the compound represented by formula (I) are white to pale reddish-white or pale yellowish-white in color. 【0032】One embodiment described herein is an anhydrous crystal of the compound represented by formula (I), having characteristic peaks at diffraction angles (2θ) of 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2° in the powder X-ray diffraction pattern (CuKα line, λ = 1.5418 Å). 【0033】 One embodiment described herein is an anhydrous crystal of the compound represented by formula (I), characterized by the following crystallographic data when single crystal structure analysis is performed using CuKα rays (λ = 1.5418 Å) at 298 K (25 °C): Space group: Pbcá a = 14.67 Å ± 0.05 Å b = 11.83 Å ± 0.05 Å c = 27.10 Å ± 0.05 Å α = 90° β = 90° γ = 90°. 【0034】 One embodiment described herein is an anhydrous crystal of the compound represented by formula (I), having a melting point of 261.3°C ± 2°C as determined by differential scanning calorimetry (DSC). Another embodiment described herein is an anhydrous crystal of the compound represented by formula (I), having a melting point of 265.6°C ± 2°C as determined by differential thermal-thermogravimetric analysis (TG / DTA). 【0035】 One aspect of this specification is the Raman spectrum at 415.2 cm⁻¹. －１ ±2cm －１ 502.7cm －１ ±2cm －１ 1431.4cm －１ ±2cm －１ 1714.8cm －１ ±2cm －１ and 3065.4 cm －１ ±2cm －１ This is an anhydrous crystal of the compound represented by formula (I), exhibiting a characteristic peak. 【0036】In the formulations according to the present invention, formulations containing a suspension of a compound represented by formula (I) having a Z-average of 0.1 to 5.0 μm, a pharmaceutically acceptable salt thereof, or a solvate thereof are preferred. Furthermore, formulations containing a suspension of a compound represented by formula (I) having a Z-average of 0.1 to 3.0 μm, a pharmaceutically acceptable salt thereof, or a solvate thereof are preferred. Particularly preferred are formulations containing a suspension of a compound represented by formula (I) having a Z-average of 0.1 to 1.0 μm, a pharmaceutically acceptable salt thereof, or a solvate thereof. Note that Z-average is the average hydrodynamic diameter based on the light intensity obtained by DLS, represents the size of the entire particle group, and is calculated as a light intensity weighted average. 【0037】 One aspect of the present invention relates to a parenteral formulation containing "a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" as an active ingredient. In the parenteral formulation of the present invention, the compound represented by formula (I) may be present in an amount of 1 to 2000 mg per vial, preferably 100 to 2000 mg. Particularly preferably 200 to 1500 mg. In another aspect, the compound represented by formula (I) may be present in an amount of 2000 to 3000 mg per vial, preferably 2000 to 2500 mg. Particularly preferably 2000 to 2400 mg. 【0038】Furthermore, in the formulations according to the present invention, formulations in which the amount of the compound represented by formula (I), its pharmaceutically acceptable salt, or their solvates is 10 to 500 mg per 1 mL of suspension are preferred. Moreover, formulations in which the amount of the compound represented by formula (I), its pharmaceutically acceptable salt, or their solvates is 10 to 200 mg per 1 mL of suspension are preferred. Examples of parenteral formulations of the present invention include injections, drips, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injectables, topical preparations, gargles, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, suppositories, etc.). The parenteral formulation of the present invention is preferably an injection and may be in the form of a solution, suspension, or emulsion such as O / W, W / O, O / W / O, or W / O / W type, with the suspension form being particularly preferred. In other words, in the present invention, an injectable formulation comprising a suspension of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is particularly preferred. 【0039】 The parenteral formulation of the present invention containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient can be manufactured by known methods. The formulation may contain pharmaceutically acceptable additives, such as stabilizers (suspending agents, dispersants), isotonic agents, pH adjusters, etc. 【0040】 One aspect of the present invention is a formulation comprising a suspension containing anhydrous crystals of a compound represented by formula (I) as an active ingredient. In one aspect, the formulation according to the present invention contains anhydrous crystals of the compound represented by formula (I) in an amount of 10 to 500 mg / mL, preferably 10 to 200 mg / mL. In another aspect, it contains anhydrous crystals of the compound represented by formula (I) in an amount of 300 to 500 mg / mL, preferably 300 to 400 mg / mL. In yet another aspect, it contains anhydrous crystals of the compound represented by formula (I) in an amount of 400 to 1000 mg / mL, preferably 400 to 700 mg / mL. 【0041】The method for producing a formulation comprising a suspension containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (preferably anhydrous crystals of the compound represented by formula (I)) as an active ingredient is not particularly limited, but specifically, the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (preferably anhydrous crystals of the compound represented by formula (I)) is pulverized together with additives such as stabilizers (suspending agents, dispersants), isotonic agents, and pH adjusters to pulverize the anhydrous crystals of the compound represented by formula (I) to a desired particle size. A wet pulverization method is used for this pulverization, in which the pharmaceutically active ingredient (drug) is suspended in an aqueous solvent containing the additives and then pulverized. Beads may also be used as the pulverization medium. The pulverization apparatus can be any apparatus commonly used in the art, such as a high-pressure homogenizer (nanovata), a wet jet mill, a bead mill, or a ball mill, but is not limited to these. It is preferable to pulverize the particles at a temperature that does not significantly decompose the drug. If necessary, the grinding device may be cooled with a cooling device. 【0042】 In this specification, “stabilizer” refers to an agent that contributes to the stabilization of the formulation of the present invention during or after its manufacture. For example, if the formulation of the present invention is in the form of a suspension, the “stabilizer” of the present invention contributes to the efficient grinding of the anhydrous crystals of the compound represented by formula (I) by suspending them during the manufacture of the formulation of the present invention, and after the manufacture of the formulation, contributes to maintaining the suspension form by dispersing the compound represented by formula (I) as a solid in the solvent. 【0043】 In this specification, the "stabilizer" of the present invention may be referred to as a "suspending agent" or a "dispersing agent," and these two may be the same substance or different substances. 【0044】In this specification, “suspending agent” means an additive for maintaining suspension in a formulation. The “suspending agent” may also contribute to efficient grinding in the grinding process of the compound represented by formula (I). Examples of suspending agents include, but are not limited to, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (polysorbates, e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.), sorbitan esters of fatty acids (SPAN), and poloxamers (e.g., poloxamer 188, poloxamer 338, poloxamer 407, etc.). Preferably, the suspending agent is a polyoxyethylene sorbitan fatty acid ester (polysorbate) or poloxamer, and particularly preferably polysorbate 20, polysorbate 80, poloxamer 188, or poloxamer 338. In one aspect of the present invention, the suspending agent is a polyoxyethylene sorbitan fatty acid ester, preferably polysorbate 20. In one embodiment of the present invention, the suspending agent is poloxamer, preferably poloxamer 338. 【0045】 In this specification, "dispersant" refers to an additive used to maintain dispersibility in a formulation. By using a "dispersant," the compound represented by formula (I) can be dispersed in a solvent and maintained in the form of a suspension. Examples of dispersants include, but are not limited to, polyethylene glycol (e.g., macrogol 4000, macrogol 600, macrogol 300, etc.), calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, amorphous cellulose, polysaccharides, hyaluronic acid, polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP). Furthermore, a "dispersant" may be added when grinding the compound according to the present invention during the production of the formulation of the present invention. Preferably, it is polyethylene glycol, and particularly preferably, macrogol 4000. 【0046】In one aspect of the present invention, the suspending agent is contained in the formulation according to the present invention in an amount of 0.1 to 4.0 w / v%, preferably 0.1 to 2.0 w / v%. In one aspect of the present invention, the suspending agent is contained in the formulation according to the present invention in an amount of 0.1 to 10.0 w / v%, preferably 1.0 to 6.0 w / v%. In one aspect of the present invention, the suspending agent is contained in the formulation according to the present invention in an amount of 4.5 to 10.0 w / v%, preferably 5.0 w / v%. 【0047】 In one aspect of the present invention, the dispersant is contained in the formulation according to the present invention in an amount of 0.1 to 4.0 w / v%, preferably 0.1 to 2.0 w / v%. 【0048】 In the formulation of the present invention, an isotonic agent may be used. Examples of isotonic agents include glucose, sucrose, fructose, trehalose, lactose, polyhydric sugar alcohols, erythritol, arabitol, xylitol, sorbitol, and D-mannitol. Preferably, sucrose, trehalose, and D-mannitol are used, and particularly preferably D-mannitol. 【0049】 In the formulation of the present invention, a pH adjusting agent can be used. Examples of pH adjusting agents include hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium acetate, citric acid, sodium citrate, phosphoric acid, sodium phosphate, potassium phosphate, lactic acid, malic acid, gluconic acid, sodium gluconate, glutamic acid, sodium glutamate, histidine, histidine hydrochloride, aminoacetic acid, sodium hydrogen phosphate, and sodium hydrogen phosphate hydrate. Particularly preferred are sodium dihydrogen phosphate hydrate and sodium hydrogen phosphate hydrate. In the formulation according to the present invention, the pH of the suspension is adjusted to 4.0 to 8.0. 【0050】The formulation according to the present invention is a sustained-release formulation. It is estimated that the formulation according to the present invention can maintain a blood concentration of the compound represented by formula (I) at 5 to 30 ng / mL two months after injection into a human. Furthermore, the formulation according to the present invention can maintain a blood concentration of the compound represented by formula (I) of 10 ng / mL or higher in rats for 180 days after injection. In other words, the formulation according to the present invention can sustainably release the compound represented by formula (I) for two months or more after injection (for example, three months or more, four months or more, five months or more, six months or more). In one embodiment of the present invention, the compound represented by formula (I) can be sustainably released for about one week and then for eight weeks or more, twelve weeks or more, sixteen weeks or more, twenty weeks or more, twenty-four weeks or more, and twenty-eight weeks or more. 【0051】 (Powder X-ray Diffraction (XRPD)) Powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystalline morphology and crystallinity of solids. When X-rays are irradiated onto a crystal, they are reflected by the crystal lattice planes and interfere with each other, showing ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, amorphous solids usually do not have an ordered repeating periodicity in their structure, so diffraction does not occur, and they show a featureless broad XRPD pattern (also called a halo pattern). 【0052】 The characteristic diffraction peaks used herein are peaks selected from the observed diffraction pattern. Preferably, the characteristic diffraction peaks are selected from about 10, more preferably about 5, peaks in the diffraction pattern. In distinguishing between multiple crystals, a peak observed in a particular crystal but not in others is a preferred characteristic peak for identifying that crystal, rather than a peak with high intensity. Even one or two such characteristic peaks can characterize the crystal. If the measured patterns are compared and these characteristic peaks match, the powder X-ray diffraction patterns can be said to be substantially identical. 【0053】Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error within a range of ±0.2°. Therefore, it is necessary to understand that the diffraction angle value in powder X-ray diffraction includes values ​​within a range of approximately ±0.2°. Accordingly, the present invention includes not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction perfectly match, but also crystals in which the diffraction angles of the peaks match with an error of approximately ±0.2°. 【0054】 The peak intensity shown in the following figure is generally known to vary depending on many factors, such as the effect of selective orientation of the crystal on the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample. The peak position may also shift based on variations in sample height. Furthermore, measurements using different wavelengths yield different shifts according to the Bragg equation (nλ = 2dsinθ), and these alternative XRPD patterns obtained using different wavelengths are also within the scope of the present invention. 【0055】 By combining a powder X-ray diffractometer with a temperature and / or relative humidity control device, powder X-ray diffraction measurements can be performed under specific temperature and / or relative humidity conditions. For example, when anhydrous crystals change to hydrate crystals due to moisture absorption, when hydrate crystals change to anhydrous crystals due to dehydration, when solvate crystals undergo a crystal transition to anhydrous crystals due to solvent desorption, or when anhydrous crystals and hydrate crystals reversibly change due to moisture absorption and dehydration, measurements under specific temperature and / or relative humidity conditions, or measurements with continuously changing temperature and / or relative humidity, are suitable. In such cases, it is possible to estimate the relative humidity at which the change occurs and the amount of crystal water and / or crystal solvent. 【0056】 The crystalline form of the compound represented by formula (I) can be identified by the powder X-ray diffraction pattern and the diffraction angle (2θ) of the characteristic peak. The crystalline form of the compound represented by formula (I) (for example, the anhydride of the compound represented by formula (I)) can be distinguished from other crystalline forms by the presence of a characteristic peak. 【0057】(Powder X-ray diffraction - Differential scanning calorimetry (XRD-DSC)) Simultaneous measurement of powder X-ray diffraction and differential scanning calorimetry (XRD-DSC measurement) allows for the simultaneous observation of changes in crystal morphology (crystal structure) and calorimetry in response to temperature and / or relative humidity. For example, it is suitable for observing changes in crystal morphology (crystal structure) when anhydrous crystals undergo a crystal transition to hydrate crystals due to moisture absorption, when hydrate crystals undergo a crystal transition to anhydrous crystals due to dehydration, when solvate crystals undergo a crystal transition to anhydrous crystals due to solvent desorption, and when anhydrous crystals and hydrate crystals undergo a reversible crystal transition due to moisture absorption and dehydration. 【0058】 (Single Crystal Structure Analysis) Single crystal structure analysis is one method for determining crystal morphology, and it can obtain crystallographic parameters, as well as atomic coordinates (values ​​indicating the spatial positional relationship of each atom) and a three-dimensional structural model. For single crystal structure analysis, refer to "A Guide to X-ray Structure Analysis" by Toshio Sakurai, published by Shokabo (1983), and "X-Ray Structure Determination: A Practical Guide" by Stout & Jensen, Macmillan Co., New York (1968). Single crystal structure analysis is useful when identifying the structures of optical isomers, tautomers, geometric isomers, salts, cocrystals, and solvates (hydrates). It is known that the quality of data from single crystal X-ray diffraction experiments can be improved by performing measurements at low temperatures, so measurements should be performed at room temperature or low temperature depending on the crystal being measured. Furthermore, it is known that the quality of data obtained from single-crystal X-ray diffraction experiments of hydrates and / or solvates can be improved by coating the crystals with paraffin oil or the like before measurement. 【0059】(Raman Spectroscopy) Raman spectra exhibit the vibrational characteristics of molecules or complex systems. Their origin lies in the inelastic collisions between molecules and photons, which are particles of light. Collisions between molecules and photons result in an exchange of energy, which in turn changes the energy and thus the wavelength of the photons. In other words, since Raman spectra are spectral lines with an extremely narrow wavelength range emitted when photons are incident on a target molecule, lasers and the like are used as light sources. The wavelength of each Raman line is expressed by the wavenumber shift from the incident light, which is the difference between the wavelength of the Raman line and the reciprocal of the wavelength of the incident light. Raman spectra measure the vibrational state of a molecule, which is determined by its molecular structure. Generally, the wavelength shift amount (cm) in a Raman spectrum is... －１ ) ±2cm －１ Because errors can occur within this range, the Raman spectral peak values ​​are ±2 cm. －１ It is necessary to understand that this includes values ​​within a certain range. Therefore, not only crystals where the Raman spectral peaks perfectly match in the Raman spectrum, but also crystals where the Raman spectral peaks are within ±2 cm. －１ Crystals that match with a degree of error are also included in this invention. 【0060】(Differential Scanning Calorimetry (DSC)) Differential scanning calorimetry (DSC) is one of the main measurement methods for thermal analysis, and it is a method for measuring the thermal properties of a substance as an aggregate of atoms and molecules. DSC measures the change in heat quantity of a pharmaceutical active ingredient with respect to temperature or time, and a differential scanning calorimetry curve is obtained by plotting the obtained data against temperature or time. From the differential scanning calorimetry curve, information can be obtained regarding the onset temperature (extrapolated melting point onset temperature) when the pharmaceutical active ingredient melts, the maximum value of the endothermic peak curve associated with melting, and enthalpy. It is known that the temperature observed in DSC may depend on the rate of temperature change, the sample preparation technique used, and the specific equipment. Therefore, the "melting point" in DSC refers to the onset temperature (extrapolated melting point onset temperature), which is less affected by the sample preparation technique. The error range of the onset temperature (extrapolated melting point onset temperature) obtained from the differential scanning calorimetry curve is approximately ±2°C. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this may vary to some extent depending on the measurement conditions and measuring equipment. 【0061】 (Differential Thermal-Thermogravimetric Analysis (TG / DTA)) Differential thermal-thermogravimetric analysis (TG / DTA) is one of the main measurement methods for thermal analysis, and it is a method for measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules. TG / DTA is a method for measuring the change in weight and heat quantity of a pharmaceutical active ingredient with respect to temperature or time, and by plotting the obtained data against temperature or time, TG (thermogravimetric) and DTA (differential thermal) curves are obtained. From the TG / DTA curve, information on the change in weight and heat quantity related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the pharmaceutical active ingredient can be obtained. It is known that the temperature and weight changes observed in TG / DTA may depend on the rate of temperature change, the sample preparation technique used, and the specific equipment. Therefore, the "melting point" in TG / DTA refers to the onset temperature (extrapolated melting point onset temperature), which is less affected by the sample preparation technique. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this can vary somewhat depending on the measurement conditions and equipment. 【0062】(Particle Size Distribution) In this specification, "D10, D50, D90" refers to the particle size at which the cumulative curve reaches 10%, 50%, and 90% when the total volume of the powder aggregate is taken as 100%, and can be measured by dry or wet methods. 【0063】 (Laser Diffraction Scattering Method) The laser diffraction scattering method is one method for measuring particle size. When a particle is irradiated with laser light, the particle size and distribution can be calculated from the intensity pattern of the light diffracted and scattered according to the particle size. In this application, the laser diffraction scattering method was used when measuring particle size using the dry method. 【0064】 (Dynamic Light Scattering (DLS)) Dynamic Light Scattering (DLS) is a technique specifically designed for measuring the particle size distribution of nanoscale particles in solution (1 × 10⁻⁶). －９ This is a practical and simple method for measuring microparticles on the order of m. Microparticles dispersed in suspensions or solutions usually undergo Brownian motion, and it is known that the smaller the particle, the faster its motion. By irradiating particles dispersed in a solvent with laser light, the phenomenon of light scattering is measured, and the autocorrelation function of the light scattering pattern is analyzed from this data. From the motion velocity of the microparticles and the time scale of the correlation function, the size and distribution of the microparticles can be calculated. Z-average is the average hydrodynamic diameter based on the light intensity obtained by DLS. It is useful when the particle size is relatively uniform and is used as a measurement result. In this application, DLS was used when measuring particle size in a wet state. 【0065】 The present invention will be described in more detail below with reference to examples and test examples. The present invention is not limited thereto. With respect to numerical values ​​(e.g., quantity, temperature, etc.), some errors and deviations should be taken into consideration. 【0066】(Method for producing the compound represented by formula (I)) The compound represented by formula (I) is compound (I-077) described in International Publication No. 2023 / 195529 and International Publication No. 2023 / 195530, and can be produced by the synthesis method of Examples 5-6 described in said literature. It can also be synthesized by referring to methods known in the art. Extraction, purification, etc., can be carried out using the same procedures as in a normal organic chemistry experiment. 【0067】 (Biological tests of the compound represented by formula (I)) The results of the biological tests of the compound represented by formula (I) are described as compound (I-077) in International Publication No. 2023 / 195529 and International Publication No. 2023 / 195530. 【0068】 (Example 1: Grinding of the compound represented by formula (I)) The compound represented by formula (I), prepared by the synthesis methods of Examples 5-6 in International Publication No. 2023 / 195529 and International Publication No. 2023 / 195530, was sieved through a 1000 μM mesh and then ground under the following conditions: Apparatus: A-O Jet Mill (Seishin Corporation) Feeding method: Feeder Feeding rate: 20 g / hour Grinding pressure: 0.30 MPa Feeding pressure: 0.40 MPa 【0069】(Test Example 1: Powder X-ray Diffraction Experiment (XRPD) Powder X-ray diffraction measurement was performed on the compound shown in formula (I) after grinding in Example 1, according to the powder X-ray diffraction measurement method described in the general test methods of the Japanese Pharmacopoeia. The measurement conditions are as follows. Measurement conditions 1: Powder X-ray diffractometer: Rigaku SmartLab Measurement method: Reflection method Wavelength used: CuKα rays (λ = 1.5418 Å) Tube current: 200 mA Tube voltage: 45 kV Sample plate: Aluminum X-ray incident angle: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (2D detection mode) As a result, it was found that the compound shown in formula (I) is crystalline. The powder X-ray diffraction pattern is shown in Figure 1, and the peak list of the powder X-ray diffraction pattern is shown in Figure 2. In the table below of the peak list of the powder X-ray diffraction pattern, Position is 2θ (°) and Intensity is intensity. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 6.5°±0.2°, 10.1°±0.2°, 13.0°±0.2°, 14.1°±0.2°, 15.3°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.7°±0.2°, 23.0°±0.2°, 23.8°±0.2°, 25.8°±0.2°, 28.8°±0.2°, and 30.6°±0.2°. Characteristic peaks were observed at diffraction angles (2θ): Examples include 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2°. Furthermore, diffraction angles (2θ) include 6.5°±0.2°, 10.1°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.7°±0.2°, 23.0°±0.2°, and 23.8°±0.2°. 【0070】(Test Example 2: Single Crystal Structure Analysis) The single crystal structure of the compound shown in equation (I) was analyzed. The measurement conditions and analysis method are shown below. (Equipment) Rigaku XtaLAB P200 MM007 (Measurement Conditions) Measurement temperature: 25°C Temperature controller: Rigaku sample spraying cryogenic device Wavelength: CuKα line (λ = 1.5418 Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data Processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data was corrected for Lorentz, polarization, and absorption. (Crystal structure analysis) Phase determination was performed using the direct method program ShelXT (Sheldrick, G.M., 2015), and refinement was performed using the full-matrix least squares method with ShelXL (Sheldrick, G.M., 2015). All temperature factors of non-hydrogen atoms were refined using anisotropy. Unless otherwise specified, hydrogen atoms were introduced computationally using ShelXL's default parameters and treated as riding atoms. Hydrogen atoms were also refined using isotropy parameters. The following structural diagrams were drawn using PLATON (Spek, 1991) / ORTEP (Johnson, 1976) (30% PROBABILITY level). 【0071】 <Method for preparing single crystals> 1 mg of crystals of the compound shown in formula (I) was mixed with 400 μL of methanol and heated to 50°C to dissolve. The solution was dispensed into a 1.5 mL HPLC vial, the HPLC vial was capped, a syringe needle was inserted into the cap, and the vial was left to stand at room temperature. Single crystals were prepared by solvent evaporation. <Single crystal structure analysis> Single crystal diffraction experiments and analysis were performed using the above method. Since Cl1 and Cl7C, and H5CA and H6CA are disordered, the analysis was performed using occupancy ratios of Cl1:Cl7C = 0.75:0.25 and H5CA:H6CA = 0.25:0.75. 【0072】 The results of the single-crystal structure analysis are shown below. １(I > 2.00 s(I)) is 0.0555, and the final difference Fourier analysis confirmed that there was no omission or misplacement of electron density. 【0073】 The crystallographic data is shown in Table 1. Here, V represents the unit cell volume, and Z represents the number of molecules in the unit cell. 【0074】 Atomic fraction coordinates x, y, z of a non-hydrogen atom (Å × 10⁻¹⁰) ４ ) and the equivalent isotropic temperature factor U(eq) (Equivalent Isotropic Displacement Parameters, Å ２ ×10 ３ Table 2 shows the results. Here, U(eq) is the orthogonalized U ｉｊ It is defined as one-third of the tensor's locus. 【0075】 Next, the atomic coordinates x, y, z of a hydrogen atom (Å × 10⁻¹⁰) ４ ) and isotropic temperature factor U(eq) (Isotropic Displacement Parameters, Å ２ ×10 ３ Table 3 shows the results. 【0076】 Figure 3 shows the structure within the asymmetric unit of the crystal structure. The label numbers for the non-hydrogen atoms in Figure 3 correspond to the non-hydrogen atom numbers in Table 2. 【0077】 The crystal structure was identified as an anhydrous crystal of the compound represented by formula (I) because only one molecule of the compound represented by formula (I) was present in the asymmetric unit. 【0078】 Based on the crystal structure, the powder X-ray diffraction pattern (λ = 1.5418 Å) calculated using Mercury (The Cambridge Crystallographic Data Centre, Ver. 4.0.0) was found to be in general agreement with the powder X-ray diffraction pattern of Test Example 1 (Figure 1). 【0079】(Test Example 3: Differential Scanning Calorimetry (DSC)) DSC measurements were performed on the compound represented by formula (I) (anhydrous crystals of the compound represented by formula (I)) after grinding in Example 1. Approximately 2 mg of the sample was weighed into an aluminum pan, sealed in a simple manner, and measured. The measurement conditions are as follows. Note that differential scanning calorimetry (DSC) measurements may have an error within a range of ±2°C. Apparatus: Discovery DSC / TA Instrument Measurement temperature range: -10°C to 270°C Heating rate: 10°C / min Atmosphere: N ２ The measurement results at 50 mL / min are shown in Figure 4. The onset temperature showed an endothermic peak at approximately 261.3°C. 【0080】 (Test Example 4: Differential Thermal-Thermogravimetric Analysis (TG / DTA)) Differential thermal-thermogravimetric analysis (TG / DTA) was performed on the compound represented by formula (I) (anhydrous crystals of the compound represented by formula (I)) after grinding in Example 1. The samples obtained in each example were weighed, placed in aluminum pans, and measured in an open system. The measurement conditions were as follows: Apparatus: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: Room temperature - 350°C Heating rate: 10°C / min The measurement results are shown in Figure 5. The onset temperature showed an endothermic peak of approximately 265.6°C. Furthermore, no weight loss was observed. 【0081】 (Test Example 5: Raman Spectrum) The Raman spectrum was measured for the compound represented by formula (I) (anhydrous crystals of the compound represented by formula (I)) after grinding in Example 1. The measurement conditions are as follows: Measurement method: Micro-laser Raman spectroscopy Laser wavelength: 671 nm Number of integrations: 1 Exposure time: 1 second The measurement results are shown in Figure 6. The main Raman peaks are also shown below. The anhydrous crystals of the compound represented by formula (I) show a Raman spectrum of 415.2 cm⁻¹. －１ ±2cm －１ 502.7cm －１ ±2cm －１ 1431.4cm －１ ±2cm －１ 1714.8cm －１ ±2cm －１ , and 3065.4 cm －１ ±2cm －１It showed a characteristic peak. 【0082】 (Example 2: Preparation of Formulation and Measurement of Particle Size - 1) (Manufacturing Method) Polysorbate 20 (Merck), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound shown in formula (I) (anhydrous form of the compound shown in formula (I)) was added and dispersed. After confirming that a suspension with uniform properties had been obtained, the concentration was adjusted using water for injection to the formulations shown in Examples 2-1 to 2-3. Subsequently, for Examples 2-2 and 2-3, the suspensions were wet-milled using beads with a rotation-orbit mixer (Thinky) so that the Z-average of the compound shown in formula (I) was approximately 670 nm and approximately 210 nm, respectively, to obtain the samples. (Grinding conditions) ・Bead type: YTZ beads (φ0.1 mm, Nikkatoh made) ・Chamber atmosphere temperature: 5℃ (set) ・Grinding conditions (Z-average measurement) Particle size was measured using dynamic light scattering with a Zetasizer Nano (Malvern). (Z-average measurement conditions) Instrument: Zetasizer Nano (Malvern) Cell: UV-Transparent Cuvettes (SARSTEDT) Refractive index of sample: 1.59 Absorbency of sample: 0.01 Dispersion medium: Water Temperature: 25°C Refractive index of dispersion medium: 1.33 Viscosity: 1.0000 (Preparation of sample solution for Z-average measurement) 20 μL of suspension was added to a 20 mL volumetric flask, diluted with sterile water for injection (Otsuka Pharmaceutical Co., Ltd.), and used for particle size measurement. *1: The compound represented by formula (I) used in Example 2-1 has a D50 of 3.3 μm and is white in color. D50 is a value measured using a laser diffraction device, and is the particle size at the point where the cumulative curve reaches 50% when the total volume of the powder aggregate is taken as 100%. The Z-average of the compound represented by formula (I) used in the preparation of the suspension has not been calculated, but it is estimated to be about half of the D50. 【0083】 (Test Example 6: Rat PK Test (Subcutaneous (100 mg / head, different formulations of Z-average))) The concentration of the compound represented by formula (I) in rat plasma was evaluated using the formulations of Examples 2-1 to 2-3. Male rats were subcutaneously administered the samples shown in Table 5. The dosage of the samples was adjusted so that the dose of the compound represented by formula (I) was 100 mg. Blood was collected from the tail vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer, and the maximum plasma drug concentration (C) was determined. ｍａｘ The area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. (Results) The C of the compound shown in equation (I) ｍａｘ The results for AUC, BA, and the disappearance rate constant kel are shown in Table 8 and Figure 7 below. C ｍａｘ (Maximum plasma drug concentration): Indicates the maximum blood concentration after drug administration. AUC (Area under the plasma drug concentration-time curve): An indicator of the amount of drug taken into the body. BA (Bioavailability): An indicator of how much of the administered drug (formulation) reaches the systemic circulation and exerts its effect. kel (Elimination rate constant): An indicator of the rate at which a drug or substance is removed from the blood in the body. For BA, the amount absorbed (ng) for each period was calculated by multiplying the AUC (ng・hr / mL) between blood sampling times by CLtot (systemic clearance, obtained separately in an iv (intravenous administration) test (mL / hr / kg)) and body weight (kg), and then dividing the total absorbed amount (sum of absorbed amounts for each period (including extrapolation)) by the administered dose. For kel, it was calculated from the slope of plasma concentrations at six retrospective time points using Phoenix WinNonlin (Ver. 8.4). AUC was evaluated for Example 2-1 from day 0 to day 84, and for Examples 2-2 and 2-3 from day 0 to day 193. 【0084】(Example 3: Manufacturing of the formulation and measurement of particle size - 2) (Manufacturing method) Polysorbate 20 (Merck), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound shown in formula (I) was added and dispersed. After confirming that a suspension with uniform properties had been obtained, the concentration was adjusted using water for injection to the formulation shown in Example 3. Subsequently, the suspension was wet-milled using a NanoVeta (Yoshida Machinery Industry Co., Ltd.) so that the Z-average of the compound shown in formula (I) was approximately 300 nm, and a sample was obtained. The particle size was measured by dynamic light scattering using a Zetasizer Nano (Malvern). (Grinding conditions) - Number of passes: 35 passes - No cooling machine used (product temperature is left as is) - Grinding pressure: 180 MPa 【0085】 (Test Example 7: Rat PK Test, Subcutaneous (200 mg / head)) The concentration of the compound represented by formula (I) in rat plasma was evaluated using the formulation from Example 3. Male rats were subcutaneously administered the samples shown in Table 10. The dosage of the samples was adjusted so that the dose of the compound represented by formula (I) was 200 mg. Blood was collected from the tail vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer, and the maximum plasma drug concentration (C) was determined. ｍａｘ The area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. (Results) The C of the compound shown in equation (I) ｍａｘ The results for AUC, BA, and kel are shown in Table 10 and Figure 8 below. The formulation shown in Example 3 showed good persistence. 【0086】(Test Example 8: Rat PK Test (Intramuscular, 40 mg / head)) The concentration of the compound represented by formula (I) in rat plasma was evaluated. The sample was administered intramuscularly to male rats. The dosage of the sample was adjusted so that the dose of the compound represented by formula (I) was 40 mg. Blood was collected from the tail vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer, and the maximum plasma drug concentration (C) was determined. ｍａｘ The area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. The formulation and manufacturing method of the sample were the same as in Example 3. (Results) The C of the compound shown in formula (I) ｍａｘ The results for AUC, BA, and kel are shown in Table 11 and Figure 9 below. The formulation shown in Example 3 showed good persistence. 【0087】 (Test Example 9: Canine PK Test (Subcutaneous, 300 mg / head)) The concentration of the compound represented by formula (I) in canine plasma was evaluated. The sample was administered subcutaneously to male beagles. The sample dosage was adjusted so that the dose of the compound represented by formula (I) was 300 mg. Blood was collected from the tail vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer, and the maximum plasma drug concentration (C) was determined. ｍａｘ The area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. The formulation and manufacturing method of the samples were the same as in Example 3. (Results) The results for Cmax, AUC, BA, and Kel of the compound represented by formula (I) are shown in Table 12 and Figure 10 below. The formulation shown in Example 3 showed good persistence. 【0088】(Test Example 10: Canine PK Test (Intramuscular, 300 mg / head)) The concentration of the compound represented by formula (I) in canine plasma was evaluated. The sample was administered intramuscularly to male beagles. The dosage of the sample was adjusted so that the dose of the compound represented by formula (I) was 300 mg. Blood was collected from the tail vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer, and the maximum plasma drug concentration (C) was determined. ｍａｘ The area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. The formulation and manufacturing method were the same as in Example 3. (Results) The results for Cmax, AUC, BA, and keel of the compound represented by formula (I) are shown in Table 13 and Figure 11 below. The formulation shown in Example 3 showed good persistence. 【0089】 (Example 4: Examination of formulation: Examination of compound concentration and polysorbate 20 concentration) Using the formulations shown in Examples 4-1 to 4-8, it was evaluated whether the Z-average of the compound represented by formula (I) could be wet-milled down to approximately 300 nm. (Manufacturing Method) Polysorbate 20 (Merck), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound shown in formula (I) was added and dispersed. After confirming that a uniform suspension was obtained, the concentration was adjusted using water for injection to the formulations shown in Examples 4-1 to 4-8. Subsequently, the suspension was wet-milled using a NanoVeta (Yoshida Machinery Industry Co., Ltd.) to obtain the sample. Z-average was measured using a Zetasizer Nano (Malvern) by dynamic light scattering under the same conditions and method as in Example 2. (Manufacturing Conditions) ・No cooler used (product temperature is left to chance) (Results) Table 16 shows the feasibility of grinding based on visual evaluation and the Z-average. When the concentration of polysorbate 20 is 2.0%, it was confirmed that the compound represented by formula (I) can be wet-ground down to approximately 300 nm if the concentration of the compound represented by formula (I) is 100 to 250 mg / mL. Furthermore, when the concentration of polysorbate 20 is 1.5%, it was confirmed that the compound represented by formula (I) can be wet-ground down to approximately 300 nm if the concentration of the compound represented by formula (I) is 100 to 200 mg / mL. In addition, when the concentration of polysorbate 20 is 1.0% or 0.5%, it was confirmed that the compound represented by formula (I) can be wet-ground down to approximately 300 nm if the concentration of the compound represented by formula (I) is 100 mg / mL. (Criteria for visual judgment) Grindable: The suspension remains in a slurry state and the Z-average reaches approximately 300 nm. 【0090】 (Example 5: Examination of Formulation: Examination of Dispersant Type and Concentration - 1) Using the formulation shown in Example 5, it was evaluated whether the Z-average of the compound represented by formula (I) could be wet-milled to approximately 300 nm. The manufacturing method was the same as in Example 2. (Manufacturing Method) Polysorbate 20 (Merck), polysorbate 80 (Merck), poloxamer 188 (BASF), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), sodium carboxymethylcellulose (Ashland), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound shown in formula (I) was added and dispersed. After confirming that a suspension with uniform properties had been obtained, the concentration was adjusted using water for injection to the formulation shown in Example 5. Subsequently, the suspension was wet-milled using a rotation-orbit mixer (Thinky). The Z-average in the obtained suspension was measured using a Zetasizer Nano (Malvern) by dynamic light scattering under the same method and conditions as in Example 2. (Grinding conditions) ・Bead type: YTZ beads (φ0.1 mm, Nikkatoh made) ・Chamber atmosphere temperature: 5℃ (set) ・Grinding conditions (Results) The feasibility of grinding and the Z-average, as evaluated visually, are shown in Table 20 below. In Example 5, where the concentration of polysorbate 80 was 4.0%, it was confirmed that the compound represented by formula (I) could be wet-ground down to approximately 300 nm. Visual Inspection Criteria for Grinding: The suspension remains in a slurry state when the particle size reaches approximately 300 nm. 【0091】 (Example 6: Examination of Formulation: Examination of Dispersant Type and Concentration - 2) Using the formulations shown in Examples 6-1 to 6-3, it was evaluated whether the Z-average of the compound represented by formula (I) could be wet-milled to approximately 300 nm. The manufacturing method was the same as in Example 3. (Manufacturing Method) Polysorbate 20 (Merck), poloxamer 338 (BASF), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound shown in formula (I) was added and dispersed. After confirming that a suspension with uniform properties had been obtained, the concentration was adjusted using water for injection to the formulation shown in Example 6. Subsequently, the suspension was wet-milled using a NanoVeta (Yoshida Machinery Industry Co., Ltd.) to obtain the sample. Z-average was measured using a Zetasizer Nano (Malvern) by dynamic light scattering under the same method and conditions as in Example 2. (Manufacturing Conditions) ・No cooler used (product temperature is left to chance) (Experimental Results) The feasibility of grinding and the Z-average, as evaluated visually, are shown in Table 23 below. Examples 6-1 to 6-3 confirmed that the compound represented by formula (I) can be wet-ground down to approximately 300 nm. (Visual Inspection Criteria) Grindable: The suspension remains in a slurry state while the Z-average reaches approximately 300 nm. 【0092】 (Test Example 11: Stability Test (Related Substances)) The stability (related substances) of the formulations shown in Examples 4-1 to 4-3 and 4-5 to 4-8 was evaluated. For the formulations of Examples 4-1 to 4-3 and 4-5 to 4-8, approximately 0.5 mL of the obtained suspension was filled into a 3 mL vial (manufactured by Taisei Chemical Co., Ltd.), sealed, and sterilized by irradiation with 50 kGy of gamma rays. The irradiated samples were placed in a 60°C constant temperature bath, and the amount of related substances was measured after 1 week and 2 weeks. (Related Substance Test Method) The amount of related substances was measured by liquid chromatography using the following method and conditions. Detector: UV absorbance spectrophotometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 100 mm, Waters) Column temperature: Constant temperature around 40°C Mobile phase A: Water / formic acid mixture (1000:1) Mobile phase B: Acetonitrile mobile phase for liquid chromatography Delivery: Control the concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as follows (Experimental Results) The amounts of related substances in Examples 4-1 to 4-3 and 4-5 to 4-8 are shown in the table below. Related substances with relative retention times of 0.36 and 0.55 did not show an increasing trend in any of the formulations under 2 weeks of 60°C sealed conditions. 【0093】 (Test Example 12: Evaluation of Redispersibility) The sample from Example 6-1 was left standing for 3 days at 5°C. After that, its properties were observed and its dispersibility was evaluated. The results are shown in Figures 12-14. The redispersibility was good. Redispersibility method: The stored sample was shaken up and down for 10 seconds. 【0094】 (Test Example 13: Long-term stability test (related substances and redispersibility)) The long-term stability (related substances and redispersibility) of the formulation shown in Example 7 was evaluated. (Manufacturing Method) Polysorbate 20 (Merck), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound shown in formula (I) was added and dispersed. After confirming that a uniform suspension had been formed, the concentration was adjusted using water for injection to match the formulation shown in Example 7-1. Subsequently, the suspension was wet-milled using a Microfluidizer M110EH (Pawrec) to obtain the sample. Approximately 10 mL of the obtained suspension was filled into a 14 mL vial (Taisei Chemicals Co., Ltd.), sealed, and sterilized by irradiation with 200 kGy of gamma rays. Irradiated samples were placed in constant temperature baths at 5°C, 25°C, and 40°C, and the amount of related substances was measured after 12 months of storage. Redispersibility was also evaluated. (Related Substance Test Method) The same method as in Test Example 11 was used. (Redispersibility) Redispersion Method: The stored samples were shaken up and down for 10 seconds. (Experimental Results) The formulations of Example 7 did not show an increasing trend in related substances with relative retention times of 0.35 and 0.55 after storage under any temperature conditions. Furthermore, the formulations stored at 5°C and 25°C showed good redispersibility. 【0095】(Examples 8 and 9: Preparation of formulations and measurement of particle size - 3) Polysorbate 20 (Merck), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound represented by formula (I) (anhydrous form of the compound represented by formula (I)) was added and dispersed. After confirming that a uniform suspension was obtained, the concentration was adjusted using water for injection to the formulations shown in Examples 8-1 to 8-2. Subsequently, the suspension of the compound represented by formula (I) was wet-milled using beads with a rotation-orbit mixer (Thinky) to obtain a sample. Samples using poloxamer 338 (Examples 9-1 to 9-2) were obtained by the same method. Particle size was measured using dynamic light scattering with a Zetasizer Nano (Malvern). (Grinding conditions) ・Bead type: YTZ beads (φ0.1 mm, Nikkatoh made) ・Chamber atmosphere temperature: 5℃ (set) ・Grinding conditions *1: The compound represented by formula (I) used for grinding had D50: 2.33 μm, D90: 6.83 μm, and a pale reddish-white color. (Z-average measurement) Particle size was measured using dynamic light scattering with a Zetasizer Nano (Malvern). (Z-average measurement conditions) Instrument: Zetasizer Nano (Malvern) Cell: UV-Transparent Cuvettes (SARSTEDT) Refractive index of sample: 1.59 Absorbency of sample: 0.01 Dispersion medium: Water Temperature: 25°C Refractive index of dispersion medium: 1.33 Viscosity: 0.8872 【0096】(Test Example 14: Rat PK Test (Subcutaneous, 400 mg / kg)) The concentration of the compound represented by formula (I) in rat plasma was evaluated using the formulations of Examples 8-1, 8-2, 9-1, and 9-2. Male rats were subcutaneously administered the samples shown in Table 26. The dosage of the samples was adjusted so that the dose of the compound represented by formula (I) was 400 mg / kg. Blood was collected from the jugular vein or tail vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer to determine the maximum plasma drug concentration (C). ｍａｘ The area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. (Results) The C of the compound shown in equation (I) ｍａｘ The results for AUC, BA, and kel are shown in Table 29 and Figure 15 below. The formulations shown in Table 26 showed good persistence. C ｍａｘ (Maximum plasma drug concentration): Indicates the maximum blood concentration after drug administration. AUC (Area under the plasma drug concentration-time curve): An indicator of the amount of drug taken into the body. BA (Bioavailability): An indicator of how much of the administered drug (formulation) reaches the systemic circulation and exerts its effect. kel (Elimination rate constant): An indicator of the rate at which a drug or substance is removed from the blood in the body. For BA, the amount absorbed (ng) for each period was calculated by multiplying the AUC (ng・hr / mL) between blood sampling times by CLtot (systemic clearance, obtained separately in an iv (intravenous administration) test (mL / hr / kg)) and body weight (kg), and then dividing the total absorbed amount (sum of absorbed amounts for each period (including extrapolation)) by the administered dose. For kel, it was calculated using Microsoft Excel from the slope of plasma concentrations at five retrospective time points. AUC was evaluated for Examples 8-1 and 9-1 from day 0 to 93, and for Examples 8-2 and 9-2 from day 0 to 86. 【0097】(Test Example 15: Rat PK Test (Intramuscular, 140 mg / kg)) The concentration of the compound represented by formula (I) in rat plasma was evaluated using the formulations of Examples 8-1, 8-2, 9-1, and 9-2. Male rats were administered the samples shown in Table 26 intramuscularly. The dosage of the sample was adjusted so that the dose of the compound represented by formula (I) was 140 mg / kg. Blood was collected from the jugular vein or tail vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer to determine the maximum plasma drug concentration (C). ｍａｘ The area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. (Results) The C of the compound shown in equation (I) ｍａｘ The results for AUC, BA, and kel are shown in Table 30 and Figure 16 below. The formulations shown in Table 26 showed good persistence. 【0098】 (Test Example 16: Long-term stability test (related substances and redispersibility) - 2) The long-term stability (related substances and redispersibility) of the formulations shown in Examples 10 to 13 was evaluated. Polysorbate 20 (Merck), poloxamer 338 (BASF), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in sterile water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound shown in formula (I) was added and dispersed. After confirming that a uniform suspension was obtained, the concentration was adjusted using sterile water for injection to the formulations shown in Examples 10 to 13. Subsequently, the suspension was wet-milled using beads with a rotary-orbit mixer (Thinky) to obtain the sample. Approximately 0.5 mL of the obtained suspension was filled into a 3 mL vial (Taisei Chemicals Co., Ltd.), sealed, and sterilized by irradiation with 50 kGy of gamma rays. The irradiated sample was placed in constant temperature baths at 5°C, 25°C, and 30°C, and the amount of related substances was measured after 6 months of storage. In addition, the redispersibility was evaluated. (Related substance test method) The same method as in Test Example 11 was used. (Redispersibility) Redispersion method: The stored sample was shaken up and down for 10 to 30 seconds. (Z-average measurement) Particle size was measured using a Zetasizer Nano (Malvern) by dynamic light scattering under the same conditions as in Examples 8 and 9. (Results) The formulations of Examples 10 to 13 did not show an increasing trend in related substances with relative retention times of 0.35 and 0.55 after storage under any temperature conditions. Furthermore, the formulations of Examples 10 to 13 showed good redispersibility after storage under any temperature conditions, and no significant changes in particle size were observed. 【0099】(Examples 14 and 15: Preparation of formulations and measurement of particle size - 4) Polysorbate 20 (Merck), macrogol 4000 (Fujifilm Wako Pure Chemical Industries), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.). After confirming complete dissolution, the compound represented by formula (I) (anhydrous form of the compound represented by formula (I)) was added and dispersed. After confirming that a suspension with uniform properties had been obtained, the concentration was adjusted using water for injection to the formulations shown in Examples 14-1 and 14-2. Subsequently, the suspension of the compound represented by formula (I) was wet-milled using beads with a rotation-orbit mixer (Thinky) to obtain a sample. A sample using poloxamer 338 (Example 15-1) was obtained by the same method. The particle size was measured under the same conditions as in Examples 8 and 9. (Grinding conditions) ・Bead type: YTZ beads (φ0.1 mm, Nikkatoh made) ・Chamber atmosphere temperature: 5℃ (set) ・Grinding conditions *1: The compound represented by formula (I) used for grinding has a D50 of 2.33 μm, a D90 of 6.83 μm, and a pale reddish-white color. 【0100】 (Test Example 17: Monkey PK Test (Intramuscular, 40 mg / kg)) The concentration of the compound represented by formula (I) in monkey plasma was evaluated using the formulations of Examples 14-1, 14-2, 15-1, and 9-2. Male monkeys were intramuscularly administered the samples shown in Tables 32 and 26 (Examples 14-1, 14-2, 15-1, and 9-2). The dosage of the samples was adjusted so that the dose of the compound represented by formula (I) was 40 mg / kg. Blood was collected from the femoral vein at each blood collection time after administration, and the concentration of the compound represented by formula (I) in the plasma was measured using a mass spectrometer, and the maximum plasma drug concentration (C) was measured. ｍａｘThe area under the plasma drug concentration-time curve (AUC), bioavailability (BA), and elimination rate constant (Kel) were calculated. (Results) The results for Cmax, AUC, BA, and Kel of the compound represented by equation (I) are shown in Table 35 and Figure 17 below. The formulations shown in Tables 32 and 26 showed good persistence. For BA, it was calculated by dividing the AUC after intramuscular administration by the dose, and then dividing that by the AUC after intravenous administration (separate study) by the dose. For kel, it was calculated using Microsoft Excel from the slope of plasma concentration elimination. AUC was evaluated for the period from day 0 to day 84. 【0101】 (Test Example 18: Stability Test (Redispersibility and Sliding Resistance) The stability (particle size and sliding resistance) of the formulations shown in Examples 16-17 after a harsh test (storage at 60°C for 2 weeks) was evaluated. Polysorbate 20 (CRODA), macrogol 4000 (CLARIANT), D-mannitol (Merck), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (J.T. Baker) were dissolved in water for injection (Cytiva). After confirming complete dissolution, the compound represented by formula (I) (the anhydrous form of the compound represented by formula (I)) was added and dispersed until a uniform suspension was obtained. Subsequently, the suspension was wet-milled using beads (NETZSCH) with an agitator bead mill (NETZSCH) to obtain the sample (Example 16). Approximately 6 mL of the obtained suspension was filled into a 10 mL vial (SCHOTT Pharma), sealed, and sterilized by irradiation with 25 kGy of gamma rays. A sample using poloxamer 338 (BASF) (Example 17) was obtained by the same method. Gamma-ray irradiated samples were placed in a 60°C constant temperature bath, and the particle size and sliding resistance were evaluated after storage for two weeks. (Redispersibility) Redispersion method: The stored samples were shaken up and down for 30 to 180 seconds. (Z-average measurement) Particle size was measured using a Zetasizer Nano (Malvern) by dynamic light scattering under the same conditions as in Examples 8 and 9. (Evaluation of sliding resistance) The resistance force generated when the formulation slides in contact with another object. Apparatus: Autograph AG-X Plus (Shimadzu Corporation) Syringe: Terumo syringe 2.5 mL Needle: 25 gauge Sliding speed: 1 mL / 10 sec (Results) The formulations of Examples 16 and 17 did not show an increasing trend in particle size even after storage at 60°C for two weeks. The measurement results of the sliding resistance of the formulations of Examples 16 and 17 are shown in Figures 18 and 19. The formulations of Example 16 and Example 17 did not show any significant change in sliding resistance even after storage at 60°C for two weeks. 【0102】(Example 18: Preparation of ethyl acetate crystalline form of the compound represented by formula (I)) The following experiment was performed using compound I-055 prepared by the synthesis method of Example 5 in International Publication No. 2023 / 195529 and International Publication No. 2023 / 195530. Compound I-055 (800 mg, 1.880 mmol) and 6,6-difluoro-2-azaspiro[3.3]heptanetrifluoroacetate (557 mg, 2.256 mmol) were dissolved in DMF (8.0 mL), and N,N-diisopropylethylamine (985 μL, 5.64 mmol) was added, followed by stirring at 60°C for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, then saturated brine, dried over magnesium sulfate, and filtered. After removing the solvent from the filtrate under reduced pressure, it was subjected to silica gel column chromatography. After elution with hexane / ethyl acetate, the fraction containing the desired compound was collected. The solvent was concentrated under reduced pressure, then diisopropyl ether was added, and the precipitated solid was collected by filtration. The resulting residue was dried under reduced pressure to obtain compound (I) (954 mg, 1.563 mmol, yield 83%). NMR analysis was performed. A peak of ethyl acetate was observed in the NMR chart. １ H-NMR (DMSO-D ６δ: 1.18 (3H, t, J=7.0 Hz), 1.99 (3H, s), 2.79 (4H, t, J=12.4 Hz), 4.03-4.06 (6H, m), 4.82 (2H, s), 7.21 (1H, s), 7.39-7.42 (2H, m), 7.96 (1H, s), 8.46 (1H, s), 8.69 (1H, s). Powder X-ray diffraction experiments were performed on the obtained compound and confirmed that it was a different crystal from the anhydrous crystal of the compound shown in formula (I). From the NMR chart and the results of the powder X-ray diffraction experiment, it was estimated to be an ethyl acetate dihydrate crystal of the compound shown in formula (I). Single crystal diffraction experiments and analysis were performed on the crystal and confirmed that it was an ethyl acetate dihydrate crystal with a molar ratio of the compound shown in formula (I) and ethyl acetate of 1:1. The powder X-ray diffraction patterns of the ethyl acetate crystals of the compound represented by formula (I) are as follows: Diffraction angles (2θ) in the powder X-ray diffraction pattern: 6.9°±0.2°, 8.8°±0.2°, 11.2°±0.2°, 13.1°±0.2°, 13.6°±0.2°, 13.9°±0.2°, 16.3°±0.2°, 17.6°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.1°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 21.2° Peaks were observed at ±0.2°, 21.7°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 22.9°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.1°±0.2°, 25.4°±0.2°, 25.7°±0.2°, 26.7°±0.2°, 27.0°±0.2°, 27.4°±0.2°, 28.0°±0.2°, 28.7°±0.2°, and 29.7°±0.2°. Characteristic peaks include diffraction angles (2θ) of 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 13.6°±0.2°, 16.3°±0.2°, 17.6°±0.2°, 18.6°±0.2°, 20.9±0.2°, 21.7±0.2°, and 23.7°±0.2°. Furthermore, diffraction angles (2θ) of 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 16.3°±0.2°, and 23.7°±0.2° are also included.The solubility of the ethyl acetate crystalline form of the compound represented by formula (I) in water (measured at 25°C) was 0.002 mg / mL. 【0103】 The formulation of the present invention is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions involving coronavirus 3CL protease.

Claims

1. Equation (I): A preparation for subcutaneous, intradermal, or intramuscular injection comprising a suspension of a compound indicated by, a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. The formulation according to claim 1, comprising a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a crystal of a solvate thereof.

3. The formulation according to claim 2, comprising a compound represented by formula (I) having a solubility in water of 0.01 mg / mL or less, a pharmaceutically acceptable salt thereof, or crystals of a solvate thereof.

4. The formulation according to claim 3, comprising anhydrous crystals of the compound represented by formula (I).

5. The formulation according to any one of claims 1 to 4, wherein a stabilizer is contained in the suspension.

6. The formulation according to claim 5, wherein the stabilizer is a suspending agent.

7. The formulation according to claim 6, wherein the suspending agent is one or more selected from the group consisting of polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan esters of fatty acids, and poloxamers.

8. The formulation according to claim 7, wherein the suspending agent is polyoxyethylene sorbitan fatty acid ester.

9. The formulation according to claim 8, wherein the suspending agent is polysorbate 20.

10. The formulation according to claim 7, wherein the suspending agent is poloxamer.

11. The formulation according to claim 10, wherein the suspending agent is poloxamer 338.

12. A formulation according to any one of claims 7 to 11, comprising 0.1 to 4.0 w / v% of a suspending agent.

13. The formulation according to any one of claims 7 to 11, comprising 5.0 w / v% of a suspending agent.

14. The formulation according to claim 5, wherein the stabilizer is a dispersant.

15. The formulation according to claim 14, wherein the dispersant is one or more selected from the group consisting of polyethylene glycol, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, amorphous cellulose, polysaccharides, hyaluronic acid, polyvinyl alcohol, and polyvinylpyrrolidone.

16. The formulation according to claim 14 or 15, comprising 0.1 to 2.0 w / v% of a dispersant.

17. The formulation according to any one of claims 1 to 16, wherein a pH adjusting agent is contained in the suspension.

18. The formulation according to claim 17, wherein the pH of the suspension is adjusted to 4.0 to 8.

0.

19. A formulation according to any one of claims 1 to 18, wherein a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is pulverized in a suspension.

20. The formulation according to claim 19, wherein the Z-average after pulverization of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is 0.1 to 3.0 μm.

21. The formulation according to claim 20, wherein the Z-average is 0.1 to 1.0 μm.

22. The formulation according to any one of claims 1 to 21, wherein the amount of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is 10 to 500 mg per 1 mL of suspension.

23. The formulation according to claim 22, wherein the amount of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is 10 to 200 mg per 1 mL of suspension.

24. The formulation according to any one of claims 1 to 21, wherein the amount of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is 400 to 700 mg per 1 mL of suspension.

25. The formulation according to any one of claims 1 to 24, wherein the blood concentration of the compound represented by formula (I) at two months after injection is 5 to 30 ng / mL.

26. The formulation according to any one of claims 1 to 25, which redisperses when shaken.

27. A formulation according to any one of claims 1 to 26, which continuously releases a compound represented by formula (I) for more than two months after injection.

28. Equation (I) A method for producing a formulation for subcutaneous, intradermal, or intramuscular injection comprising a suspension of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising the step of grinding the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof in a suspension.

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