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 submicron particles.

[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 submicron particles, 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 submicron particles 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 is in the form of a suspension of submicron particles. [Item 2] The composition according to Item 1, wherein the submicron particles have an average particle size of 500 nm or less. [Item 3] The composition according to Item 1 or 2, wherein the submicron particles have a polydispersity index of 0.5 or less. [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 poloxamer, D-α-tocopherol polyethylene glycol succinate, and polyoxyethylene sorbitan fatty acid ester. [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 in terms of 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, which is used for intramuscular or subcutaneous administration. [Item 9] The composition according to any one of Items 1 to 8, which is administered at intervals of one week or more (or two weeks 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 of mixing the ingredients, a suspending agent, and a dispersion medium; Step 2 of wet-pulverizing the suspension obtained by the mixing; and Step 3 of recovering the suspension obtained by the wet-pulverization. [Item 14] The method according to Item 13, wherein the wet milling is wet milling using a bead mill. [Item 15] The method according to Item 13 or 14, further comprising step 4 of sterilizing the recovered suspension by radiation.[Item 16] A method for preventing and / or treating mycobacteriosis, comprising intramuscularly or subcutaneously administering an effective amount of a composition in the form of a suspension of submicron particles 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 at intervals of one week or more. [Item 17] The method of Item 16, wherein the administration comprises intramuscularly or subcutaneously administering an effective amount of the composition to the subject at intervals of one month or more. [Item 18] The method of Item 16 or 17, wherein the administration comprises intramuscularly or subcutaneously administering an effective amount of the composition to the subject 1 to 6 times at intervals of one to two months. [Item 19] The method of any of Items 16 to 18, wherein the mycobacteriosis is tuberculosis. [Item 20] A method for preventing and / or treating latent tuberculosis, comprising administering intramuscularly or subcutaneously one to three times at intervals of one to two 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 submicron particles containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof. [Item 21] A method for preventing and / or treating mycobacteriosis, comprising administering an effective amount of the composition according to any one of Items 1 to 10 and 11-4 to a subject in need of prevention and / or treatment of mycobacteriosis. [Item 22] The method according to Item 21, wherein the mycobacteriosis is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 23] 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 24] The method of Item 21, wherein the mycobacterial disease is tuberculosis. [Item 25] 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 26] The use of Item 25, wherein the mycobacterial disease is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 27] 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 28] The use according to Item 25 or 26, wherein the mycobacterial disease is an infection caused by Mycobacterium smegmatis, or Mycobacterium aurum. [Item 29] The use according to any of Items 25 to 28, wherein the medicament is administered intramuscularly or subcutaneously 1 to 6 times at intervals of one week or more, one month or more, one to two months, or one to three times at intervals of one to two months.

[0007] The present invention provides a composition in the form of a suspension of submicron particles useful as a composition containing at least one selected from quabodepistat, its salts and cocrystals, and solvates thereof. The composition may have the following advantages, for example: Rapid onset of action and prolonged duration of action (e.g., rapid achievement and sustained attainment of effective blood concentrations), allowing administration at intervals of one week or more (particularly two weeks or more), contributing to improved adherence, improved success rates in treatment of mycobacteriosis (including tuberculosis), and suppression of the development of resistant bacteria. It is also useful for the treatment of latent mycobacteriosis (particularly latent tuberculosis) and the prevention of high-risk mycobacteriosis. Highly concentrated suspensions allow for intramuscular or subcutaneous administration of an effective therapeutic dose. Submicron particles exhibit excellent long-term storage stability without settling. Minimal irritation upon administration. Small, easy-to-use formulations are possible.

[0008] Figure 1 shows the blood concentration profile when a formulation of Example 4 was administered subcutaneously (SC) to rats at a dose of 50 mg / kg. Figure 2 shows the blood concentration profile when a formulation of Example 18 was administered intramuscularly (IM) to rats at a dose of 50 mg / kg. Figure 3 shows the blood concentration profile when a formulation of Example 19 was administered subcutaneously (SC) to dogs at a dose of 25 mg / kg. Figure 4 shows the inhibitory effect of administering a formulation of Example 19 in a single dose or in two divided doses to an experimental mouse tuberculosis model on the increase or reduction of viable bacterial counts in the lungs.

[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 polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, D-α-tocopherol polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol (also known as "macrogol"), hydroxypropyl cellulose, polyvinylpyrrolidone, and dioctyl sodium sulfosuccinate (DOSS).

[0031] Poloxamers typically have the formula: HO-[CH ２ CH ２ O]x-[CH(CH ３ )CH ２ O]y-[CH ２ CH ２O]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.

[0032] Examples of D-α-tocopherol polyethylene glycol (PEG) succinate esters include D-α-tocopherol PEG1000 succinate esters.

[0033] Polyoxyethylene sorbitan fatty acid esters are generally represented by the following formula: where a+b+c+d is about 20 (e.g., 15-25), and R is C 11－17 Alkyl group or C 11－17 It is an alkenyl group.

[0034] Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, and mixtures thereof. In one embodiment, the suspending agent preferably contains polysorbate 20.

[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 one type alone or a combination of two or more types. In one embodiment, when the suspending agent contains at least one selected from the group consisting of poloxamer, D-α-tocopherol polyethylene glycol succinate, and polyoxyethylene sorbitan fatty acid ester as a first suspending agent, it is preferred to contain PEG as a second suspending agent in order to adjust the viscosity to a desired level.

[0037] 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.

[0038] When the first suspending agent contains poloxamer 338, it is preferable that the first suspending agent is 20 mg / mL or more and the second suspending agent is 5 mg / mL or more. It is also preferable that the first suspending agent is 25 mg / mL or more and the second suspending agent is 0 mg / mL or more. When the first suspending agent contains poloxamer 188, it is preferable that the first suspending agent is 50 mg / mL or more and the second suspending agent is 20 mg / mL or more. When the first suspending agent contains D-α-tocopherol polyethylene glycol succinate, it is preferable that the first suspending agent is 50 mg / mL or more and the second suspending agent is 0 mg / mL or more. When the first suspending agent contains polysorbate 20, it is preferable that the first suspending agent is 30 mg / mL or more and the second suspending agent is 30 mg / mL or more.

[0039] The concentration of the suspending agent in the composition is, for example, 10 mg / mL or more, preferably 15 mg / mL or more, and more preferably 20 mg / mL or more. The concentration of the suspending agent in the composition is, for example, 150 mg / mL or less, preferably 120 mg / mL or less, and more preferably 100 mg / mL or less. The concentration of the suspending agent in the composition is, for example, 10 to 150 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 free form).

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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, and glycerin. The concentration of the isotonicity agent in the composition is, for example, 1 to 50 mg / mL, and preferably 5 to 40 mg / mL.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] The composition is in the form of a suspension of submicron particles. The suspension is preferably an aqueous suspension. The submicron particles contain at least an active ingredient. The submicron particles may contain a suspending agent on their surface or the like.

[0048] The average particle size of the submicron particles is, for example, 500 nm or less, preferably 400 nm or less, and more preferably 300 nm or less. The average particle size of the submicron particles may be, for example, 10 nm or more, 20 nm or more, 30 nm or more, 40 nm or more, 50 nm or more, 60 nm or more, 70 nm or more, 80 nm or more, 90 nm or more, or 100 nm or more. The average particle size of the submicron particles is, for example, 10 to 500 nm, 50 to 400 nm, or 100 to 300 nm. The average particle size of the submicron particles may be 300 nm or more, for example, 300 to 500 nm. Submicron particles with an average particle size of 100 nm or less may also be referred to as nanoparticles. This average particle size range is preferable in terms of rapid increase in blood concentration, rapid onset of action, and long-lasting effect.

[0049] The polydispersity index of the submicron particles is, for example, 0.5 or less, preferably 0.45 or less, and more preferably 0.4 or less. The polydispersity index of the submicron particles may be, for example, 0.01 or more, 0.05 or more, or 0.1 or more. The polydispersity index of the submicron particles is, for example, 0.01 to 0.5.

[0050] The average particle size and polydispersity index can be measured by dynamic light scattering using a measurement sample diluted with water at a desired dilution ratio (for example, 10 times). For measuring the average particle size by dynamic light scattering, for example, ELSZneo (manufacturer: Otsuka Electronics Co., Ltd.) can be used.

[0051] The composition may exhibit a viscosity that does not change (or does not substantially change) with shear rate, i.e., Newtonian, or a viscosity that decreases with increasing shear rate, i.e., thixotropic (shear thinning).

[0052] When the average particle size of the submicron particles is 300 nm or more, the composition preferably exhibits thixotropy, more preferably satisfies the following (A) and (B), and even more preferably satisfies the following (A), (B), and (C): (A) The composition has a 0.1s -1 The viscosity (VL) at a shear rate of 900 to 1000 s of the composition is, for example, 10 Pa·s or less, preferably 8 Pa·s or less, and more preferably 5 Pa·s or less, from the viewpoint of, for example, the resistance value during injection (slidability) and manufacturability. The viscosity VL of the composition is, for example, 0.005 Pa·s or more, preferably 0.01 Pa·s or more. The viscosity VL of the composition is, for example, 0.005 to 10 Pa·s. (B) The viscosity VL of the composition at a shear rate of 900 to 1000 s of the composition is, for example, 0.005 to 10 Pa·s. -1 Any value within the range (e.g. 900s -1 or 1000s -1 The viscosity at a shear rate (VH) of the composition is, for example, 0.5 Pa·s or less, preferably 0.2 Pa·s or less, more preferably 0.15 Pa·s or less, and may be 0.1 Pa·s or less. 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 0.5 Pa·s. The viscosity VH of the composition is, for example, 900 to 1000 s -1The viscosity may be the viscosity at which no change in viscosity is observed even when the shear rate is changed within this range. (C) The viscosity ratio VL / VH of the composition is, for example, 1.1 or more, preferably 2 or more, more preferably 5 or more, and even more preferably 10 or more. 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, allowing for reduced administration frequency. The composition is administered, for example, at intervals of one week or more, two weeks or more, three weeks or more, four weeks or more, or one month or more. The longer the administration interval, the more preferable it is. There is no particular upper limit, but it may be, for example, two months, three months, four months, five months, or six months. Administration at such intervals is preferred from the viewpoint of patient compliance. The administration period (or treatment period) may be, for example, six months or less. In one embodiment, the composition is preferably administered subcutaneously no more than once a month or once every two months. In another embodiment, the composition is preferably administered intramuscularly no more than once every two months or once every three months. The composition may also be administered in combination with a composition in the form of a microparticle suspension containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof, a suspending agent, and a dispersion medium. Because the LAI formulation acts rapidly, it can be administered in combination with other LAI formulations (e.g., formulations that have a long-lasting effect but a slower 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 viewpoint of suppressing particle aggregation and / or reducing the viscosity of the composition, sterilization is preferably performed by radiation sterilization. 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 is preferably prepared by a wet milling method. Examples of the wet milling method include wet ball milling, high-pressure homogenization, high-shear homogenization, and bead mills (e.g., Dyno-Mill). In addition to the milling methods, other low- and high-energy mills (e.g., roller mills) can also be used. Other preparation methods include controlled crystallization.

[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, wet pulverization is preferably performed using a bead mill or a high-pressure homogenizer, and more preferably using a bead mill. 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 a batch method, a continuous (pass) method, or a circulation method. 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 the like. The method of using a high-pressure homogenizer is also not particularly limited. The processing pressure (or final pressure) is, for example, 2000 bar or more, preferably 2000 to 4000 bar, and more preferably 2000 to 3000 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] 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 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.

[0069] 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).

[0070] 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 suspension of submicron particles 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 6 times at intervals of at least one week, preferably at intervals of at least one month, and more preferably at intervals of 1 to 2 months. Furthermore, the present invention encompasses a method for preventing and / or treating latent tuberculosis, comprising administering intramuscularly or subcutaneously 1 to 3 times at intervals of 1 to 2 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 submicron particles comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof.

[0071] 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 6 times at intervals of one week or more, one month or more, one to two months, or one to three times at intervals of one to two months.

[0072] 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.

[0073] Examples 1-18 and Comparative Examples 1-2: Poloxamer 338 (Kolliphore P338) obtained from BASF, poloxamer 188 (Kolliphore P188) obtained from BASF, d-α-tocopherol polyethylene glycol (PEG) 1000 succinate (TPGS) obtained from Sigma-Aldrich, or polysorbate 20, optionally PEG 3350 (POLYGLYKOL 3350 S) obtained from CLARIANT, and / or PEG 400 (Super Refined PEG 400) obtained from CRODA, as the suspending agent shown in Table 1. Mannitol was used as an isotonicity agent, and sodium dihydrogen phosphate monohydrate was used as a buffer. The vehicle solution was then dissolved in water (water for injection) and adjusted to pH 7.0 with sodium hydroxide solution. The active ingredient quabodepistat (OPC-167832) and the vehicle solution were weighed into vials and mixed to prepare a suspension. Furthermore, 3 g of 0.2 mm diameter zirconia beads per 1 mL of suspension was added to the vial, and a stir bar was placed inside. The vial containing the stir bar was stirred with a stirrer and subjected to a bead mill (1500 rpm, 24 hours). 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 that of the 0.2 mm diameter zirconia beads (a syringe needle of 29 G or less) or an 80 μm nylon mesh filter, and the injectable formulations shown in Table 1 were obtained.

[0074] The resulting injectable formulations were diluted 10-fold with water for injection, and the particle size of the diluted solution was measured using an ELSZneo (manufacturer: Otsuka Electronics Co., Ltd.). The particle sizes in Table 2 were measured using dynamic light scattering and are shown as scattering intensity. In addition, when the ELSZneo measurement results indicated microparticles, the particle size was measured using a SALD-3100 (manufacturer: Shimadzu Corporation) using laser diffraction scattering. Purified water was used as the solvent during measurement. The particle size was measured while irradiating the SALD-3100's built-in ultrasound.

[0075] 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°C Use a 40 mm cone plate or a 40 mm flat plate Gap: 50 μm (40 mm cone plate) or 500 μm (40 mm flat plate)

[0076]

[0077] [Test Example 1] The average particle size and polydispersity index of each example were measured using ELSZneo. The results are shown in Table 2.

[0078]

[0079] As shown in Table 2, suspensions of less than 500 nm could be prepared in all Examples, whereas homogeneous suspensions could not be prepared in Comparative Examples.

[0080] Test Example 2 The viscosities of Examples 1 to 6, 8, and 9 were measured using a rheometer. The results are shown in Table 3.

[0081]

[0082] As shown in Table 3, 0.1 s -1 It was presumed that the viscosity at low shear rates was reduced in the formulations to which PEG was added (Examples 2, 4, 6, 8, and 9), resulting in reduced sliding properties and excellent manufacturability.

[0083] Test Example 3: An injectable formulation with an average particle size of 125.6 nm was prepared using the formulation of Example 4, and the injectable formulation was subcutaneously injected into the dorsal region 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 by LC-MS / MS. The results are shown in Figure 1. The peak blood concentration of OPC-167832 was reached 0.083 days after administration, and serum drug concentrations were maintained for more than 21 days.

[0084] Test Example 4: An injectable formulation with an average particle size of 293.8 nm, prepared as in Example 18, was injected into the calf muscle of male 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 by LC-MS / MS. The results are shown in Figure 2. The peak blood concentration of OPC-167832 was reached 6 days after administration, and serum drug concentrations were maintained for more than 42 days.

[0085] Example 19 and Comparative Example 3: Poloxamer 338 and PEG 3350 as suspending agents, mannitol as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer (see 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, 3 g of 0.2 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 subjected to a bead milling process (1500 rpm, 24 hours). 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 0.2 mm zirconia beads (29 G or smaller) or an 80 μm nylon mesh filter to obtain Example 19 shown in Table 4. Comparative Example 3 was prepared by dissolving the additive in water for injection and adjusting the pH to 7.0 with sodium hydroxide solution. 3.5 mL of each of Example 19 and Comparative Example 3 was filled into vials, which were then stoppered and sealed with aluminum caps. The vials were then irradiated with gamma rays at 25-35 kGy.

[0086]

[0087] [Test Example 5] The average particle size and polydispersity index of each example were measured using ELSZneo. The results are shown in Table 5.

[0088]

[0089] Test Example 6: Local Irritation Test of OPC-167832 LAI Formulations The formulation of Example 19 was injected subcutaneously into manually restrained rabbits at a dose of 15 mg / kg of OPC-167832 using a 23G injection needle. Comparative Example 3, 0.425% acetic acid aqueous solution as a positive control, 1.7% acetic acid aqueous solution as a positive control, and physiological saline as a negative control were each collected in disposable syringes at 0.4 mL / kg, and male Kbl / JW rabbits were manually restrained and injected subcutaneously using a 23G injection needle. On days 7 and 14 after administration, the rabbits were anesthetized by exsanguination from the abdominal aorta under anesthesia with a 2.5% thiopental sodium aqueous solution (2 mL / kg) administered intravenously through the auricular vein. The subcutaneous injection site (skin and subcutaneous tissue) was then excised, and the excised subcutaneous tissue was fixed in 10% neutral buffered formalin. After embedding in paraffin according to the usual method, HE-stained tissue specimens were prepared and subjected to histopathological examination, and local irritation at the administration site was evaluated as the average value of three animals.

[0090] Grade of findings (score). -: None (1), ±: slight (2), +: mild (3), 2+: moderate (4), 3+: marked (5).

[0091] Table 6 shows the subcutaneous residual and subcutaneous irritation. Visual observation at autopsy revealed that test formulation-like substances remained in Example 19 7 and 14 days after administration, whereas the control substance without OPC-167832 did not. Histopathological examination revealed that Example 19 showed weaker necrosis, partial necrosis / repair reaction, and fibrosis than the positive control substances 0.425% acetic acid and 1.7% acetic acid, and all irritation was within the acceptable range. Furthermore, immune responses such as foam cell aggregates and mononuclear cell infiltration were observed in Example 19, but all irritation was within the acceptable range.

[0092] Test Example 7 Dog PK Study of OPC-167832 LAI Formulation and Post-Test Histopathological Examination Example 19 was dispensed into a disposable syringe at a dose of 25 mg / kg of OPC-167832, and male dogs were manually restrained and injected subcutaneously into the back using a 23G injection needle. Blood samples were collected at 2 and 6 hours after administration and 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, HE-stained tissue specimens were prepared according to standard procedures, and the injection sites were evaluated by histopathological examination, using the average of three animals. Plasma OPC-167832 concentrations were measured using LC-MS / MS. As shown in Figure 3, plasma OPC-167832 concentrations reached their peak 9 days after administration, and were maintained for more than one month in dogs.

[0093] Grade of findings (score). -: None (1), ±: slight (2), +: mild (3), 2+: moderate (4), 3+: marked (5).

[0094] As shown in Table 7, the histopathological examination after administration of Example 19 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.

[0095] Test Example 8: The injectable formulation of Example 19 was diluted 10-fold or 100-fold with vehicle solution to give OPC-167832. The diluted formulations were injected subcutaneously into the backs of female mice at doses of 6 and 20 mg / kg for the 100-fold diluted formulation, and 60 and 120 mg / kg for the 10-fold diluted formulation. To evaluate the blood distribution of OPC-167832 after administration, blood samples were collected from the tail vein 0.083, 1, 3, 7, 14, 21, and 28 days after administration, and the plasma OPC-167832 concentration was measured. The results are shown in Table 8. Blood concentrations were dose-dependent.

[0096]

[0097] Examples 20 and 21: Poloxamer 338 and PEG 3350 as suspending agents, mannitol as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer (see 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, 0.2 mm diameter zirconia beads were placed in the grinding container to achieve an 80% filling rate. The peripheral speed was set to 10 m / s and the flow rate to 50 mL / min. The suspension was collected by bead milling. 3.5 mL of the injection formulation was filled into a vial, stoppered, and sealed with an aluminum cap to obtain Example 20. Example 20 was subjected to gamma irradiation at 25-35 kGy to obtain Example 21.

[0098]

[0099] Test Example 9: The formulations of Examples 20 and 21 were stored at 40°C for 1 month and 3 months, and their stability was evaluated. In the stability test, the average particle size and viscosity were measured using an average value of n = 3. The average particle size was measured using a Zetasizer (Malvern Panalytical). For the Zetasizer measurement, the vehicle solution was diluted 100 times with purified water, and the injection formulation was diluted to the optimal concentration. The viscosity was measured using a rheometer. The crystal form was also measured using a multipurpose X-ray diffractometer, Empyrean (Malvern Panalytical).

[0100]

[0101] As shown in Table 10, the stability of the injectable formulations of Examples 20 and 21 was evaluated after storage at 40°C for 1 month and 3 months. As a result, it was revealed that both formulations were stable, with no change in particle size or viscosity or particle sedimentation occurring after storage at 40°C for 1 month and 3 months. It was also revealed that the crystalline form in the injectable formulations did not change from the drug substance after bead milling or gamma-ray irradiation.

[0102] Test Example 10: In vivo experiment on the therapeutic effect of LAI submicron formulation of OPC-167832 An experimental mouse tuberculosis model was created by transtracheally inoculating 460 CFU of the Mycobacterium tuberculosis Kurono strain into BALB / c mice and allowing the mice to stand for 2 weeks. To this model, the LAI formulation of Example 19 was diluted to 4 mg / mL or 40 mg / mL with a vehicle solution excluding the active ingredient, and the drug solution was administered subcutaneously (SC) to the back of the mouse either once on the day of treatment initiation or in two divided doses on the day of treatment initiation and 2 weeks after the initiation of treatment, so that the total dose was 12 mg / kg, 40 mg / kg, or 120 mg / kg (indicated as "QBS-LAI 12 mg / kg*1," "QBS-LAI 40 mg / kg*1," "QBS-LAI 120 mg / kg*1," "QBS-LAI 6 mg / kg*2," "QBS-LAI 20 mg / kg*2," and "QBS-LAI 60 mg / kg*2" in Figure 4). As a control, a suspension of jet-milled quabodepistat powder was prepared in 5% gum arabic solution and administered orally (PO) at 3.5 mg / kg for 28 consecutive days starting from the start of treatment (shown as "QBS-PO 3.5 mg / kg*28" in Figure 4). To confirm the reduction in lung viable bacterial counts, mice were euthanized by exsanguination via the inferior vena cava under anesthesia the day after 28 days of treatment, and the lungs were aseptically removed. The excised 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, and 0.1 mL of each dilution was spread onto 7H11 agar plates containing 0.4% activated charcoal. The plates were incubated in an incubator until colonies appeared, and the post-treatment lung viable bacterial counts were calculated. As controls for evaluating the effect of reducing the number of viable bacteria in the lungs, the number of viable bacteria in the lungs of the group at the start of treatment (shown as "Initial" in Figure 4), the group receiving a subcutaneous (SC) injection of a vehicle solution excluding the active ingredient of Example 19 twice, on the day of the start of treatment and two weeks after the start of treatment (shown as "LAI-Vehicle*2" in Figure 4), and the group receiving oral administration of 5% gum arabic solution for 28 days from the day of the start of treatment (shown as "PO-Vehicle*28" in Figure 4), were each measured using the same method.As shown in Figure 4, the QBS-LAI 6 mg / kg*2 and QBS-LAI 12 mg / kg*1 groups showed lung bacterial counts that were the same as or slightly lower than those of the initial group, demonstrating an inhibitory effect on the increase of lung bacterial counts. The other LAI treatment groups showed lower lung bacterial counts than the initial group, confirming their bactericidal effect. The QBS-LAI 60 mg / kg*2 group showed a stronger pharmacological effect than the QBS-PO 3.5 mg / kg*28 group. The QBS-LAI 40 mg / kg*1 group also showed a similar effect on reducing lung bacterial counts to the QBS-PO 3.5 mg / kg*28 group, while the QBS-LAI 120 mg / kg*1 group reduced lung bacterial counts more effectively than the QBS-PO 3.5 mg / kg*28 group. The QBS-LAI 120 mg / kg*1 group (single dose) and the QBS-LAI 60 mg / kg*2 group (two divided doses) showed similar effects in reducing the number of bacteria in the lungs. Subcutaneous administration of the QBS LAI submicron formulation in one or two treatments is expected to produce therapeutic effects comparable to or even greater than those of oral administration for 28 consecutive days.

Claims

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

2. The composition of claim 1, wherein the submicron particles have an average particle size of 500 nm or less.

3. The composition of claim 1, wherein the submicron particles have a polydispersity index of 0.5 or less.

4. The composition of claim 1, wherein the suspending agent comprises at least one selected from the group consisting of poloxamer, D-α-tocopherol polyethylene glycol succinate, and polyoxyethylene sorbitan fatty acid ester.

5. The composition of claim 4, 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 at least one week.

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, vial, or ampoule 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.

15. The method of claim 13 or 14, further comprising step 4 of sterilizing the recovered suspension by radiation.

16. 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 submicron particles containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof.

17. The method of claim 16, wherein said administering comprises administering an effective amount of said composition intramuscularly or subcutaneously to said subject at intervals of one month or more.

18. The method of claim 16, wherein said administering comprises administering to said subject an effective amount of said composition intramuscularly or subcutaneously 1 to 6 times at intervals of 1 to 2 months.

19. The method of any one of claims 16 to 18, wherein the mycobacterial disease is tuberculosis.

20. A method for preventing and / or treating latent tuberculosis, comprising administering intramuscularly or subcutaneously one to three times at intervals of one to two 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 submicron particles comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof.