Parenteral formulation containing uracil derivative

Abstract

To provide an extended-release formulation containing a compound that exhibits coronavirus 3CL protease inhibitory activity.SOLUTION: The present invention relates to a parenteral formulation containing uracil derivatives, relates to an extended-release formulation containing uracil derivatives, in detail, relates to the parenteral formulation composed of a suspension suspended by the uracil derivatives that exhibit coronavirus 3CL protease inhibitory activity, and in further detail, relates to a formulation for subcutaneous injection, intradermal injection or intramuscular injection composed of the suspension suspended by the uracil derivatives that exhibit coronavirus 3CL protease inhibitory activity.SELECTED DRAWING: None

Description

[Technical field]

[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 in which a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity is suspended. More specifically, the present invention relates to a formulation for subcutaneous, intradermal or intramuscular injection comprising a suspension in which a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity is suspended. [Background technology]

[0002] When coronaviruses infect cells, they synthesize two polyproteins. These two polyproteins contain a replication complex that creates the viral genome and two proteases. The proteases cleave the polyproteins synthesized by the virus and play an essential role in allowing each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the cleavage of the polyprotein (Non-Patent Document 1). Compounds having 3CL protease inhibitory activity are disclosed in Patent Documents 1 to 4 and Non-Patent Documents 2 to 12, but none of these documents describes or suggests the uracil derivative contained in the formulation of the present invention. The uracil derivative, its pharma- ceutically acceptable salt, or their solvates contained in the formulation of the present invention are described in Patent Documents 5 and 6. However, Patent Documents 5 and 6 do not describe a specific formulation containing the uracil derivative, its pharma- ceutically acceptable salt, or their solvates contained in the formulation of the present invention. Patent Documents 7 and 8 disclose an injection exhibiting sustained release, but do not describe a parenteral agent containing the uracil derivative of the present invention. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2021 / 205298

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Patent document 6

Patent document 7

Patent document 8

Non-licensed literature

[0004]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

[0005] There is a demand for the development of a sustained-release formulation for the treatment of viral infections from the viewpoints of improving QOL and pre-exposure prophylaxis of viral infections. Many compounds that exhibit coronavirus 3CL protease inhibitory activity are known as therapeutic agents for coronavirus infections, but it is unclear which of these compounds can be used in sustained-release formulations. In other words, there is a demand for the provision of a sustained-release formulation containing a compound that exhibits coronavirus 3CL protease inhibitory activity. An object of the present invention is to provide a parenteral formulation containing a uracil derivative. Preferably, the present invention is to provide a parenteral formulation comprising a suspension in which a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity is suspended. The present invention is to provide a sustained-release formulation comprising a suspension in which a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity is suspended. Another object of the present invention is to provide a preparation for subcutaneous, intradermal or intramuscular injection comprising a suspension of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity. [Means for solving the problem]

[0006] The present inventors have found that the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof has low solubility in water and is suitable as an active ingredient of a sustained-release preparation, and have produced a parenteral preparation comprising a suspension of the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof, which can be used as a preparation for subcutaneous injection, intradermal injection, or intramuscular injection, thereby completing the present invention. The present invention relates to the following: (1) Formula (I): [ka] A preparation for subcutaneous, intradermal or intramuscular injection comprising a suspension of a compound represented by the following formula (I): (2) The formulation according to the above (1), which contains a crystal of the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof. (3) The formulation according to (2) above, which contains a crystal of the compound represented by formula (I), its pharma- ceutically acceptable salt, or a solvate thereof, having a solubility in water of 0.01 mg / mL or less. (4) The formulation according to (3) above, comprising anhydrous crystals of the compound represented by formula (I). (5) The formulation according to any one of (1) to (4) above, which contains a stabilizer in the suspension. (6) The formulation according to (5) above, wherein the stabilizer is a suspending agent. (7) The formulation 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 formulation according to (6) or (7) above, comprising 0.1 to 4.0 w / v % of a suspending agent. (9) The formulation according to (5) above, wherein the stabilizer is a dispersant. (10) The formulation according to (9) above, wherein the dispersing agent is one or more selected from the group consisting of polyethylene glycol, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, amorphous cellulose, polysaccharides, hyaluronic acid, polyvinyl alcohol and polyvinylpyrrolidone. (11) The formulation according to (9) or (10) above, comprising 0.1 to 2.0 w / v % of a dispersant. (12) The preparation according to any one of (1) to (11) above, which contains a pH adjuster in the suspension. (13) The formulation according to (12) above, wherein the pH of the suspension is adjusted to 4.0 to 8.0. (14) The formulation according to any one of the above (1) to (13), which is prepared by grinding the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof in a suspension. (15) The formulation according to the above (14), wherein the compound represented by the formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof has a Z-average of 0.1 to 3.0 μm after pulverization. (16) The formulation according to (15) above, wherein the Z-average is 0.1 to 1.0 μm. (17) The formulation according to any one of the above (1) to (16), wherein the amount of the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof is 10 to 500 mg per 1 mL of the suspension. (18) The formulation according to the above (17), wherein the amount of the compound represented by the formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof is 10 to 200 mg per 1 mL of the suspension. (19) The formulation according to any one of (1) to (18) above, wherein the blood concentration of the compound represented by formula (I) is 5 to 30 ng / mL two months after injection. (20) The formulation according to any one of (1) to (19) above, which redisperses when shaken. (21) The formulation according to any one of (1) to (20) above, which sustains the release of the compound represented by formula (I) for at least 2 months after injection. (22) A method for producing a formulation for subcutaneous injection, intradermal injection, or intramuscular injection comprising a suspension of a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof, the method comprising the step of grinding the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof in a suspension. Effect of the Invention

[0007] The preparation according to the present invention has an inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and / or preventive agent for coronavirus infection. Furthermore, 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. Furthermore, the anhydrous crystals of the compound represented by formula (I) contained in the formulation of the present invention are highly stable in the formulation and can be stored for a long period of time. [Brief description of the drawings]

[0008] [Figure 1] 1 shows a powder X-ray diffraction pattern of the anhydrous crystal of the compound represented by formula (I), where the horizontal axis represents 2θ (°) and the vertical axis represents intensity. [Diagram 2] The peak list of the powder X-ray diffraction pattern of Figure 1 is shown below. In the table, Position indicates 2θ(°) and Intensity indicates intensity. [Diagram 3] 1 shows the crystal structure (structure in the asymmetric unit) of an anhydrous crystal of the compound represented by formula (I). [Figure 4] 1 shows the results of differential scanning calorimetry (DSC) of the anhydrous crystals of the compound represented by formula (I), where the horizontal axis represents temperature (° C.) and the vertical axis represents heat (W / g). [Diagram 5] The figure shows the results of simultaneous differential thermal analysis and thermogravimetry (TG / DTA) of the anhydrous crystals of the compound represented by formula (I). The vertical axis shows the amount of heat (μV) or the weight change (%), and the horizontal axis shows the temperature (°C). In the figure, Cel means degrees Celsius (°C). [Figure 6] 1 shows the Raman spectrum of anhydrous crystals of the compound represented by formula (I), where the horizontal axis represents the Raman shift (cm-1) and the vertical axis represents the peak intensity. [Figure 7] In Test Example 6, the results of Cmax, AUC, BA and elimination rate constant kel when the compound represented by formula (I) was administered at each particle size using the preparations of Examples 2-1 to 2-3 are shown. [Figure 8] In Test Example 7, the results of Cmax, AUC, BA and elimination rate constant kel when the compound represented by formula (I) was administered using the formulation of Example 3 are shown. [Figure 9] In Test Example 8, the results of Cmax, AUC, BA and elimination rate constant kel when the compound represented by formula (I) was administered using the formulation of Example 3 are shown. [Figure 10] In Test Example 9, the results of Cmax, AUC, BA and elimination rate constant kel when the compound represented by formula (I) was administered using the formulation of Example 3 are shown. [Figure 11]In Test Example 10, the results of Cmax, AUC, BA and elimination rate constant kel when the compound represented by formula (I) was administered using the formulation of Example 3 are shown. [Figure 12] 1 shows the appearance of the sample of Example 6-1 after being left to stand for 3 days in a 5° C. environment. [Figure 13] 1 shows the state of the bottom surface when the container of the sample of Example 6-1 was tilted after being left standing in a 5° C. environment for 3 days. [Figure 14] This shows the state of the bottom surface of the sample of Example 6-1 after it was left standing for 3 days in a 5° C. environment and then shaken for 10 seconds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The meaning of each term used in this specification will be explained below. The terms "comprise" and "include" are meant to be open ended and not excluding unrecited elements. Hereinafter, the present invention will be described with reference to the embodiments. Throughout this specification, it should be understood that the singular expression includes the plural concept unless otherwise specified. Therefore, it should be understood that the singular article (e.g., in the case of English, "a", "an", "the", etc.) includes the plural concept unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the same sense as commonly used in the above field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the present specification (including definitions) shall prevail.

[0010] Unless otherwise noted, numerical values ​​in the specification and claims are approximate and variations in numerical values ​​are due to instrument calibration, instrument error, purity of materials, crystal size, sample size, temperature, and other factors.

[0011] The present invention relates to a compound of formula (I): [ka] The present invention relates to a parenteral formulation containing a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof, and relates to a sustained release formulation. More specifically, the present invention relates to a parenteral formulation comprising a suspension in which a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof is suspended. More specifically, the present invention relates to a formulation for subcutaneous, intradermal, or intramuscular injection comprising a suspension in which a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof is suspended.

[0012] The compound represented by formula (I) is a 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 to 6 of the documents. In addition, it is described in the documents that the compound represented by formula (I) has a coronavirus 3CL protease inhibitory effect and inhibits coronavirus 3CL protease. In this specification, the compound represented by formula (I) may be referred to as compound (I).

[0013] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced with isotopes of the respective hydrogen, carbon and / or other atoms. Examples of such isotopes include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 18 F and 36As Cl, hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine are included. The compounds represented by formula (I) also include compounds substituted with such isotopes (e.g., deuterium exchangers, etc.). The compounds substituted with such isotopes are also useful as pharmaceuticals. The compounds represented by formula (I) include all radiolabeled products substituted with radioisotopes contained in the isotopes. The present invention also includes a "radiolabeling method" for producing the "radiolabeled product", and the "radiolabeled product" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0014] Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a particular compound of formula (I) through catalytic dehalogenation reaction with tritium. This method involves reacting a suitable halogen-substituted precursor of the compound of formula (I) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "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 having C carbon.

[0015] The compound represented by formula (I) may form a prodrug, and the compound represented by formula (I) contained in the formulation of the present invention also includes such various prodrugs. A prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically decomposed, and is a compound that becomes a pharmacologic 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 vivo, and compounds that are converted to the compound represented by formula (I) by hydrolysis by gastric acid, etc. Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.

[0016] As used herein, the "compound represented by formula (I)" may form a salt, a cocrystal, or a solvate thereof. As used herein, "a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof" also encompasses such various salts, cocrystals, and solvates thereof.

[0017] The term "salt" as used herein means, for example, that the "compound represented by formula (I)" and a counter molecule are regularly arranged in the same crystal lattice, and may contain any number of counter molecules. It refers to a salt formed by ionic bonding through proton transfer between the compound and the counter molecule in the crystal lattice.

[0018] As used herein, the term "co-crystal" refers to a compound in which co-former molecules are regularly arranged in the same crystal lattice and may contain any number of co-former molecules. Co-crystals also refer to compounds in which the intermolecular interaction between the compound and the co-former molecules is mediated by non-covalent and non-ionic chemical interactions such as hydrogen bonds or van der Waals forces.

[0019] In general, salts are considered to be a state in which proton transfer occurs between a compound and a counter molecule, but it is also known that in some cases, proton transfer may not be complete. This state is sometimes called a cocrystal because it is not a true salt. It is also known that proton transfer may change continuously depending on temperature. Thus, as used herein, "a pharma- ceutically acceptable salt of a compound represented by formula (I)" includes co-crystals and refers to a pharma- ceutically acceptable salt or co-crystal of a compound represented by formula (I).

[0020] One embodiment in the present specification is a pharma- ceutically acceptable salt or co-crystal of a compound represented by formula (I) with hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric acid, sulfuric acid, methanesulfonic acid, 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, glycerophosphoric acid, tartaric acid, benzoic acid, glutamic acid, aspartic acid, 2-naphthalenesulfonic acid, hexanoic acid, acetylsalicylic acid, or the like.

[0021] Salt and co-crystal formation studies provide a means to modify the physicochemical and resulting biological characteristics of a drug without changing its chemical structure. Salt and co-crystal formation can dramatically affect the properties of a drug. Hygroscopicity, stability, solubility, and processing properties are also important aspects in the selection of an appropriate salt or co-crystal. The solubility of a salt or co-crystal can affect its suitability for use as a drug. If the aqueous solubility is low, the dissolution rate upon in vivo administration may be rate-limited by the absorption process, resulting in low bioavailability. Also, low water solubility may make administration by injection difficult, limiting the selection of an appropriate route of administration.

[0022] The compound of formula (I) can form a solvate with water (i.e., a hydrate) or a common organic solvent. The pharma- ceutically acceptable salt of the compound of formula (I) can form a solvate with water (i.e., a hydrate) or a common organic solvent.

[0023] The term "solvate" as used herein refers to a regular arrangement of any number of solvent molecules with, for example, the "compound represented by formula (I)." 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, methyl tetrahydrofuran, 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, pentane, Examples of suitable solvents include ethanol, 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, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, xylene, and t-butanol. Preferred examples of the solvent include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid. Most preferred is ethyl acetate. Furthermore, when the "compound represented by formula (I)" is left in the air, it may absorb moisture, and may adhere to adsorbed water or form a hydrate.

[0024] The compound represented by formula (I), its pharma- ceutically acceptable salt, or solvate thereof has low solubility in water, and is therefore useful for producing a parenteral preparation consisting of a suspension in which an active ingredient exhibiting coronavirus 3CL protease inhibitory activity is suspended. By using this parenteral preparation for subcutaneous, intradermal, or intramuscular injection, the active ingredient can be released sustainedly.

[0025] The suspension of the present invention means a suspension in which the compound represented by formula (I), its pharma- ceutically acceptable salt, or their solvates are suspended. In this suspension, the compound represented by formula (I), its pharma- ceutically acceptable salt, or their solvates are dispersed. In the suspension of the present invention, the compound represented by formula (I), its pharma- ceutically acceptable salt, or their solvates can be easily redispersed. For example, in the case of a vial filled with the suspension, the compound represented by formula (I), its pharma- ceutically acceptable salt, or their solvates 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 of the present invention has coronavirus 3CL protease inhibitory activity, and therefore the formulation of the present invention is useful as a therapeutic agent and / or preventive agent for diseases involving coronavirus 3CL protease. In the present invention, the term "therapeutic agent and / or preventive agent" also includes agents for improving symptoms. Diseases involving coronavirus 3CL protease include viral infections, preferably coronavirus infections.

[0027] 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 more preferably infections caused by SARS-CoV-2. A particularly preferred example of the coronavirus infection is novel coronavirus disease (COVID-19).

[0028] The formulation of the present invention has at least any of the following characteristics: (1) The active ingredient has excellent dispersibility. (2) The active ingredient is less likely to settle. (3) The active ingredient has excellent redispersibility. (4) The active ingredient has good stability against heat, humidity, light, etc. (5) The formulation has excellent storage stability. (6) The active ingredient can be released continuously. (7) The administration method is simple.

[0029] One aspect of the present invention is a formulation containing a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a crystalline solvate thereof. More specifically, the formulation contains a poorly water-soluble compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a crystalline solvate thereof. More specifically, the formulation contains a compound represented by formula (I) or a crystalline solvate thereof. In one embodiment, the solubility in water of the compound represented by formula (I), its pharma- ceutically acceptable salt, or a crystal of a solvate thereof is 0.1 mg / mL or less, preferably 0.01 mg / mL or less, more preferably 0.001 mg / mL or less. The solubility in water can be measured at 20±5° C. In particular, the compound represented by formula (I), its pharma-ceutically acceptable salt, or a crystal of a solvate thereof, whose solubility in water measured at 25° C. is 0.1 mg / mL or less, preferably 0.01 mg / mL or less, more preferably 0.001 mg / mL or less, is preferred. Another embodiment of the present invention is a formulation containing 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 solvate of the compound represented by formula (I) in water at 25° C. is 0.002 mg / mL. The solubility of the anhydrous crystals of the compound represented by formula (I) in water at 37° C. is 0.0007 mg / mL. Here, the 18th revision of the Japanese Pharmacopoeia defines solubility as "the degree to which a drug dissolves within 30 minutes when, unless otherwise specified, it is powdered in the case of a solid drug, placed in a solvent, and vigorously shaken for 30 seconds every 5 minutes at 20±5°C." The term "almost insoluble" is used when the "volume 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." Therefore, if the solubility in water is 0.1 mg / mL or less, it can be said to be "almost insoluble." In addition, the compound represented by formula (I), its pharma- ceutical acceptable salt or solvate thereof is suitable as an active ingredient of a sustained-release preparation. As described above, the compound is suitable as an active ingredient of a sustained-release preparation for subcutaneous, intradermal or intramuscular injection not only because of its low solubility in water, but also because of its molecular weight, CLogP, lipophilicity, particle size upon administration, dissolution rate in the body, damage at the administration site, blood protein binding rate, stability, etc.

[0030] In addition, the term "crystal" as used herein means a solid in which constituent atoms, ions, molecules, etc. are arranged in a three-dimensional order, and is distinguished from amorphous solids that do not have such an orderly internal structure. The term "crystal" as used herein may be a single crystal, a twin crystal, a polycrystal, etc. Furthermore, "crystals" can have "crystal polymorphs" that have the same composition but different arrangements within the crystal, and all of these are referred to as "crystal forms." The "compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof" includes crystal polymorphs thereof. As used herein, crystals may be deuterium converted. As used herein, crystals may be isotopes (e.g., 3 H, 14 C. 35 S, 125 I, etc.) may be used. The crystal morphology and / or crystallinity can be confirmed by spectroscopic methods such as, for example, X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, solid-state NMR, etc. Additionally, the physical properties of the crystals can be confirmed by a number of techniques such as differential scanning calorimetry, moisture adsorption / desorption measurements, dissolution characteristics, etc.

[0031] One embodiment herein is an anhydrous crystalline form of the compound represented by formula (I). As used herein, "anhydrous" is synonymous with "nosolvate," "nonsolvate," "anhydrate," and "nonhydrate." The theoretical content of water of crystallization in the anhydrous crystals of the compound represented by formula (I) is 0% by weight. However, in the analysis of the water content and / or the solvent content, the value may be higher than the theoretical content of water of crystallization due to the influence of the water and / or the solvent attached to the crystal surface. The color of the anhydrous crystals of the compound represented by formula (I) is white to pale reddish white or pale yellowish white.

[0032] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (I) having characteristic peaks at diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2° in a powder X-ray diffraction pattern (CuKα radiation, λ=1.5418 Å).

[0033] In one embodiment of the present specification, when single crystal structure analysis was performed using CuKα radiation (λ=1.5418 Å) at 298 K (25° C.), Crystallographic data for: Space group: Pbca a=14.67ű0.05Å b = 11.83 Å ± 0.05 Å c=27.10ű0.05Å α=90° β=90° γ=90° The anhydrous crystalline form of the compound of formula (I) is characterized by:

[0034] One embodiment herein is a crystalline anhydrous form of the compound of formula (I) having a melting point of 261.3° C.±2° C. as measured by differential scanning calorimetry (DSC). One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (I) having a melting point of 265.6° C.±2° C. as measured by simultaneous differential thermal analysis-thermogravimetry (TG / DTA).

[0035] In one embodiment of the present invention, a Raman spectrum of 415.2 cm -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 The anhydrous crystals of the compound represented by formula (I) have characteristic peaks.

[0036] In the preparation according to the present invention, a preparation in which the compound represented by formula (I), its pharma- ceutically acceptable salt, or solvate thereof, having a Z-average of 0.1 to 5.0 μm, is suspended is preferred.Furthermore, a preparation in which the compound represented by formula (I), its pharma- ceutically acceptable salt, or solvate thereof, having a Z-average of 0.1 to 3.0 μm, is suspended is preferred.In particular, a preparation in which the compound represented by formula (I), its pharma- ceutically acceptable salt, or solvate thereof, having a Z-average of 0.1 to 1.0 μm, is suspended is preferred. The Z-average is the average hydrodynamic diameter based on the light intensity obtained by DLS, which represents the size of the entire particle group, and is calculated as the light intensity-weighted average.

[0037] One aspect of the present invention relates to a parenteral formulation containing "a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof" as an active ingredient. In the parenteral preparation of the present invention, the compound represented by formula (I) may be contained in an amount of 1 to 2000 mg, preferably 100 to 2000 mg, and particularly preferably 200 to 1500 mg per vial.

[0038] In addition, the formulation according to the present invention is preferably one in which the amount of the compound represented by formula (I), its pharma- ceutically acceptable salt, or their solvates is 10 to 500 mg per 1 mL of suspension, and more preferably one in which the amount of the compound represented by formula (I), its pharma- ceutically acceptable salt, or their solvates is 10 to 200 mg per 1 mL of suspension. Examples of the parenteral preparation of the present invention include injections, drops, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). The parenteral preparation 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, and is particularly preferably in the form of a suspension. That is, in the present invention, a preparation for injection consisting of a suspension in which the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof is particularly preferred.

[0039] The "parenteral preparation containing the compound represented by formula (I), its pharma- ceutically acceptable salt, or a solvate thereof as an active ingredient" of the present invention can be produced by a known method. The preparation may contain pharma- ceutically acceptable additives, such as stabilizers (suspending agents, dispersing agents), isotonicity agents, pH adjusters, etc.

[0040] One aspect of the present invention is a preparation consisting of a suspension containing an anhydrous crystal of the compound represented by formula (I) as an active ingredient. In one aspect, the preparation according to the present invention contains the anhydrous crystal of the compound represented by formula (I) at 10 to 500 mg / mL, preferably 10 to 200 mg / mL.

[0041] The method for producing a formulation of the present invention, which is a suspension containing the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof (preferably, an anhydrous crystal of the compound represented by formula (I)) as an active ingredient, is not particularly limited, but specifically, the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof (preferably, an anhydrous crystal of the compound represented by formula (I)) is milled together with additives such as a stabilizer (suspending agent, dispersing agent), an isotonicity agent, and a pH adjuster, and the anhydrous crystal of the compound represented by formula (I) is milled to a desired particle size. The milling method includes a wet milling method in which a medicament active ingredient (drug) is suspended in an aqueous solvent in which an additive is dissolved, and milling may be performed using beads as a milling medium. The milling device may be any device commonly used in the art, and may include, but is not limited to, a high-pressure homogenizer (nanovater), a wet jet mill, a bead mill, a ball mill, and the like. It is preferable to mill the particles at a temperature at which the drug does not significantly decompose. If necessary, the grinding apparatus may be cooled by a cooling apparatus.

[0042] In the present specification, the term "stabilizer" refers to a compound represented by formula (I) that contributes to stabilization during or after the preparation of the formulation of the present invention. For example, when the formulation of the present invention is in the form of a suspension, the "stabilizer" of the present invention suspends the anhydrous crystals of the compound represented by formula (I) during the preparation of the formulation of the present invention, thereby contributing to efficient grinding of the anhydrous crystals, and after the preparation of the formulation, the compound represented by formula (I) disperses as a solid in the solvent, thereby contributing to maintaining the form of the suspension.

[0043] In this specification, the "stabilizer" of the present invention may be referred to as a "suspending agent" or a "dispersing agent", and both may be the same substance or different substances.

[0044] As used herein, the term "suspending agent" refers to an additive for maintaining the suspension in a formulation. The "suspending agent" may also contribute to efficient pulverization in the pulverization 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, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.), sorbitan esters of fatty acids (SPAN), poloxamers (such as poloxamer 188, poloxamer 338, poloxamer 407, etc.). Preferred are polyoxyethylene sorbitan fatty acid esters (polysorbates) and poloxamers, and particularly preferred are polysorbate 20, polysorbate 80, poloxamer 188, and poloxamer 338.

[0045] In this specification, the term "dispersant" refers to an additive for maintaining dispersibility in a formulation. By using the "dispersant", the compound represented by formula (I) can be dispersed in a solvent to maintain 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.), carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, noncrystalline cellulose, polysaccharides, hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), etc. In addition, the "dispersant" may be added when the compound according to the present invention is pulverized in the production of the formulation of the present invention. Preferably, it is polyethylene glycol, and particularly preferably, it is macrogol 4000.

[0046] In one embodiment of the present invention, the suspending agent is contained in the formulation according to the present invention at 0.1 to 4.0 w / v %, preferably 0.1 to 2.0 w / v %.

[0047] In one embodiment of the present invention, the dispersing agent is contained in the formulation according to the present invention at 0.1 to 4.0 w / v %, preferably 0.1 to 2.0 w / v %.

[0048] In the preparation of the present invention, an isotonicity agent can be used. Examples of the isotonicity agent include glucose, sucrose, fructose, trehalose, lactose, polyhydric sugar alcohol, erythritol, arabitol, xylitol, sorbitol and D-mannitol. Sucrose, trehalose and D-mannitol are preferred, and D-mannitol is particularly preferred.

[0049] In the preparation of the present invention, a pH adjuster can be used. Examples of the pH adjuster 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 preparation of 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 the blood concentration of the compound represented by formula (I) at 5 to 30 ng / mL two months after injection into humans. The formulation according to the present invention can maintain the blood concentration of the compound represented by formula (I) at 10 ng / mL or more for 180 days after injection in rats. That is, the formulation according to the present invention can continuously release the compound represented by formula (I) for two months or more (e.g., three months or more, four months or more, five months or more, six months or more) after injection. In one embodiment of the present invention, the compound of formula (I) can be released continuously for about 1 week, 8 weeks or more, 12 weeks or more, 16 weeks or more, about 20 weeks or more, 24 weeks or more, or 28 weeks or more.

[0051] (X-ray powder diffraction (XRPD)) X-ray powder diffraction (XRPD) is one of the most sensitive analytical techniques for measuring the crystal morphology and crystallinity of solids. When X-rays are irradiated onto a crystal, they reflect off the crystal lattice planes and interfere with each other, producing ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, amorphous solids usually do not have an ordered repeating period in their structure, so no diffraction phenomenon occurs and they produce a featureless broad XRPD pattern (also called a halo pattern).

[0052] As used herein, a characteristic diffraction peak is a peak selected from the observed diffraction pattern. Preferably, the characteristic diffraction peak is selected from about 10, more preferably from about 5, peaks in the diffraction pattern. In distinguishing between multiple crystals, a peak that is confirmed in the crystal and not confirmed in other crystals is a preferred characteristic peak for identifying the crystal, rather than the peak intensity. If there are such characteristic peaks, even one or two peaks can characterize the crystal. When the measured patterns are compared and these characteristic peaks match, it can be said that the powder X-ray diffraction patterns are substantially the same.

[0053] Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error within the range of ±0.2°, and therefore the value of the diffraction angle in powder X-ray diffraction should be understood to include a numerical value within the range of about ±0.2°. Therefore, not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction are completely the same, but also crystals in which the diffraction angles of the peaks are the same with an error of about ±0.2° are included in the present invention.

[0054] It is known that the intensities of the peaks displayed in the following figures may generally vary due to many factors, such as the effect of the preferred orientation of the crystals relative to the X-ray beam, the influence of coarse particles, the purity of the material being analyzed, or the crystallinity of the sample. The peak positions may also shift based on the height variation of the sample. Furthermore, measurements using different wavelengths will result in different shifts according to the Bragg equation (nλ=2dsinθ), and other XRPD patterns obtained using such different wavelengths are also within the scope of the present invention.

[0055] By combining a powder X-ray diffraction instrument with a temperature and / or relative humidity control device, powder X-ray diffraction measurements can be performed under specific temperatures and / or relative humidity. For example, when an anhydrous crystal changes to a hydrate crystal due to moisture absorption, when a hydrate crystal changes to an anhydrous crystal due to dehydration, when a solvate crystal transitions to an anhydrous crystal due to solvent desorption, when an anhydrous crystal and a hydrate crystal change reversibly due to moisture absorption and dehydration, etc., it is suitable to perform measurements at a specific temperature and / or relative humidity, or to perform measurements with a continuous change in temperature and / or relative humidity. In such cases, it is possible to estimate the relative humidity at which the change occurs and the amount of water of crystallization and / or solvent of crystallization.

[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) (e.g., the anhydride of the compound represented by formula (I)) can be distinguished from other crystalline forms by the presence of characteristic peaks.

[0057] (X-ray powder diffraction-differential scanning calorimetry (XRD-DSC)) Simultaneous measurement of powder X-ray diffraction and differential scanning calorimetry (XRD-DSC measurement) allows simultaneous observation of changes in crystal morphology (crystal structure) and heat quantity changes with temperature and / or relative humidity. For example, it is suitable for observing changes in crystal morphology (crystal structure), such as when anhydrous crystals transition to hydrate crystals due to moisture absorption, when hydrate crystals transition to anhydrous crystals due to dehydration, when solvate crystals transition to anhydrous crystals due to solvent desorption, and when anhydrous crystals and hydrate crystals transition reversibly due to moisture absorption and dehydration.

[0058] (Single crystal structure analysis) Single crystal structure analysis is one of the methods to identify the crystal form, and can obtain crystallographic parameters, atomic coordinates (values ​​that indicate the spatial relationship of each atom), and a three-dimensional structure model. For information on single crystal structure analysis, see "X-Ray Structure Analysis Handbook" by Toshio Sakurai, published by Shokabo Publishing (1983), and X-Ray Structure Determination: A Practical Guide by Stout & Jensen, Macmillan Co., New York (1968). Single crystal structure analysis is useful in identifying the structures of optical isomers, tautomers, geometric isomers, salts, co-crystals, and solvates (hydrates). In single crystal X-ray diffraction experiments, since it is known that data quality is improved by performing measurements at low temperatures, measurements are performed at room temperature or low temperatures depending on the crystal being measured. In addition, it is known that data quality is improved in single crystal X-ray diffraction experiments of hydrates and / or solvates by coating the crystals with paraffin oil or the like before measurement.

[0059] (Raman spectroscopy) Raman spectra show the vibrational characteristics of a molecule or complex system. It originates from inelastic collisions between molecules and photons, which are light particles that comprise a beam of light. Collisions between molecules and photons result in an exchange of energy, which changes the energy and thus the wavelength of the photon. That is, Raman spectra are spectral lines with extremely narrow wavelengths that are emitted when photons are incident on a molecule of interest, so a laser or similar light source is used. The wavelength of each Raman line is represented by a wavenumber shift from the incident light, which is the difference between 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. In general, the wavelength shift in a Raman spectrum (cm -1 ) is ±2cm -1 Since there may be an error within the range of ±2 cm -1 It should be understood that the values ​​include values ​​within the range of about 1 cm. Therefore, not only crystals with perfectly matching Raman spectrum peaks in the Raman spectrum, but also crystals with Raman spectrum peaks within ±2 cm -1 Crystals that match to within a certain degree of error are also included in the present invention.

[0060] (Differential Scanning Calorimetry (DSC)) Differential scanning calorimetry (DSC) is one of the main methods of thermal analysis, and 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 with respect to temperature or time of a pharmaceutical active ingredient, and the obtained data is plotted against temperature or time to obtain a differential scanning calorimetry curve. 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 accompanying melting, and enthalpy. It is known that for DSC, the observed temperatures may depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. Thus, 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 for the onset temperature (extrapolated melting point onset temperature) obtained from a 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, which may vary somewhat depending on the measurement conditions and the measurement instrument.

[0061] (Differential thermal / thermogravimetric simultaneous measurement method (TG / DTA)) Simultaneous thermogravimetry and differential thermal analysis (TG / DTA) is one of the main methods in thermal analysis, and 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 to measure the change in weight and heat quantity of a pharmaceutical active ingredient with respect to temperature or time, and the obtained data is plotted against temperature or time to obtain TG (thermogravimetry) and DTA (differential thermal) curves. 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 observed temperature and weight changes in TG / DTA may depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. 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 identifying the identity of a crystal, not only the melting point but also the overall pattern is important, and may vary somewhat depending on the measurement conditions and the measurement instrument.

[0062] (particle size distribution) As used herein, "D10, D50, and D90" refer to the particle sizes at the points of 10%, 50%, and 90% of the cumulative curve when the total volume of a powder aggregate is taken as 100%, and can be measured by a dry method or a wet method.

[0063] (Laser diffraction scattering method) The laser diffraction scattering method is one of the methods for measuring particle size. When particles are irradiated with laser light, the size and distribution of the particles 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 specialized for measuring nano-sized particle size distribution. It is used to measure nanometers (1×10 -9 DLS is a practical and simple method for measuring microparticles of the order of 1000 nm. Microparticles dispersed in a suspension or solution usually undergo Brownian motion, and it is known that the smaller the particle, the faster the movement. By irradiating a laser beam onto particles dispersed in a solvent, the phenomenon of light scattering is measured, and the autocorrelation function of the light scattering pattern is analyzed from the data, and the size and distribution of the microparticles can be calculated from the motion speed of the microparticles and the time scale of the correlation function. Z-average is the average hydrodynamic diameter based on the light intensity obtained by DLS. It is useful when the size of the particles is relatively uniform, and is used as a measurement result. In this application, DLS was used to measure particle diameter in a wet state. EXAMPLES

[0065] The present invention will be described in more detail below with reference to examples and test examples. The present invention is not limited to these. Some errors and deviations should be taken into account with respect to numerical values ​​(e.g., amounts, temperatures, etc.).

[0066] (Method for producing the compound represented by formula (I)) The compound represented by formula (I) is a compound (I-077) described in WO 2023 / 195529 and WO 2023 / 195530, and can be produced by the synthesis method of Examples 5 to 6 described in the literature. In addition, it can be synthesized with reference to a method known in the art. Extraction, purification, etc. may be performed by the treatment performed in a normal organic chemistry experiment.

[0067] (Biological Testing of Compounds Represented by Formula (I)) The biological test results of the compound represented by formula (I) are described as compound (I-077) in WO 2023 / 195529 and WO 2023 / 195530.

[0068] Example 1: Grinding of the compound of formula (I) The compound represented by formula (I) produced by the synthesis methods of Examples 5 to 6 of WO 2023 / 195529 and WO 2023 / 195530 was sieved through a 1000 μM mesh and then pulverized under the following conditions. Equipment: AO Jet Mill (Seishin Enterprise Co., Ltd.) Supply method: Feeder Feeding rate: 20g / hour Grinding pressure: 0.30MPa Supply pressure: 0.40MPa

[0069] (Test Example 1: Powder X-ray Diffraction Experiment (XRPD) The powder X-ray diffraction measurement was carried out on the compound of formula (I) after pulverization in Example 1 according to the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia. The measurement conditions are shown below. Measurement condition 1: Powder X-ray diffraction equipment: Rigaku SmartLab Measurement method: Reflection method Wavelength used: CuKα ray (λ=1.5418Å) Tube current: 200mA Tube voltage: 45kV Sample plate: Aluminum X-ray incidence angle: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (2D detection mode) As a result, it was found that the compound represented by formula (I) was 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 showing the peak list of the powder X-ray diffraction pattern, Position indicates 2θ(°) and Intensity indicates 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 include diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2°, and further include diffraction angles (2θ): 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 represented by formula (I) was analyzed under the following measurement conditions and analytical method. (Device) Rigaku XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25℃ Temperature controller: Rigaku sample spray low temperature device Wavelength used: CuKα ray (λ=1.5418Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data Processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data were Lorentzian, polarization and absorption corrected. (Crystal structure analysis) Phase determination was performed using the direct method program ShelXT (Sheldrick, GM, 2015), and refinement was performed using full-matrix least-squares fitting with ShelXL (Sheldrick, GM, 2015). All non-hydrogen atom temperature factors were refined anisotropically. Hydrogen atoms were introduced by calculation using the default parameters of ShelXL unless otherwise noted, and were treated as riding atoms. Hydrogen atoms were also refined with isotropic parameters. The following structural diagram was drawn using PLATON (Spek, 1991) / ORTEP (Johnson, 1976) (30% PROBABILITY level).

[0071] <How to prepare single crystals> 400μL of methanol was added to 1mg of crystals of the compound represented by formula (I) and dissolved by heating to 50℃. The solution was dispensed into 1.5mL HPLC vials, the HPLC vials were capped, a syringe needle was inserted into the cap, and the solution was allowed to stand at room temperature. Single crystals were prepared by the solvent evaporation method. <Single crystal structure analysis> Single crystal diffraction experiments and analysis were carried out using the above method. Note that since Cl1 and Cl7C, and H5CA and H6CA are in a disordered relationship, the analysis was carried out with the 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: R1(I>2.00s(I)) was 0.0555, and the final difference Fourier confirmed that there was no missing or misplaced electron density.

[0073] The crystallographic data are shown in Table 1. [Table 1] Here, V is the unit cell volume, and Z is the number of molecules in the unit cell.

[0074] Atomic fraction coordinates x, y, z of non-hydrogen atoms (Å×10 4 ) and the equivalent isotropic temperature factor U(eq) (Equivalent Isotropic Displacement Parameters, Å 2 ×10 3 ) are shown in Table 2. Here, U(eq) is the orthogonalized U ij Define it as one third of the trajectory of the tensor. [Table 2]

[0075] Next, the atomic coordinates x, y, z of the hydrogen atom (Å×10 4 ) and isotropic temperature factor U(eq) (Isotropic Displacement Parameters, Å 2 ×10 3 ) are shown in Table 3. [Table 3]

[0076] The structure in the asymmetric unit of the crystal structure is shown in FIG. The label numbers of the non-hydrogen atoms in FIG. 3 correspond to the numbers of the non-hydrogen atoms in Table 2.

[0077] Since the crystal structure contained only one molecule of the compound represented by formula (I) in the asymmetric unit, the crystal structure was identified as an anhydrous crystal of the compound represented by formula (I).

[0078] From 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 confirmed to be generally consistent with the powder X-ray diffraction pattern of Test Example 1 (FIG. 1).

[0079] (Test Example 3: Differential Scanning Calorimetry (DSC)) DSC measurement was carried out for the compound represented by formula (I) after pulverization in Example 1 (anhydrous crystals of the compound represented by formula (I)). Approximately 2 mg of the sample was weighed into an aluminum pan, simply sealed, and measured. The measurement conditions are shown below. Note that measurement by differential scanning calorimetry (DSC) may have an error within the range of ±2°C. Instrument: Discovery DSC / TA Instrument Measurement temperature range: -10℃-270℃ Heating rate: 10℃ / min Atmosphere: N250mL / min The measurement results are shown in Figure 4. An endothermic peak was observed with an onset temperature of approximately 261.3°C.

[0080] (Test Example 4: Differential Thermal-Thermogravimetric Simultaneous Measurement (TG / DTA)) The compound represented by formula (I) after pulverization in Example 1 (anhydrous crystals of the compound represented by formula (I)) was subjected to simultaneous differential thermal analysis and thermogravimetry (TG / DTA). The samples obtained in each Example were weighed, placed in an aluminum pan, and measured in an open system. The measurement conditions were as follows. Equipment: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: Room temperature - 350℃ Heating rate: 10℃ / min The measurement results are shown in Figure 5. An endothermic peak was observed with an onset temperature of approximately 265.6°C. No weight loss was observed.

[0081] (Test Example 5: Raman Spectrum) The Raman spectrum was measured for the compound represented by formula (I) after pulverization in Example 1 (anhydrous crystals of the compound represented by formula (I)). The measurement conditions are as follows. Measurement method: Microscopic laser Raman spectroscopy Laser wavelength: 671nm Number of times accumulated: 1 Exposure time: 1 second The measurement results are shown in Figure 6. The main Raman peaks are shown below. [Table 4] The anhydrous crystal of the compound represented by formula (I) has a Raman spectrum of 415.2 cm -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 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, Ltd.), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Factory, Ltd.), and after confirming that the solution was completely dissolved, the compound represented by formula (I) (anhydrous compound represented by formula (I)) was added and dispersed. After confirming that the suspension had a uniform property, the suspension was adjusted to the concentration of the formulation shown in Examples 2-1 to 2-3 using water for injection. Then, for Examples 2-2 and 2-3, the suspension was wet-pulverized using beads using a planetary centrifugal mixer (Thinky) so that the Z-average of the compound represented by formula (I) was about 670 nm and about 210 nm, and samples were obtained. [Table 5] (Crushing conditions) Bead type: YTZ beads (φ0.1mm, made by Nikkato) Chamber ambient temperature: 5℃ (set) Crushing conditions [Table 6] [Table 7] (Z-average measurement) The particle size was measured by dynamic light scattering using a Zetasizer Nano (Malvern). (Z-average measurement conditions) Equipment: Zetasizer Nano (Malvern) Cell: UV-Transparent Cuvettes (SARSTEDT) Refractive index of sample: 1.59 Sample absorption: 0.01 Dispersion medium: water Temperature: 25℃ Refractive index of dispersion medium: 1.33 Viscosity: 1.0000 (Preparation of sample solution for Z-average measurement) 20 μL of the suspension was added to a 20 mL measuring flask, and the solution was made up to volume with water for injection (Otsuka Pharmaceutical Factory), and used for particle size measurement. [Table 8] *1: The compound represented by formula (I) used in Example 2-1 has a D50 of 3.3 μm and a white 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 mass is taken as 100%. Although the Z-average of the compound represented by formula (I) used in preparing the suspension was not calculated, it is estimated to be about half of the D50.

[0083] (Test Example 6: Rat PK test (subcutaneous (100 mg / head, different Z-average formulations)) The concentrations of the compound represented by formula (I) in rat plasma were evaluated using the preparations of Examples 2-1 to 2-3. The samples shown in Table 5 were subcutaneously administered to male rats. The dose of the sample 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 concentrations of the compound represented by formula (I) in plasma were measured using a mass spectrometer, and the maximum plasma drug concentrations (C max ), area under the plasma drug concentration-time curve (AUC), bioavailability (BA) and elimination rate constant (kel) were calculated. (result) C of the compound represented by formula (I) max The results for AUC, BA and elimination rate constant kel are shown in Table 9 below and in FIG. [Table 9] C max (Maximum plasma drug concentration): Indicates the maximum blood concentration after drug administration. AUC (area under the plasma drug concentration-time curve): An index showing the amount of drug absorbed into the body. BA (bioavailability): An index of the extent to which an administered drug (formulation) reaches the systemic circulating blood and acts. kel (elimination rate constant): A measure of the rate at which a drug or substance is removed from the blood in the body. For BA, the amount absorbed (ng) in each period was calculated by multiplying the AUC (ng hr / mL) between blood sampling times (CLtot (total clearance, obtained separately in an IV (intravenous) test (mL / hr / kg)) by the body weight (kg), and the total amount absorbed (the sum of the amount absorbed in each period (including the extrapolated range)) was divided by the administered amount. Kel was calculated from the slope of the plasma concentration at the six subsequent time points using Phoenix WinNonlin (Ver. 8.4). The AUC was evaluated from day 0 to day 84 in Example 2-1, and from day 0 to day 193 in Examples 2-2 and 2-3.

[0084] (Example 3: Preparation of formulation and measurement of particle size-2) (Manufacturing method) Polysorbate 20 (Merck), Macrogol 4000 (Fujifilm Wako Pure Chemical Industries, Ltd.), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Factory, Ltd.), and after confirming that the solution was completely dissolved, the compound represented by formula (I) was added and dispersed. After confirming that the suspension had a uniform property, the concentration of the formulation shown in Example 3 was adjusted using water for injection. Thereafter, the suspension was wet-pulverized using NanoVeita (Yoshida Kikai Kogyo Co., Ltd.) so that the Z-average of the compound represented by formula (I) was about 300 nm, and a sample was obtained. The particle size was measured by dynamic light scattering using Zetasizer Nano (Malvern). [Table 10] (Crushing conditions) Number of passes: 35 No cooling machine used (product temperature varies with the season) Crushing pressure: 180MPa

[0085] (Test Example 7: Rat PK test, subcutaneous (200mg / head)) The concentration of the compound represented by formula (I) in rat plasma was evaluated using the formulation of Example 3. The samples shown in Table 10 were subcutaneously administered to male rats. The dose of the sample 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 plasma was measured using a mass spectrometer, and the maximum plasma drug concentration (C max ), area under the plasma drug concentration-time curve (AUC), bioavailability (BA) and elimination rate constant (kel) were calculated. (result) C of the compound represented by formula (I) max The results for AUC, BA and kel are shown in Table 11 below and in Figure 8. The formulation shown in Example 3 showed good sustained release. [Table 11]

[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 test sample was administered intramuscularly to male rats. The dose of the test sample was adjusted so that the dose of the compound represented by formula (I) was 40 mg. After administration, blood was collected from the tail vein at each blood collection time, 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 max ), 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. (result) C of the compound represented by formula (I) max The results for AUC, BA and kel are shown in Table 12 below and in Figure 9. The formulation shown in Example 3 showed good sustained release. [Table 12]

[0087] (Test Example 9: Dog PK test (subcutaneous, 300 mg / head)) The concentration of the compound represented by formula (I) in dog plasma was evaluated. A sample was administered subcutaneously to a male beagle. The dose of the sample was adjusted so that the dose of the compound represented by formula (I) was 300 mg. After administration, blood was collected from the tail vein at each blood collection time, 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 max ), 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. (result) The results for Cmax, AUC, BA and kel for the compound of formula (I) are shown in Table 13 below and Figure 10. The formulation shown in Example 3 showed good sustained release. [Table 13]

[0088] (Test Example 10: Dog PK test (intramuscular, 300 mg / head)) The concentration of the compound represented by formula (I) in dog plasma was evaluated. A sample was intramuscularly administered to a male beagle. The dose of the sample was adjusted so that the dose of the compound represented by formula (I) was 300 mg. After administration, blood was collected from the tail vein at each blood collection time, 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 max ), 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. (result) The results for Cmax, AUC, BA and kel for the compound of formula (I) are shown in Table 14 below and in Figure 11. The formulation shown in Example 3 showed good sustained release. [Table 14]

[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, an evaluation was made as to whether the compound represented by formula (I) could be wet-pulverized to a Z-average of about 300 nm. [Table 15] (Manufacturing method) Polysorbate 20 (Merck), Macrogol 4000 (Fujifilm Wako Pure Chemical Industries, Ltd.), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Factory, Ltd.), and after confirming that the solution was completely dissolved, the compound represented by formula (I) was added and dispersed. After confirming that the suspension had a uniform property, the concentration of the formulation shown in Examples 4-1 to 4-8 was adjusted using water for injection. Then, the suspension was wet-pulverized using NanoVeta (Yoshida Kikai Kogyo Co., Ltd.) to obtain a sample. Z-average was measured by dynamic light scattering using Zetasizer Nano (Malvern) according to the method and conditions described in Example 2. (Manufacturing conditions) No cooling machine used (product temperature varies with the season) [Table 16] (result) Table 17 shows the feasibility of pulverization and Z-average by visual evaluation. When the concentration of polysorbate 20 is 2.0%, it was confirmed that the compound represented by formula (I) can be wet-pulverized to about 300 nm if the concentration of the compound represented by formula (I) is 100 to 250 mg / mL. In addition, when the concentration of polysorbate 20 is 1.5%, it was confirmed that the compound represented by formula (I) can be wet-pulverized to about 300 nm if the concentration of the compound represented by formula (I) is 100 to 200 mg / mL. Furthermore, 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-pulverized to about 300 nm if the concentration of the compound represented by formula (I) is 100 mg / mL. [Table 17] (Visual Judgment Criteria) Pulverizable: The suspension maintains a slurry state and the Z-average reaches approximately 300 nm.

[0090] (Example 5: Examination of formulation: Examination of type and concentration of dispersant-1) Using the formulation shown in Example 5, it was evaluated whether the compound represented by formula (I) can be wet-pulverized to a Z-average of about 300 nm. The manufacturing method was the same as in Example 2. [Table 18] (Manufacturing method) Polysorbate 20 (Merck), polysorbate 80 (Merck), poloxamer 188 (BASF), macrogol 4000 (Fujifilm Wako Pure Chemical Industries, Ltd.), sodium carboxymethylcellulose (Ashland), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Factory, Ltd.), and after confirming that the solution was completely dissolved, the compound represented by formula (I) was added and dispersed. After confirming that the suspension had a uniform property, the concentration of the formulation shown in Example 5 was adjusted using water for injection. The suspension was then wet-pulverized using a planetary centrifugal mixer (Thinky). The Z-average in the obtained suspension was measured by dynamic light scattering using a Zetasizer Nano (Malvern) according to the method and conditions described in Example 2. (Crushing conditions) Bead type: YTZ beads (φ0.1mm, made by Nikkato) Chamber ambient temperature: 5℃ (set) Crushing conditions [Table 19] (result) The visual evaluation of whether or not the powder could be ground and the Z-average are shown in Table 20 below. In Example 5, in which the concentration of polysorbate 80 was 4.0%, it was confirmed that the compound represented by formula (I) could be wet-ground to about 300 nm. [Table 20] Visual Judgment Criteria Pulverizable: The particle size reaches approximately 300 nm while the suspension maintains a slurry state.

[0091] (Example 6: Examination of formulation: Examination of type and concentration of dispersant-2) Using the formulations shown in Examples 6-1 to 6-3, it was evaluated whether the compound represented by formula (I) can be wet-pulverized to a Z-average of about 300 nm. [Table 21] (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 Factory), and after confirming that the solution was completely dissolved, the compound represented by formula (I) was added and dispersed. After confirming that the suspension had a uniform property, the concentration of the formulation shown in Example 6 was adjusted using water for injection. The suspension was then wet-pulverized using NanoVeita (Yoshida Kikai Kogyo) to obtain a sample. The Z-average was measured by dynamic light scattering using Zetasizer Nano (Malvern) according to the method and conditions described in Example 2. (Manufacturing conditions) No cooling machine used (product temperature varies with the season) [Table 22] (Experimental Results) The visual evaluation of whether or not the powder could be ground and the Z-average are shown in the following Table 23. It was confirmed that in Examples 6-1 to 6-3, the compound represented by formula (I) could be wet-ground to a size of about 300 nm. [Table 23] (Visual Judgment Criteria) Grindable: The suspension maintains a slurry state and 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 preparations of Examples 4-1 to 4-3 and 4-5 to 4-8, about 0.5 mL of the obtained suspension was filled into a 3 mL vial (manufactured by Taisei Chemical Industry Co., Ltd.) and sterilized by irradiating with gamma rays of 50 kGy in a sealed state. The irradiated specimen was placed in a 60°C thermostatic 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 spectrophotometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 100 mm, Waters) Column temperature: constant temperature around 40℃ Mobile phase A: Water / formic acid mixture (1000:1) Mobile phase B: Acetonitrile for liquid chromatography Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows: [Table 24] (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. The related substances with relative retention times of 0.36 and 0.55 did not show an increasing tendency after 2 weeks at 60° C. under stoppered conditions in any of the preparation formulations. [Table 25]

[0093] (Test Example 12: Evaluation of redispersibility) The specimen of Example 6-1 was allowed to stand in a 5°C environment for 3 days. Thereafter, the properties were observed and the dispersibility was evaluated. The results are shown in Figures 12 to 14. The redispersibility was good. Redispersion method: The stored sample was shaken up and down for 10 seconds.

[0094] (Test Example 13: Long-term stability test (related substances, redistribution)) The long-term stability (related substances, redispersibility) of the formulation shown in Example 7 was evaluated. [Table 26] (Manufacturing method) Polysorbate 20 (Merck), Macrogol 4000 (Fujifilm Wako Pure Chemical Industries, Ltd.), D-mannitol (Pfanstiehl), sodium dihydrogen phosphate hydrate (Merck), and sodium hydrogen phosphate (Merck) were dissolved in water for injection (Otsuka Pharmaceutical Factory, Ltd.), and after confirming that the solution was completely dissolved, the compound represented by formula (I) was added and dispersed. After confirming that the suspension had a uniform property, the concentration of the formulation shown in Example 7-1 was adjusted using water for injection. The suspension was then wet-pulverized using Microfluidizer M110EH (Powrex, Ltd.) to obtain a sample. Approximately 10 mL of the obtained suspension was filled into a 14 mL vial (Taisei Kako Co., Ltd.), and sterilized by irradiating with gamma rays of 200 kGy in a sealed state. The irradiated sample was placed in a constant temperature bath at 5°C, 25°C, and 40°C, and the amount of related substances after 12 months of storage was measured. In addition, redispersibility was evaluated. (Related Substances Test Method) The same method as in Test Example 11 was used. (Experimental Results) The preparation of Example 7 showed no tendency to increase in the related substances with relative retention times of 0.35 and 0.55 after storage at any temperature condition. Furthermore, the preparations stored at 5°C and 25°C showed good redispersibility.

[0095] (Example 8: Preparation of crystals of ethyl acetate solvate of the compound represented by formula (I)) The following experiment was carried out using compound I-055 prepared by the synthesis method of Example 5 of WO 2023 / 195529 and WO 2023 / 195530. Compound I-055 (800 mg, 1.880 mmol) and 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate (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 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, dried over magnesium sulfate, and filtered. The filtrate was subjected to silica gel column chromatography after the solvent was removed under reduced pressure. After elution with hexane / ethyl acetate, fractions containing the desired compound were collected. The solvent was concentrated under reduced pressure, and diisopropyl ether was added, and the precipitated solid was filtered. The resulting residue was dried under reduced pressure to obtain compound (I) (954 mg, 1.563 mmol, yield 83%). NMR measurement was performed. The NMR chart showed a peak for ethyl acetate. 1H-NMR (DMSO-D6)δ:1.18(3H,t ,J=7.0Hz),1.99(3H,s),2.79(4H,t,J=12.4Hz),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). A powder X-ray diffraction experiment was carried out on the obtained compound, and it was confirmed that the crystals were different from the anhydrous crystals of the compound represented by formula (I). From the results of the NMR chart and the powder X-ray diffraction experiment, it was presumed to be an ethyl acetate solvate crystal of the compound represented by formula (I). As a result of carrying out a single crystal diffraction experiment and analysis on the crystals, it was confirmed that the compound represented by formula (I) and ethyl acetate were ethyl acetate solvate crystals with a molar ratio of 1:1. The powder X-ray diffraction pattern of the ethyl acetate solvate crystal of the compound represented by formula (I) is as follows. In the powder X-ray diffraction pattern, diffraction angles (2θ): 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 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): 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°, and further include diffraction angles (2θ): 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 16.3°±0.2° and 23.7°±0.2°. The solubility of the crystals of the ethyl acetate solvate of the compound represented by formula (I) in water (measured at 25° C.) was 0.002 mg / mL. [Industrial Applicability]

[0096] The formulations of the present invention are believed to be useful as therapeutic and / or prophylactic agents for diseases or conditions in which coronavirus 3CL protease is involved.

Claims

1. Formula (I): 【Chemistry 1】 A preparation for subcutaneous, intradermal or intramuscular injection comprising a suspension of a compound represented by the following formula (I):

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

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

4. 4. The formulation of claim 3, comprising anhydrous crystalline of the compound of formula (I).

5. The formulation according to any one of claims 1 to 4, which contains a stabilizer in the suspension.

6. 6. The formulation of claim 5, wherein the stabilizing agent is a suspending agent.

7. 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 6 or 7, comprising 0.1 to 4.0 w / v % of a suspending agent.

9. 6. The formulation of claim 5, wherein the stabilizing agent is a dispersing agent.

10. The formulation according to claim 9, wherein the dispersing agent is one or more selected from the group consisting of polyethylene glycol, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, hydroxyethylpropylcellulose, noncrystalline cellulose, polysaccharides, hyaluronic acid, polyvinyl alcohol, and polyvinylpyrrolidone.

11. The formulation according to claim 9 or 10, comprising 0.1 to 2.0 w / v % of a dispersant.

12. The formulation according to any one of claims 1 to 11, further comprising a pH adjuster in the suspension.

13. The formulation according to claim 12, wherein the pH of the suspension is adjusted to 4.0 to 8.

0.

14. The formulation according to any one of claims 1 to 13, which is prepared by triturating the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof in a suspension.

15. The preparation according to claim 14, wherein the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof has a Z-average of 0.1 to 3.0 μm after milling.

16. The preparation according to claim 15, wherein the Z-average is 0.1 to 1.0 μm.

17. The formulation according to any one of claims 1 to 16, wherein the amount of the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof is 10 to 500 mg per mL of the suspension.

18. The preparation according to claim 17, wherein the amount of the compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof is 10 to 200 mg per mL of the suspension.

19. The formulation of any one of claims 1 to 18, wherein the blood concentration of the compound of formula (I) is 5 to 30 ng / mL at 2 months after injection.

20. 20. The formulation of any one of claims 1 to 19, which redisperses upon shaking.

21. The formulation according to any one of claims 1 to 20, which provides sustained release of the compound of formula (I) for at least 2 months after injection.

22. Formula (I) 【Chemistry 2】 A method for producing a preparation for subcutaneous, intradermal or intramuscular injection comprising a suspension of a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof, the method comprising the step of grinding a compound represented by formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof in a suspension.

Images