Quabodepistat-containing composition

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

Quabodepistat-containing composition

[0001] The present invention relates to a composition comprising at least one selected from quabodepistat, a salt and cocrystal thereof, and a solvate thereof, the composition being in the form of a suspension of microparticles.

[0002] Quabodepistat has the following formula: and has antibacterial activity against Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis, and / or non-tuberculous mycobacteria (Patent Document 1).

[0003] International Publication No. 2016 / 031255

[0004] One of the problems to be solved by the present invention is to provide a composition in the form of a suspension of microparticles, which is useful as a composition comprising at least one selected from quabodepistat, its salts and cocrystals, and solvates thereof.

[0005] Means for Solving the Problems The present inventors have conducted extensive research to solve the above problems, and as a result have found a composition in the form of a suspension of microparticles that is useful as a composition containing at least one selected from quabodepistat, its salts and cocrystals, and solvates thereof. Further investigations have led to the completion of the present invention.

[0006] The present invention encompasses the following embodiments: [Item 1] A composition comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof, wherein the composition comprises a suspending agent and a dispersion medium, and the composition is in the form of a suspension of microparticles. [Item 2] 0.1s -1 The viscosity at a shear rate of 0.2 to 200 Pa·s and 900 to 1000 s -1The composition according to Item 1, wherein the viscosity at any shear rate within this range is 0.1 Pa s or less. [Item 3] The composition according to Item 1 or 2, wherein the microparticles have an average primary particle size of 0.5 to 20 μm and an average secondary particle size of 1 to 30 μm. [Item 4] The composition according to any one of Items 1 to 3, wherein the suspending agent comprises at least one selected from the group consisting of carboxymethylcellulose or a salt thereof and a poloxamer. [Item 5] The composition according to Item 4, wherein the suspending agent further comprises polyethylene glycol. [Item 6] The composition according to any one of Items 1 to 5, wherein the concentration of the component in the composition is 100 to 500 mg / mL, calculated as the free form. [Item 7] The composition according to any one of Items 1 to 6, wherein the concentration of the component in the composition is 200 to 500 mg / mL, calculated as the free form. [Item 8] The composition according to any one of Items 1 to 7, wherein the composition is administered intramuscularly or subcutaneously. [Item 9] The composition according to any one of Items 1 to 8, wherein the composition is administered at intervals of one month or more. [Item 10] The composition according to any one of Items 1 to 9, which is an injectable formulation. [Item 11] The composition according to any one of Items 1 to 10, which is used for the prevention and / or treatment of mycobacteriosis. [Item 11-1] The composition according to Item 11, wherein the mycobacteriosis is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 11-2] The mycobacterial disease is Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium microti, Mycobacterium leprae, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, Mycobacterium Item 11: The composition according to Item 11, wherein the mycobacterial disease is an infection caused by Mycobacterium chelonae, Mycobacterium smegmatis, or Mycobacterium aurum. [Item 11-3] The composition according to Item 11, wherein the mycobacterial disease is tuberculosis. [Item 11-4] The composition according to any one of Items 1 to 11, 11-1, 11-2, and 11-3, which is a sterile composition. [Item 12] A pre-filled syringe, vial, or ampoule containing the composition according to any one of Items 1 to 11, 11-1, 11-2, 11-3, and 11-4. [Item 13] A method for producing the composition according to any one of Items 1 to 11, 11-1, 11-2, 11-3, and 11-4, comprising: Step 1: mixing the ingredients, a suspending agent, and a dispersion medium; Step 2: wet-pulverizing the suspension obtained by the mixing; and Step 3: recovering the suspension obtained by the wet-pulverization. [Item 14] The method according to Item 13, wherein the wet pulverization is carried out using a bead mill or a high-pressure homogenizer.[Item 15] A method for producing the composition according to any one of Items 1 to 11, 11-1, 11-2, 11-3, and 11-4, comprising: Step 1: dry-milling the ingredients; Step 2: mixing the ingredients after the dry-milling, a suspending agent, and a dispersion medium; and Step 3: recovering the suspension obtained by the mixing. [Item 16] The method according to Item 15, wherein the dry-milling is performed using a hammer mill, jet mill, or pin mill. [Item 17] The method according to any one of Items 13 to 16, further comprising Step 4: radiation sterilizing the recovered suspension. [Item 18] A method for preventing and / or treating mycobacteriosis, comprising intramuscularly or subcutaneously administering, at intervals of one week or more, to a subject in need of prevention and / or treatment of mycobacteriosis, an effective amount of a composition in the form of a suspension of microparticles containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof. [Item 19] The method of Item 18, wherein the administering comprises intramuscularly or subcutaneously administering an effective amount of the composition to the subject at intervals of one month or more. [Item 20] The method of Item 18 or 19, wherein the administering comprises intramuscularly or subcutaneously administering an effective amount of the composition to the subject one to four times at intervals of two to three months. [Item 21] The method of any of Items 18 to 20, wherein the mycobacterial disease is tuberculosis. [Item 22] A method for preventing and / or treating latent tuberculosis, comprising intramuscularly or subcutaneously administering one to three times at intervals of one to three months to a subject in need of prevention and / or treatment of latent tuberculosis an effective amount of a composition in the form of a suspension of microparticles comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof. [Item 23] A method for preventing and / or treating mycobacteriosis, comprising administering to a subject in need of prevention and / or treatment of mycobacteriosis an effective amount of the composition according to any one of Items 1 to 10 and 11-4. [Item 24] The method according to Item 23, wherein the mycobacteriosis is an infectious disease caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 25] The mycobacterial disease is Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium microti, Mycobacterium leprae, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium [Item 26] The method of Item 23 or 24, wherein the mycobacterial disease is an infection caused by Mycobacterium smegmatis, or Mycobacterium aurum. [Item 27] ​​Use of the composition of any of Items 1 to 10 and 11-4 for the manufacture of a medicament for the prevention and / or treatment of mycobacterial disease. [Item 28] The use of Item 27, wherein the mycobacterial disease is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 29] The mycobacterial disease is Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium microti, Mycobacterium leprae, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium [Item 30] The use according to Item 27, wherein the mycobacterial disease is tuberculosis. [Item 31] The use according to any of Items 27 to 30, wherein the medicament is administered intramuscularly or subcutaneously 1 to 4 times at intervals of one week or more, one month or more, or two to three months, or 1 to three times at intervals of one to three months.

[0007] The present invention provides a composition in the form of a suspension of microparticles useful as a composition comprising at least one selected from quabodepistat, its salts and cocrystals, and solvates thereof. The composition may have the following advantages, for example: It can be administered at intervals of two weeks or more (particularly one month or more), which contributes to improving adherence and thereby improving the success rate of treatment for mycobacterial diseases (including tuberculosis) and suppressing the development of resistant bacteria. It is also useful for treating latent mycobacterial diseases (particularly latent tuberculosis) and preventing mycobacterial diseases in high-risk groups. The microparticles exhibit excellent long-term storage stability without caking. They cause minimal irritation upon administration. They can be formulated into small, easy-to-use formulations.

[0008] FIG. 1 shows the viscosity profiles of Examples 1 to 5, which are 300 mg / mL (30% (w / v)) quabodepistat suspensions, and Comparative Example 1. FIG. 2 shows the viscosity profiles of Examples 7 to 10, 15, and 16, which are 400 mg / mL (40% (w / v)) quabodepistat suspensions. FIG. 3 shows the blood concentration profiles of Examples 4, 18, or 19 when administered subcutaneously (SC) to rats at a dose of 50 mg / kg. FIG. 4 shows the blood concentration profiles of Examples 4, 18, or 19 when administered intramuscularly (IM) to rats at a dose of 50 mg / kg. FIG. 5 shows the effect of the formulation of Example 4 on reducing the number of viable bacteria in the lungs when administered subcutaneously (SC) to a mouse tuberculosis infection model at a dose of 12 mg / kg or 120 mg / kg. FIG. 6 shows the blood concentration profile of Examples 21 or 22 when administered subcutaneously (SC) to dogs at a dose of 25 mg / kg.

[0009] In this specification, the term "comprise" encompasses the concepts of "essentially consist of" and "consist of."

[0010] All documents mentioned herein are incorporated herein by reference.

[0011] The composition of the present invention comprises at least one active ingredient selected from quabodepistat, its salts and cocrystals, and solvates thereof (hereinafter also referred to as "active ingredient"), a suspending agent, and a dispersion medium. The active ingredient may be a single active ingredient or a combination of two or more active ingredients. The composition is typically a pharmaceutical composition.

[0012] As used herein, quabodepistat (also referred to as "OPC-167832") refers to 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolinone-2(1H)-one (non-salt form, free form). Quabodepistat can be produced, for example, by the method described in International Publication No. 2016 / 031255 (or U.S. Patent Application Publication No. 2017 / 253576). Quabodepistat may be either Form I crystal or Form II crystal described in Japanese Patent Application Laid-Open No. 2020-79206 and Japanese Patent Application Laid-Open No. 2021-178818. The form I crystal is a crystal that, in a powder X-ray diffraction pattern obtained using CuKα radiation as an X-ray source, has diffraction peaks at diffraction angles (2θ) of 4.9±0.2°, 10.6±0.2°, 13.9±0.2°, and 21.9±0.2°, and may further have diffraction peaks at one, two, three, four, five, six, or seven diffraction angles (2θ) selected from the group consisting of 9.9±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 23.1±0.2°, 26.2±0.2°, and 31.9±0.2°. The form II crystal is a crystal that has diffraction peaks at diffraction angles (2θ) of 10.8±0.2°, 14.2±0.2°, 21.0±0.2°, and 25.3±0.2° in a powder X-ray diffraction pattern obtained using CuKα radiation as an X-ray source, and may further have diffraction peaks at one, two, three, four, five, or six diffraction angles (2θ) selected from the group consisting of 8.7±0.2°, 16.5±0.2°, 16.7±0.2°, 17.3±0.2°, 23.9±0.2°, and 28.2±0.2°.

[0013] As used herein, the term "cocrystal" refers to a cocrystal of quabodepistat and a coformer.

[0014] As used herein, the term "solvate" refers to a solvate of quabodepistat or a salt thereof, or a solvate of a co-crystal of quabodepistat and a coformer.

[0015] In one embodiment, the composition comprises quabodepistat, a suspending agent, and a dispersion medium.

[0016] In another embodiment, the composition comprises a salt of quabodepistat, a suspending agent, and a dispersion medium. The salt of quabodepistat is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; salts with organic bases such as alkylamines (e.g., methylamine, diethylamine, trimethylamine, and triethylamine), alkanolamines (e.g., ethanolamine, diethanolamine, triethanolamine, and tris(hydroxymethyl)methylamine), cycloalkylamines (e.g., dicyclohexylamine), alkylenediamines (e.g., ethylenediamine and N,N'-dibenzylethylenediamine), guanidine, pyridine, picoline, and choline; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; and salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, and lactic acid.

[0017] In yet another embodiment, the composition comprises a co-crystal of quabodepistat and a coformer, a suspending agent, and a dispersion medium.

[0018] The co-crystal may be a crystalline substance in which quabodepistat and a co-former are present in the same crystal lattice at any molar ratio, and may exist in multiple crystalline forms (also known as "polymorphs").

[0019] In one embodiment, the coformer is a non-ionizable molecule capable of forming a crystal with quabodepistat, such as, for example, an organic acid, an amino acid, an amine, an amide, vanillin, urea, pyridoxine, saccharin, or hydroquinone.

[0020] Examples of organic acids include carboxylic acids, ascorbic acid, and phenols. Carboxylic acids include aliphatic carboxylic acids, aromatic carboxylic acids, and heterocyclic carboxylic acids. Examples of aliphatic carboxylic acids include fumaric acid, succinic acid, tartaric acid, malic acid, glutaric acid, citric acid, and maleic acid. Examples of aromatic carboxylic acids include benzoic acid, 2,5-dihydroxybenzoic acid, salicylic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 4-aminosalicylic acid, 2-amino-5-hydroxybenzoic acid, hippuric acid, and phthalic acid. Examples of heterocyclic carboxylic acids include nicotinic acid. The organic acid may be a nonvolatile organic acid, such as an organic acid that does not volatilize at room temperature (15°C to 25°C) and normal pressure. The nonvolatile organic acid may also be a water-soluble organic acid.

[0021] The amino acid may be a natural or unnatural amino acid, and examples of the amino acid include proline, lysine, tyrosine, and histidine.

[0022] Examples of the amine include aliphatic amines such as meglumine and tromethamine; and aromatic amines.

[0023] Examples of the amide include carboxylic acid amides such as nicotinamide.

[0024] The coformer may be one type alone or a combination of two or more types. In a preferred embodiment, the coformer is a non-volatile organic acid or an amino acid. The non-volatile organic acid is preferably a carboxylic acid, more preferably a benzoic acid optionally substituted at least at one of the o-, m-, or p-positions with a group selected from the group consisting of hydroxy, amino, and carboxy, and even more preferably 2,5-dihydroxybenzoic acid or salicylic acid.

[0025] In the cocrystal, the amount of the coformer relative to 1 mole of quabodepistat is, for example, 0.5 moles or more, preferably 0.8 moles or more, more preferably 0.9 moles or more, and even more preferably 1 mole or more. In the cocrystal, the amount of the coformer relative to 1 mole of quabodepistat is, for example, 2.5 moles or less, preferably 2 moles or less, more preferably 1.5 moles or less, and even more preferably 1 mole or less. In the cocrystal, the amount of the coformer relative to 1 mole of quabodepistat may be, for example, 0.5 to 2.5 moles.

[0026] In yet another embodiment, the composition comprises a solvate of Quabodepistat, a salt or co-crystal thereof, a suspending agent, and a dispersion medium.

[0027] The solvate may be a solvate formed by any molar ratio of quabodepistat, the salt, or the cocrystal to solvent molecules. Examples of such solvates include hydrates, ethanolates, and tetrahydrofuran (THF) solvates. The solvate may exist, for example, as a solvate containing 0.5 to 2 solvent molecules per quabodepistat molecule, and may be, for example, a 0.5-hydrate, a monohydrate, a 1.5-hydrate, or a dihydrate.

[0028] The cocrystal or solvate thereof may be, for example, one described in WO 2021 / 230198.

[0029] The concentration of the active ingredient in the composition is not particularly limited as long as it is an effective concentration according to the intended use of the composition. The concentration of the active ingredient in the composition, calculated as the free form, is, for example, 100 mg / mL or more, preferably 150 mg / mL or more, more preferably 200 mg / mL or more, even more preferably 250 mg / mL or more, and even more preferably 300 mg / mL or more. The concentration of the active ingredient in the composition, calculated as the free form, may be, for example, 400 mg / mL or less or 450 mg / mL or less, but is preferably 500 mg / mL or less from the viewpoint of maintaining good flow properties and prolonged duration of action. The concentration of the active ingredient in the composition, calculated as the free form, is, for example, 100 to 500 mg / mL, preferably 200 to 500 mg / mL, and even more preferably 300 to 500 mg / mL.

[0030] The suspending agent contained in the composition is not particularly limited as long as it is pharmaceutically acceptable and can achieve a predetermined viscosity. Examples of suspending agents include carboxymethylcellulose and its salts, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, and polyethylene glycol (also known as "macrogol").

[0031] Examples of salts of carboxymethylcellulose include metal salts such as alkali metal salts, and ammonium salts. Specific examples include sodium carboxymethylcellulose, potassium carboxymethylcellulose, lithium carboxymethylcellulose, ammonium carboxymethylcellulose, and mixtures thereof. In one embodiment, the suspending agent preferably contains carboxymethylcellulose and / or its sodium salt, and particularly preferably contains sodium carboxymethylcellulose.

[0032] The average molecular weight of carboxymethylcellulose or a salt thereof is, for example, 5,000 or more, preferably 10,000 or more. The average molecular weight of carboxymethylcellulose or a salt thereof is, for example, 300,000 or less, preferably 250,000 or less. The average molecular weight of carboxymethylcellulose or a salt thereof is, for example, 5,000 to 300,000, preferably 10,000 to 250,000.

[0033] The viscosity of a 2% (w / v) aqueous solution of carboxymethylcellulose or a salt thereof is, for example, 1000 mPa s or less, preferably 800 mPa s or less. The viscosity is, for example, 10 mPa s or more, preferably 50 mPa s or more. The viscosity is, for example, 10 to 1000 mPa s, preferably 50 to 800 mPa s. The viscosity can be measured according to the method described in USP-NF (e.g., the 2019 edition of USP42-NF37).

[0034] Poloxamers typically have the formula: HO-[CH ２ CH ２ O]x-[CH(CH ３ )CH ２ O]y-[CH ２ CH ２ O]zH (wherein x is 2 to 150, y is 15 to 70, and z is 2 to 150). Examples of poloxamers include poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and mixtures of two or more of these. The average molecular weight of the poloxamer is, for example, 2,000 or more, preferably 3,000 or more, more preferably 4,000 or more, and even more preferably 5,000 or more, and may be, for example, 6,000 or more, 6,500 or more, 7,000 or more, or 7,500 or more. The average molecular weight of the poloxamer is, for example, 20,000 or less, preferably 19,000 or less, and even more preferably 18,000 or less. The average molecular weight of the poloxamer is, for example, 2,000 to 20,000 or less. The average molecular weight can be measured according to the method described in USP-NF (e.g., the 2019 edition of USP42-NF37). In one embodiment, the suspending agent preferably comprises poloxamer 338 and / or poloxamer 188.

[0035] The average molecular weight of polyethylene glycol (PEG) is, for example, 100 or more, preferably 150 or more, and more preferably 200 or more. The average molecular weight of PEG is, for example, 10,000 or less, preferably 8,000 or less, and more preferably 5,000 or less. The average molecular weight of PEG is, for example, 100 to 10,000. The average molecular weight can be measured according to the method described in USP-NF (e.g., the 2019 edition of USP42-NF37). Examples of PEG include PEG200, PEG300, PEG400, PEG600, PEG3350, PEG4000, PEG6000, PEG8000, and mixtures of two or more of these. Of these, PEG3350 and / or PEG400 are preferred.

[0036] The suspending agent may be a single agent or a combination of two or more agents. In one embodiment, when the suspending agent contains at least one agent selected from the group consisting of carboxymethylcellulose or a salt thereof and poloxamer as the first suspending agent, it is preferable to contain PEG as the second suspending agent to adjust the viscosity to the desired level. The amount of the second suspending agent is, for example, 10 parts by mass or more, preferably 15 parts by mass or more, and more preferably 20 parts by mass or more, relative to 100 parts by mass of the first suspending agent. The amount of the second suspending agent is, for example, 200 parts by mass or less, preferably 150 parts by mass or less, and more preferably 100 parts by mass or less, relative to 100 parts by mass of the first suspending agent. The amount of the second suspending agent is, for example, 10 to 200 parts by mass, relative to 100 parts by mass of the first suspending agent.

[0037] The concentration of the suspending agent in the composition is, for example, 0.01 mg / mL or more, preferably 0.02 mg / mL or more, and more preferably 0.05 mg / mL or more. The concentration of the suspending agent in the composition is, for example, 20 mg / mL or less, preferably 15 mg / mL or less, and more preferably 10 mg / mL or less. The concentration of the suspending agent in the composition is, for example, 0.01 to 20 mg / mL. The concentrations of the suspending agent, the first suspending agent, and the second suspending agent in the composition can each be appropriately combined with the concentration of the active ingredient in the composition (e.g., 100 to 500 mg / mL in terms of the free form).

[0038] The dispersion medium contained in the composition is not particularly limited as long as it is pharmaceutically acceptable and capable of dispersing the active ingredient. The dispersion medium may be a single type or a combination of two or more types. Preferably, the dispersion medium contains at least water. Examples of such dispersion media include water, physiological saline, and solvents containing water and an organic solvent. Examples of the organic solvent include those miscible with water, such as alcohols (e.g., methanol, ethanol, propanol, isopropanol, etc.); ketones (e.g., acetone); ethers (e.g., tetrahydrofuran); amides (e.g., dimethylformamide); and mixtures thereof. The organic solvent is preferably alcohol, more preferably ethanol. The water content in the solvent containing water and an organic solvent is, for example, 50% by mass or more but less than 100% by mass, preferably 60% by mass or more but less than 100% by mass, and more preferably 70% by mass or more but less than 100% by mass (e.g., 70-99% by mass). In a preferred embodiment, the dispersion medium is water, and purified water, sterile purified water, water for injection, etc. are particularly preferred.

[0039] The dispersion medium is contained in an appropriate amount so that the content of the active ingredient and the like falls within the above-mentioned range. For example, the dispersion medium may be contained so that the total volume of the composition is 0.2 mL or more, preferably 0.3 mL or more, more preferably 0.4 mL or more, even more preferably 0.5 mL or more, even more preferably 0.6 mL or more, particularly preferably 0.7 mL or more, especially more preferably 0.8 mL or more, and most preferably 0.9 mL or more. The dispersion medium may also be contained so that the total volume of the composition is, for example, 1 mL or more, 1.5 mL or more, 2 mL or more, or 2.5 mL or more. Furthermore, the dispersion medium may be contained so that the total volume of the composition is 5 mL or less, preferably 4.5 mL or less, more preferably 4 mL or less, even more preferably 3.5 mL or less, even more preferably 3 mL or less, especially preferably 2.5 mL or less, and especially preferably 2 mL or less. For example, the dispersion medium may be contained so that the total volume of the composition is 0.2 to 5 mL, 1 to 2 mL, 2 to 4 mL, or 2.5 to 5 mL. This amount may be, for example, the amount of the composition in a container such as a prefilled syringe, vial, or ampoule.

[0040] The composition may further contain any additive. Such additives are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include tonicity agents, buffers, pH adjusters, preservatives, etc. The additives may be used alone or in combination of two or more.

[0041] Examples of the isotonicity agent include alkali metal chlorides such as sodium chloride and potassium chloride; sugar alcohols such as mannitol, sorbitol, xylitol, and maltitol; sugars such as glucose, trehalose, and maltose; glycerin, etc. The composition may not contain an isotonicity agent, but when it contains an isotonicity agent, the concentration of the isotonicity agent in the composition is, for example, 0.5 to 10 mg / mL, and preferably 1 to 8 mg / mL.

[0042] Examples of buffering agents include phosphates such as sodium phosphate, sodium dihydrogen phosphate, monosodium hydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; borates such as sodium borate and potassium borate; citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate and sodium bicarbonate, etc. The concentration of the buffering agent in the composition is, for example, 0.01 to 1.5 mg / mL, and preferably 0.1 to 1 mg / mL.

[0043] The pH adjuster may be either an acidic pH adjuster or a basic pH adjuster. Examples of acidic pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, and citric acid. Examples of basic pH adjusters include sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide. The pH adjuster is usually added in an appropriate amount depending on the desired pH of the composition.

[0044] Examples of preservatives include benzoic acid or salts thereof (e.g., alkali metal salts such as sodium salt), parahydroxybenzoic acid esters (e.g., alkyl esters such as methyl ester, ethyl ester, propyl ester, and butyl ester), butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), benzyl alcohol, etc. The composition may be free of preservatives, but when a preservative is contained, the concentration of the preservative in the composition is, for example, 0.01 to 1 mg / mL or 0.05 to 0.5 mg / mL.

[0045] The composition is in the form of a suspension of microparticles. The suspension is preferably an aqueous suspension. The microparticles contain at least an active ingredient. The microparticles may contain a suspending agent on their surfaces.

[0046] The average primary particle size of the microparticles is, for example, 0.5 μm or more, preferably 1 μm or more. The average primary particle size of the microparticles is, for example, 20 μm or less, preferably 15 μm or less, and more preferably 10 μm or less. The average primary particle size of the microparticles is, for example, 0.5 to 20 μm. This range is preferable in terms of maintaining the effect for a long time. The average primary particle size can be measured by a laser diffraction scattering method under conditions of ultrasonic irradiation. The average secondary particle size of the microparticles is, for example, 1 μm or more, preferably 2 μm or more. The average secondary particle size of the microparticles is, for example, 30 μm or less, preferably 25 μm or less, and more preferably 20 μm or less. This range is preferable in terms of maintaining the effect for a long time. The average secondary particle size can be measured by a laser diffraction scattering method under conditions of no ultrasonic irradiation. For example, an SALD-3100 or SALD-2300 (manufacturer: Shimadzu Corporation) can be used to measure the average particle size by the laser diffraction scattering method.

[0047] The difference (d2-d1) between the average secondary particle size (d2) and the average primary particle size (d1) of the microparticles is preferably 0.5 μm or more, more preferably 1 μm or more. The difference between the average secondary particle size and the average primary particle size of the microparticles is preferably 10 μm or less, more preferably 5 μm or less. The difference between the average secondary particle size and the average primary particle size of the microparticles is, for example, 0.5 to 10 μm.

[0048] The composition preferably exhibits a property of decreasing viscosity with increasing shear rate, i.e., thixotropy (shear thinning).

[0049] 0.1s of the composition -1 The viscosity (VL) at a shear rate of 1000 Pa·s is, for example, 0.2 Pa·s or more, preferably 0.5 Pa·s or more, and more preferably 1 Pa·s or more, from the viewpoints of enhancing interparticle interactions, preventing particle settling and caking, and improving redispersibility. The viscosity VL of the composition is, for example, 200 Pa·s or less, preferably 150 Pa·s or less, more preferably 100 Pa·s or less, and even more preferably 70 Pa·s or less, from the viewpoints of ensuring flowability and preventing a decrease in grindability and filling accuracy. The viscosity VL of the composition is, for example, 0.2 to 200 Pa·s.

[0050] 900 to 1000s of the composition -1 Any value within the range (e.g. 900s -1 or 1000s -1 The viscosity at shear rate (VH) of the composition is, for example, 0.1 Pa·s or less, preferably 0.05 Pa·s or less, from the viewpoint of, for example, the resistance value (slidability) during injection. The viscosity VH of the composition is, for example, 0.001 Pa·s or more, preferably 0.005 Pa·s or more. The viscosity VH of the composition is, for example, 0.001 to 0.1 Pa·s. The viscosity VH of the composition is, for example, 900 to 1000 s -1 The viscosity may be the point at which no change in viscosity is observed even when the shear rate is changed within the range.

[0051] The viscosity ratio VL / VH of the composition is, for example, 2 or more, preferably 5 or more, and more preferably 10 or more.

[0052] The viscosity at the above shear rates can be measured at 25°C using a rotational rheometer such as a Discovery Hybrid Rheometer-2 (DHR-2), a Discovery Hybrid Rheometer-3 (DHR-3), or a Discovery Hybrid Rheometer-20 (DHR-20) (manufacturer: TA Instruments).

[0053] The pH of the composition at room temperature (e.g., 25°C) is, for example, 5 or higher, preferably 5.5 or higher, and more preferably 6 or higher. The pH of the composition at room temperature (e.g., 25°C) may optionally be 6.5 or higher. The pH of the composition at room temperature (e.g., 25°C) is, for example, 9 or lower, preferably 8.5 or lower, and more preferably 8 or lower. The pH of the composition at room temperature (e.g., 25°C) may optionally be 7.5 or lower. The pH of the composition at room temperature (e.g., 25°C) is, for example, 5 to 9, and preferably 6 to 8.

[0054] The administration route of the composition is not particularly limited, but the composition is preferably administered intramuscularly or subcutaneously. The recipient of the composition includes, for example, mammals such as humans. The recipient of the composition may be a patient in need of prevention and / or treatment of mycobacteriosis. The composition for intramuscular or subcutaneous administration is also preferably used in combination with an oral composition containing at least one selected from quabodepistat, its salts and cocrystals, and solvates thereof. This combination may be effective for patients in the early stages of mycobacteriosis prevention and / or treatment.

[0055] Because the composition has a long-lasting effect (e.g., maintains an effective blood concentration), it is suitable for use as a long-acting injection (LAI) formulation, enabling reduced administration frequency. The composition is administered, for example, at intervals of 2 weeks or more, 3 weeks or more, 4 weeks or more, 1 month or more, or 2 months or more. The longer the administration interval, the more preferable it is. There is no particular upper limit, but it can be, for example, 2 months, 3 months, 4 months, 5 months, or 6 months. Administration at such a frequency is preferable from the viewpoint of patient compliance. The administration period (or treatment period) of the composition can be, for example, 6 months, and the composition is preferably administered 1 to 6 times every 6 months, more preferably 1 to 3 times every 6 months, even more preferably 1 or 2 times every 6 months, and particularly preferably once every 6 months. In one embodiment, the composition is preferably administered subcutaneously no more than once a month or no more than once every 2 months. In another embodiment, the composition is preferably administered intramuscularly no more than once every two months or no more than once every three months. The composition may also be administered in combination with a composition in the form of a submicron particle suspension containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof, a suspending agent, and a dispersion medium. The LAI formulation may also be administered in combination with other LAI formulations (e.g., those with a longer duration of action but a faster onset of action than the LAI formulation), which may be effective in the early stages of treatment. The LAI formulation is also preferably used in combination with an orally administered formulation.

[0056] The composition is preferably administered at a daily dose of, for example, 10 mg or more or 12 mg or more (or at a monthly dose of, for example, 300 mg or more or 360 mg or more). The composition is also preferably administered at a daily dose of, for example, 20 mg or less or 18 mg or less (or at a monthly dose of, for example, 600 mg or less or 540 mg or less). Furthermore, the composition is preferably administered at a daily dose of, for example, 10 to 20 mg, preferably 12 to 18 mg.

[0057] The composition is preferably administered so that the injection amount per administration (or per month) is, for example, 0.5 mL or more, or 1 mL or more. The composition is also preferably administered so that the injection amount per administration (or per month) is, for example, 5 mL or less, 4.5 mL or less, 4 mL or less, 3.5 mL or less, 3 mL or less, 2.5 mL or less, 2 mL or less, or 1.5 mL or less. The composition is also preferably administered so that the injection amount per administration (or per month) is, for example, 0.5 to 5 mL, 0.5 to 3 mL, or 1 to 2 mL.

[0058] The composition is typically an injectable formulation. In one embodiment, the composition is an injectable formulation for administration with an 18 to 30 G (gauge) or 20 to 30 G (gauge) needle.

[0059] The composition is preferably used for the prevention and / or treatment of mycobacteriosis (including latent mycobacteriosis). Mycobacteriosis is an infectious disease caused by, for example, Mycobacterium tuberculosis, Mycobacterium leprae, nontuberculous mycobacteria, etc. Examples of Mycobacterium tuberculosis include Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium microti, etc. Examples of Mycobacterium leprae include Mycobacterium leprae, etc. Examples of nontuberculous mycobacteria include Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium smegmatis, and Mycobacterium aurum. In a preferred embodiment, the mycobacterial disease is tuberculosis (including latent tuberculosis). The tuberculosis may be multidrug-resistant tuberculosis. The tuberculosis may also be pulmonary tuberculosis.

[0060] The composition is preferably a sterile composition or a sterilized composition. From the viewpoints of suppressing particle aggregation and / or maintaining the thixotropy of the composition during long-term storage and preventing particle sedimentation and caking, radiation sterilization is preferred. Examples of radiation sterilization include gamma ray sterilization, electron beam sterilization, and X-ray sterilization.

[0061] The composition may be used in combination with other drugs for preventing or treating mycobacteriosis. As used herein, the term "used in combination" includes simultaneous administration and separate administration, such as sequential administration. In one embodiment, the composition contains another drug for preventing or treating mycobacteriosis in addition to the active ingredient, and may be administered as a single composition.

[0062] The composition can be prepared using a wet milling method. Examples of suitable wet milling methods include wet ball milling, high-pressure homogenization, high-shear homogenization, and bead mills (e.g., Dyno-Mill). In addition to the above milling methods, other low- and high-energy mills (e.g., roller mills) can also be used. Other preparation methods include controlled crystallization and methods of suspending dry-milled powder using a hammer mill, jet mill, pin mill, or the like.

[0063] In one embodiment, the composition can be produced by a method including, for example, step 1 of mixing an active ingredient, a suspending agent, and a dispersion medium, step 2 of wet-milling the suspension obtained by the mixing, and step 3 of recovering the suspension obtained by the wet-milling.

[0064] There are no particular limitations on the order in which the components are mixed in step 1. In one embodiment, step 1 comprises a step of mixing components other than the active ingredient to obtain a vehicle solution, and a step of mixing the vehicle solution with the active ingredient.

[0065] In step 2, the wet pulverization is preferably performed using a bead mill or a high-pressure homogenizer. The bead milling method is not particularly limited. In one embodiment, step 2 involves adding beads to the suspension and stirring the mixture. The bead milling method may be batch, continuous (pass), or circulating. Examples of bead materials include zirconia, alumina, and glass. The diameter of the beads is, for example, 0.1 to 5 mm, preferably 0.2 to 3 mm. The average particle size of the particles obtained using the bead mill can be appropriately adjusted by the size of the beads, the rotation speed (circumferential speed) and flow rate (flow rate) during pulverization, the pulverization time, and other factors. The high-pressure homogenizer method is also not particularly limited. The processing pressure (or final pressure) is, for example, 100 to 1,000 bar, preferably 150 to 800 bar, and more preferably 200 to 600 bar. The processing time is, for example, 1 to 60 minutes, preferably 5 to 30 minutes, per 1 L of suspension.

[0066] In step 3, the method for recovering the suspension obtained by wet-pulverization is not particularly limited. When wet-pulverization is performed using a bead mill, step 3 typically includes a step of removing beads. In one embodiment, the step of removing beads is preferably a step of separating and removing the beads using a separator (such as a gap or screen) at the outlet of the bead mill or by centrifugal separation of the bead mill, or a step of separating and removing the beads using a syringe needle with a pore size smaller than the beads (for example, 22 G or smaller) or a mesh filter (for example, 80 μm mesh).

[0067] Step 3 preferably includes a method of filling a container with the suspension after wet pulverization (if the wet pulverization is performed using a bead mill, the suspension after removing the beads). In one embodiment, a filling device such as a valve piston pump, a peristaltic pump, a mass flow system, or a time pressure system can be used. The container is not particularly limited, but examples include ampoules, vials, and pre-filled syringes, with pre-filled syringes being preferred.

[0068] In one embodiment, the composition can be produced by a method including, for example, step 1 of dry-milling an active ingredient, step 2 of mixing the active ingredient after dry-milling, a suspending agent, and a dispersion medium, and step 3 of recovering the suspension obtained by the mixing.

[0069] In step 1, the dry pulverization is preferably dry pulverization using a hammer mill or a jet mill.

[0070] There are no particular limitations on the order of mixing the components in step 2. In one embodiment, step 2 comprises a step of mixing components other than the dry-milled active ingredient to obtain a vehicle solution, and a step of mixing the vehicle solution with the dry-milled active ingredient.

[0071] Step 3 may be the same as the step of recovering the suspension obtained by wet grinding.

[0072] The composition is preferably a sterilized or aseptic composition. In this case, the production method preferably includes, in addition to steps 1, 2, and 3, step 4 of sterilizing the suspension (e.g., a wet-pulverized or dry-pulverized suspension, usually a suspension filled in a container). From the viewpoint of suppressing particle aggregation, radiation sterilization is preferred for sterilization. Examples of radiation sterilization include gamma ray sterilization, electron beam sterilization, and X-ray sterilization.

[0073] The present invention encompasses a container (also referred to as a primary container) containing the composition. Examples of containers include syringes such as prefilled syringes, vials, ampoules, bottles, cartridges, and the like. The material of these containers is not particularly limited and may be glass or plastic. In one embodiment, the container is a prefilled syringe, vial, or ampule. For example, the composition can be used as a prefilled syringe by simply filling it into a syringe. It is also preferable to perform the sterilization after filling the composition into the container (particularly a prefilled syringe, vial, or ampule). Furthermore, the present invention also encompasses a kit containing the container (particularly a prefilled syringe, vial, or ampule).

[0074] The present invention encompasses methods for preventing and / or treating mycobacteriosis, comprising administering an effective amount of the composition to a subject in need of prevention and / or treatment of mycobacteriosis. The corresponding configurations described for the composition can be employed for each element in the method. The present invention encompasses methods for preventing and / or treating mycobacteriosis (e.g., tuberculosis), comprising intramuscularly or subcutaneously administering an effective amount of a composition in the form of a microparticle suspension containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof, to a subject in need of prevention and / or treatment of mycobacteriosis (e.g., tuberculosis) 1 to 4 times at intervals of one week or more, preferably at intervals of one month or more, and more preferably at intervals of 2 to 3 months. Furthermore, the present invention encompasses a method for preventing and / or treating latent tuberculosis, comprising intramuscularly or subcutaneously administering to a subject in need of prevention and / or treatment of latent tuberculosis an effective amount of a composition in the form of a suspension of microparticles comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof, 1 to 3 times at intervals of 1 to 3 months.

[0075] The present invention encompasses use of the composition for the manufacture of a medicament for the prevention and / or treatment of mycobacteriosis. The respective configurations for such use can be the same as those described for the composition. In one embodiment, the medicament is preferably administered intramuscularly or subcutaneously 1 to 4 times at intervals of one week or more, one month or more, or two to three months, or 1 to three times at intervals of one to three months.

[0076] The present invention will be described in more detail below. However, the present invention is not limited to the following embodiments. Note that "QS" is an abbreviation for quantum sufficient, meaning sufficient quantity.

[0077] Examples 1-21 and Comparative Example 1: A vehicle solution was prepared by dissolving sodium carboxymethylcellulose (Aqualon CMC 7L2P or Blanose CMC 7LP, 7LF) obtained from Ashland as a suspending agent (as shown in Table 1), optionally PEG3350 (POLYGLYKOL 3350 S) obtained from CLARIANT or PEG400 (Super Refined PEG400) obtained from CRODA as an isotonicity agent, sodium chloride or mannitol, and sodium dihydrogen phosphate monohydrate as a buffer in water (water for injection), and adjusting the pH to 7.0 with sodium hydroxide solution. The active ingredient, quabodepistat (OPC-167832), and the prepared vehicle solution were weighed into a vial and mixed with the weighed OPC-167832 to prepare a suspension. Furthermore, 2 g of 1.5 mm diameter zirconia beads per 1 mL of suspension were added to the vial, and a stir bar was inserted. The vial containing the stirring bar was stirred with a stirrer and subjected to bead milling (500 rpm). The milling time was varied depending on the target particle size. All operations after suspending the active ingredient in the vehicle solution were carried out at 10°C or below. The milled suspension was collected using a syringe needle with a pore size smaller than the φ1.5 mm zirconia beads (a syringe needle of 22 G or less) or an 80 μm nylon mesh filter to obtain the injectable formulations shown in Table 1.

[0078] The particle size of each of the obtained injectable formulations was measured by laser diffraction scattering using a measuring device, SALD-3100 (manufacturer: Shimadzu Corporation). Purified water was used as the solvent during measurement. The particle size measured while irradiating the SALD-3100's built-in ultrasound was defined as the primary particle size, and the particle size measured without ultrasound irradiation was defined as the secondary particle size.

[0079] Furthermore, the viscosity of some of the injection formulations was measured using a rheometer, Discovery Hybrid Rheometer (DHR)-2 (manufacturer: TA Instruments). The viscosity measurement conditions were as follows: Shear rate: 10 -3→1000 (1 / s) ・Measurement temperature: 25℃ ・Used a 40 mm flat plate ・Gap: 500 μm (40 mm flat plate)

[0080]

[0081] [Test Example 1] The average primary particle size and average secondary particle size of each prepared example were measured using SALD-3100. The results are shown in Table 2.

[0082]

[0083] As shown in Table 2, a difference was observed between the average primary particle size and the average secondary particle size, with the average secondary particle size being larger than the average primary particle size. This increase in average secondary particle size indicates that particle-particle interactions are at work, causing particles to aggregate. The average primary particle size and average secondary particle size in all Examples were suitable for maintaining blood concentrations for more than one month.

[0084] [Test Example 2] The viscosity profile of each of the prepared examples was measured using a rheometer, and the results are shown in Table 3, Figures 1 and 2.

[0085]

[0086] As shown in Table 3, the viscosity decreased with increasing shear rate, and all Examples exhibited thixotropy (shear thinning). Compared to the Comparative Examples, the Examples had superior fluidity, preventing a decrease in particle grindability and filling accuracy, and also preventing particle aggregation, sedimentation, and caking, resulting in good redispersibility. Furthermore, when PEG3350 or PEG400 was added to low-concentration sodium carboxymethylcellulose, as in Examples 15 to 21, a thickening effect was observed.

[0087] Test Example 3: Injectable formulations were prepared using the formulation of Example 4, with an average primary particle size of 2.5 μm and an average secondary particle size of 4.6 μm; injectable formulations using the formulation of Example 18, with an average primary particle size of 6.8 μm and an average secondary particle size of 9.3 μm; and injectable formulations using the formulation of Example 19, with an average primary particle size of 11.7 μm and an average secondary particle size of 12.6 μm. Each injection formulation was subcutaneously injected into the dorsal skin of male SD rats at a dose of 50 mg / kg. To evaluate the blood distribution of OPC-167832 after administration, blood samples were collected 0.083, 1, 3, 6, 9, 14, 21, 28, 42, 56, 70, and 84 days after administration, and serum OPC-167832 concentrations were measured. The results are shown in Figure 3. The blood concentration of OPC-167832 microparticles was dependent on their particle size, and serum drug concentrations were maintained up to 84 days after administration.

[0088] Test Example 4: Injectable formulations were prepared using the formulation of Example 4 with an average primary particle size of 2.5 μm and an average secondary particle size of 4.6 μm. Injectable formulations were prepared using the formulation of Example 18 with an average primary particle size of 6.8 μm and an average secondary particle size of 9.3 μm. Injectable formulations were prepared using the formulation of Example 19 with an average primary particle size of 11.7 μm and an average secondary particle size of 12.6 μm. Each injection formulation was injected into the calf muscle of male SD rats at a dose of 50 mg / kg. To evaluate the blood distribution of OPC-167832 after administration, blood samples were collected 0.083, 1, 3, 6, 9, 14, 21, 28, 42, 56, 70, and 84 days after administration, and serum OPC-167832 concentrations were measured. The results are shown in Figure 4. The blood concentration of OPC-167832 microparticles was dependent on their particle size, and serum drug concentrations were maintained up to 84 days after administration.

[0089] Experimental Example 5: In vivo study of the therapeutic effect of quabodepistat LAI formulations. BALB / c mice were inoculated intratracheally with 698 CFU of Mycobacterium tuberculosis Kurono strain and left for 2 weeks to create an experimental mouse tuberculosis model. The LAI formulation of Example 4 was administered subcutaneously (SC) to the back of the mice once on the day of treatment initiation at 12 mg / kg or 120 mg / kg (shown as "QBS-LAI (12 mg / kg)" and "QBS-LAI (120 mg / kg)" in Figure 5). As a control, a suspension of jet-milled quabodepistat powder was prepared using 5% gum arabic solution and orally administered at 3.5 mg / kg for 28 consecutive days starting from the day of treatment initiation (shown as "QBS-JM (3.5 mg / kg)" in Figure 5). To confirm the reduction in lung viable bacterial counts, mice were euthanized by exsanguination from the inferior vena cava under anesthesia 3 days after the 28-day treatment, and the lungs were aseptically removed. The removed lungs were placed in a homogenizing tube containing 2 mL of sterile water and homogenized using a multi-bead shocker. Serial dilutions were then made. 0.1 mL of each dilution was spread onto 7H11 agar plates containing 0.4% activated charcoal and incubated in an incubator until colonies appeared. The post-treatment lung viable bacterial counts were calculated. As controls for evaluating the effect of reducing lung viable bacterial counts, the lung viable bacterial counts were measured in the same manner in the group at the start of treatment (labeled "Initial" in Figure 5 ) and in the group that received a single subcutaneous (SC) injection of a vehicle solution (combined with the formulation of Example 4, excluding quabodepistat) on the day of treatment (labeled "QBS-LAI-Vehicle" in Figure 5 ). As a result, as shown in Figure 5, the QBS-LAI (120 mg / kg) group showed a slightly higher reduction in lung viable bacterial counts than the QBS-JM (3.5 mg / kg) group, while the QBS-LAI (12 mg / kg) group had a therapeutic effect similar to that of the QBS-JM (3.5 mg / kg) group. All quabodepistat-administered groups showed a 1.3 to 2.4 Log reduction in lung viable bacterial counts compared to the Initial and QBS-LAI-Vehicle groups.Furthermore, although the dose of QBS-LAI (12 mg / kg) was approximately one-eighth of the total dose of QBS-JM (3.5 mg / kg) administered for 28 consecutive days, a reduction of approximately 1.3 Log was observed in the lung viable bacterial count compared to the initial group. Subcutaneous administration of the LAI formulation of OPC-167832 is expected to produce therapeutic effects comparable to those of oral administration for 28 consecutive days with a single treatment.

[0090] Examples 21-23: Carmellose sodium and PEG3350 as suspending agents, sodium chloride as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer, shown in Table 4, were dissolved in water (water for injection) and the pH was adjusted to 7.0 with sodium hydroxide solution to prepare a vehicle solution. The active ingredient, quabodepistat (OPC-167832), and the vehicle solution were weighed and mixed into a vial to prepare a suspension. Furthermore, 2 g of φ1.5 mm zirconia beads per 1 mL of suspension were added to the vial, and a stir bar was inserted. The vial containing the stir bar was stirred with a stirrer and milled using a bead mill (500 rpm). The milling time was adjusted depending on the target particle size. All operations after suspending the active ingredient in the vehicle solution were performed at 10°C or below. The milled suspension was collected using a syringe needle with a smaller pore size than the φ1.5 mm zirconia beads (22 G or smaller), to obtain the injectable formulations shown in Table 4. Each injection formulation was filled into a vial (3.5 mL), which was then stoppered and sealed with an aluminum cap, and then irradiated with gamma rays at 25-35 kGy.

[0091]

[0092] Test Example 6 The average primary particle size and average secondary particle size of each prepared example were measured using SALD-3100. The results are shown in Table 5.

[0093]

[0094] Test Example 7: Local Irritation Test of OPC-167832 LAI Formulations. Male Kbl / JW rabbits were manually restrained and injected subcutaneously or intramuscularly with a 23G needle at a dose of 15 mg / kg (OPC-167832), 0.425% acetic acid and 1.7% acetic acid (positive control), and saline (negative control) at 0.4 mL / kg. Thiamin (15 mg / kg) was then injected intramuscularly or subcutaneously using a 23G needle. On days 7 and 14 after administration, the rabbits were anesthetized by exsanguination from the abdominal aorta under anesthesia with 2.5% thiopental sodium in water (2 mL / kg) administered intravenously through the auricular vein. The subcutaneous or femoral injection sites (skin and subcutaneous tissue) were then excised, and the excised subcutaneous tissue and muscle were fixed in 10% neutral buffered formalin. After embedding in paraffin according to standard procedures, HE-stained tissue specimens were prepared and subjected to histopathological examination. Local irritation at the injection site was evaluated using the average value of three rabbits.

[0095] Grade of findings (score). -: None (1), ±: slight (2), +: mild (3), 2+: moderate (4), 3+: marked (5).

[0096] Grade of findings (score). -: None (1), ±: slight (2), +: mild (3), 2+: moderate (4), 3+: marked (5).

[0097] Table 6 shows subcutaneous retention and subcutaneous irritation, and Table 7 shows intramuscular retention and muscle irritation. Visual observation at autopsy revealed that test-formulation-like substances remained in Examples 21-23 7 days after administration and, in some cases, 14 days after administration, whereas the control substance without OPC-167832 showed no test-formulation-like substances remaining 7 or 14 days after administration. Histopathological examination revealed that Examples 21-23 showed weaker necrosis, partial necrosis / repair reactions, and fibrosis than the positive control substances 0.425% acetic acid and 1.7% acetic acid, and the irritation was within an acceptable range. Furthermore, immune responses such as foam cell aggregates and mononuclear cell infiltration were observed in Examples 21-23, but the irritation in all cases was within an acceptable range.

[0098] Test Example 8 Dog PK Study of OPC-167832 LAI Formulation and Post-Test Histopathological Examination Examples 21 and 22 were dispensed into disposable syringes at a dose of 25 mg / kg of OPC-167832, and male dogs were restrained manually and injected subcutaneously into the back using a 23G needle. Blood samples were collected at 2 and 6 hours after administration and at 1, 3, 6, 9, 14, 21, 28, 35, 42, and 56 days after administration, for a total of 12 time points. After the animals were restrained and the blood collection site was disinfected with rubbing alcohol, approximately 2 mL of blood was collected from the cephalic vein using a heparin vacuum blood collection tube (Veneject® II vacuum blood collection tube, Terumo Corporation). After all blood samples were collected, the animals were euthanized by exsanguination via the carotid artery under anesthesia with 25 mg / mL / kg thiopental sodium administered intravenously through the cephalic vein. The subcutaneous injection sites (skin and subcutaneous tissue) were then excised and fixed in 20% neutral buffered formalin. Paraffin-embedded tissue samples were prepared and HE-stained. Histopathological examination evaluated the injection sites using the average of three animals. Plasma concentrations of OPC-167832 were measured using LC-MS / MS. As shown in Figure 6, blood concentrations of OPC-167832 microparticles were dependent on their particle size, and plasma OPC-167832 concentrations were sustained for up to 56 days after injection.

[0099] Grade of findings (score). -: None (1), ±: slight (2), +: mild (3), 2+: moderate (4), 3+: marked (5).

[0100] As shown in Table 8, the histopathological examination after administration of Examples 21 and 22 did not reveal any necrosis, partial necrosis / repair reaction, or fibrosis suggestive of subcutaneous damage, but only an immune reaction, which was an acceptable level of irritation.

[0101] Examples 24-26: Carmellose sodium as a suspending agent, sodium chloride as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer (shown in Table 9) were dissolved in water (water for injection) and the pH was adjusted to 7.0 with sodium hydroxide solution to prepare a vehicle solution. OPC-167832 and the vehicle solution were weighed and mixed in a beaker. Using a DYNO-MILL MULTI LAB (Willy A. Bachofen AG) equipped with an agitator disc and a 600 mL grinding container, 1.5 mm diameter zirconia beads were placed in the grinding container to achieve an 80% filling rate. The peripheral speed was set to 10-14 m / s and the flow rate to 85-150 mL / min. After one pass through the bead mill, the suspension was collected. 3.5 mL of the injection formulation was filled into a vial, stoppered, and sealed with an aluminum cap. The vial was then subjected to gamma irradiation at 25-35 kGy. Then, the stability test in Table 10 was carried out.

[0102]

[0103] Test Example 9: The samples of Examples 24 to 26 were stored at 40°C and 50°C for one month to evaluate their stability. In the stability test, particle size and viscosity were measured using an average value of n = 3. Crystal form was also measured using a multipurpose X-ray diffractometer, Empyrean (Malvern Panalytical). In addition, samples not irradiated with gamma rays were also evaluated in the stability test.

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110] The stability of the injectable formulation was evaluated after storage at 40°C and 50°C for one month, and it was found to be stable, with no change in particle size or viscosity. It was also found that the crystalline form in the injectable formulation did not change from the drug substance when subjected to bead milling or gamma-ray irradiation.

[0111] Example 27: A vehicle solution was prepared by dissolving carmellose sodium as a suspending agent, sodium chloride as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer in water (water for injection) and adjusting the pH to 7.0 with sodium hydroxide solution. OPC-167832 and the vehicle solution were weighed and mixed in a beaker to prepare a suspension. This suspension was then wet-milled using a PANDA PLUS 1000 high-pressure homogenizer (GEA Niro Soavi). Using 500 mL of the suspension, the pressure was gradually increased by 100 bar, and the final pressure was 400-500 bar for 10 minutes. The suspension was then recovered. The average primary particle size and average secondary particle size of the recovered suspension were measured using an SALD-3100. The average primary particle size was 3.9 μm and the average secondary particle size was 4.1 μm.

[0112] Example 28: A vehicle solution was prepared by dissolving the suspending agents shown in Example 19, carmellose sodium and PEG3350, the tonicity agent sodium chloride, and the buffer sodium dihydrogen phosphate monohydrate in water (water for injection), and adjusting the pH to 7.0 with sodium hydroxide solution. OPC-167832 and the vehicle solution were weighed and mixed in a beaker to prepare a suspension. This suspension was then wet-milled using a PANDA PLUS 1000 high-pressure homogenizer (GEA Niro Soavi). Using 800 mL of the suspension, the pressure was gradually increased, ultimately milling at 200-300 bar for 20 minutes, after which the suspension was recovered. The average primary particle size and average secondary particle size of the recovered suspension were measured using an SALD-3100. The average primary particle size was 7.3 μm and the average secondary particle size was 10.6 μm.

Claims

1. A composition comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof, wherein the composition comprises a suspending agent and a dispersion medium, and the composition is in the form of a suspension of microparticles.

2. 0.1s -1 The viscosity at a shear rate of 0.2 to 200 Pa·s and 900 to 1000 s -1 2. The composition of claim 1, wherein the viscosity at any shear rate within the range is 0.1 Pa·s or less.

3. The composition according to claim 1, wherein the microparticles have an average primary particle size of 0.5 to 20 μm and an average secondary particle size of 1 to 30 μm.

4. The composition of claim 1, wherein the suspending agent comprises at least one selected from the group consisting of carboxymethylcellulose or a salt thereof and poloxamer.

5. The composition of claim 3, wherein the suspending agent further comprises polyethylene glycol.

6. The composition according to claim 1, wherein the concentration of the component in the composition is 100 to 500 mg / mL in terms of the free form.

7. The composition according to claim 1, wherein the concentration of the component in the composition is 200 to 500 mg / mL in terms of the free form.

8. The composition of claim 1, which is used for intramuscular or subcutaneous administration.

9. The composition of claim 1, administered at intervals of one month or more.

10. The composition of claim 1, which is an injectable formulation.

11. The composition described in claim 1, which is used for the prevention and / or treatment of mycobacteriosis.

12. A pre-filled syringe containing the composition of any one of claims 1 to 11.

13. A method for producing the composition according to claim 1, comprising: step 1 of mixing the components, a suspending agent, and a dispersion medium; step 2 of wet-milling the suspension obtained by the mixing; and step 3 of recovering the suspension obtained by the wet-milling.

14. The method according to claim 13, wherein the wet milling is wet milling using a bead mill or a high-pressure homogenizer.

15. A method for producing the composition of claim 1, comprising: step 1: dry-milling the components; step 2: mixing the dry-milled components, a suspending agent, and a dispersion medium; and step 3: recovering the suspension obtained by the mixing.

16. The method according to claim 15, wherein the dry milling is dry milling using a hammer mill, a jet mill, or a pin mill.

17. The method of any one of claims 13 to 16, further comprising step 4 of sterilizing the recovered suspension by radiation.

18. A method for preventing and / or treating mycobacteriosis, comprising administering intramuscularly or subcutaneously at intervals of one week or more to a subject in need of prevention and / or treatment of mycobacteriosis an effective amount of a composition in the form of a suspension of microparticles containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof.

19. The method of claim 18, wherein said administering comprises administering an effective amount of said composition intramuscularly or subcutaneously to said subject at intervals of one month or more.

20. The method of claim 18, wherein said administering comprises administering an effective amount of said composition to said subject intramuscularly or subcutaneously 1 to 4 times at intervals of 2 to 3 months.

21. The method of any one of claims 18 to 20, wherein the mycobacterial disease is tuberculosis.

22. A method for preventing and / or treating latent tuberculosis, comprising administering intramuscularly or subcutaneously 1 to 3 times at intervals of 1 to 3 months to a subject in need of prevention and / or treatment of latent tuberculosis an effective amount of a composition in the form of a suspension of microparticles comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof.