WO2025183016A1 - Quabodepistat-containing composition - Google Patents

Abstract

Provided is a composition in the form of a suspension of microparticles, which is useful as a composition comprising quabodepistat, a salt thereof, or the like. Disclosed as one example of the composition is a composition comprising at least one selected from quabodepistat, a salt thereof, a cocrystal thereof, and solvates of these, wherein the composition contains a suspending agent and a dispersion medium and is in the form of a suspension of microparticles.

Description

Quabodepistat-containing composition

The present invention relates to a composition containing at least one selected from quabodepistat, its salts and cocrystals, and solvates thereof, which is in the form of a microparticle suspension.

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

International Publication No. 2016/031255

One of the problems that the present invention aims to solve is to provide 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.

As a result of extensive research aimed at solving the above-mentioned problems, the inventors discovered a useful composition in the form of a microparticle suspension containing at least one selected from quabodepistat, its salts and cocrystals, and solvates thereof, and further research led to the completion of the present invention.

The present invention encompasses the embodiments described in the following sections.
[Section 1]
A composition comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof,
The composition comprises a suspending agent and a dispersion medium, the composition being in the form of a suspension of microparticles.
[Section 2]
Item 1. The composition according to item 1, wherein the viscosity at a shear rate of 0.1 ^s is 0.2 to 200 Pa·s, and the viscosity at any shear rate within the range of 900 to 1000 ^s is 0.1 Pa·s or less.
[Section 3]
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.
[Section 4]
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 poloxamer.
[Section 5]
Item 5. The composition according to item 4, wherein the suspending agent further comprises polyethylene glycol.
[Section 6]
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 free form.
[Section 7]
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 in terms of free form.
[Section 8]
Item 8. The composition according to any one of Items 1 to 7, which is administered intramuscularly or subcutaneously.
[Section 9]
The composition according to any one of Items 1 to 8, which is administered at intervals of one month or more.
[Section 10]
Item 10. The composition according to any one of Items 1 to 9, which is an injectable formulation.
[Section 11]
Item 11. The composition according to any one of Items 1 to 10, which is used for the prevention and/or treatment of mycobacteriosis.
[Section 11-1]
Item 12. The composition according to Item 11, wherein the mycobacterial disease is an infectious disease 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 chelonae, Mycobacterium Item 12. The composition according to Item 11, wherein the infection is caused by Mycobacterium smegmatis or Mycobacterium aurum.
[Section 11-3]
Item 12. The composition according to Item 11, wherein the mycobacterial disease is tuberculosis.
[Section 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.
[Section 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.
[Section 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,
Step 1 of mixing the ingredients, suspending agent, and dispersion medium;
Step 2: wet-pulverizing the suspension obtained by the mixing;
and step 3 recovering the suspension obtained by said wet milling.
[Section 14]
Item 14. The method according to Item 13, wherein the wet milling is wet milling using a bead mill or a high-pressure homogenizer.
[Section 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,
Step 1: dry-milling the ingredients;
Step 2: mixing the dry-milled components, a suspending agent, and a dispersion medium;
and step 3 recovering the suspension obtained by said mixing.
[Section 16]
Item 16. The method according to Item 15, wherein the dry milling is hammer mill, jet mill, or pin mill dry milling.
[Section 17]
Item 17. The method according to any one of Items 13 to 16, further comprising step 4 of sterilizing the recovered suspension by radiation.
[Section 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.
[Section 19]
Item 19. The method according to 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.
[Section 20]
Item 20. The method according to Item 18 or 19, wherein the administration comprises intramuscularly or subcutaneously administering an effective amount of the composition to the subject 1 to 4 times at intervals of 2 to 3 months.
[Section 21]
Item 21. The method according to any one of Items 18 to 20, wherein the mycobacterial disease is tuberculosis.
[Section 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 containing at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof.
[Section 23]
A method for preventing and/or treating mycobacteriosis, comprising administering an effective amount of the composition described in any one of Items 1 to 10 and 11-4 to a subject in need of prevention and/or treatment of mycobacteriosis.
[Section 24]
Item 24. The method according to Item 23, wherein the mycobacterial disease 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 25. The method according to Item 23 or 24, wherein the infection is caused by Mycobacterium smegmatis or Mycobacterium aurum.
[Section 26]
Item 24. The method of Item 23, wherein the mycobacterial disease is tuberculosis.
[Section 27]
Use of the composition according to any one of Items 1 to 10 and 11-4 for the manufacture of a medicament for the prevention and/or treatment of mycobacteriosis.
[Section 28]
Item 28. The use according to Item 27, wherein the mycobacterial disease is an infectious disease 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 29. The use according to Item 27 or 28, wherein the infection is caused by Mycobacterium smegmatis or Mycobacterium aurum.
[Section 30]
Item 28. The use according to Item 27, wherein the mycobacterial disease is tuberculosis.
[Section 31]
Item 31. The use according to any one of Items 27 to 30, wherein the medicament is administered intramuscularly or subcutaneously 1 to 4 times at intervals of 1 week or more, 1 month or more, 2 to 3 months, or 1 to 3 times at intervals of 1 to 3 months.

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 (especially one month or more), which improves adherence and contributes to improving the success rate of treatment for mycobacterial diseases (including tuberculosis) and suppressing the emergence of resistant bacteria.
-It is also useful for treating latent mycobacterial disease (especially latent tuberculosis) and preventing mycobacterial disease in high-risk groups.
- The microparticles do not caking and have excellent long-term storage stability.
- Less irritating when administered.
- It is possible to create small, easy-to-use formulations.

Figure 1 shows the viscosity profiles of Examples 1 to 5, which are suspensions of 300 mg/mL (30% (w/v)) Quabodepistat, and Comparative Example 1. Figure 2 shows the viscosity profiles of Examples 7-10, 15, and 16, which are suspensions of 400 mg/mL (40% (w/v)) Quabodepistat. FIG. 3 shows the blood concentration profiles of Examples 4, 18, or 19 in rats after subcutaneous (SC) injection at a dose of 50 mg/kg. FIG. 4 shows the blood concentration profiles of Examples 4, 18, or 19 after intramuscular (IM) injection in rats at a dose of 50 mg/kg. FIG. 5 shows the effect of reducing the number of viable bacteria in the lungs when the formulation of Example 4 was administered subcutaneously (SC) at a dose of 12 mg/kg or 120 mg/kg to a mouse tuberculosis infection model. 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.

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

All documents mentioned in this specification are incorporated herein by reference.

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

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, as described in Japanese Patent Application Laid-Open Nos. 2020-79206 and 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, in a powder X-ray diffraction pattern obtained using CuKα radiation as an X-ray source, 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°, 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°.

As used herein, "cocrystal" refers to a cocrystal of quabodepistat and a coformer.

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.

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

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.

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

The cocrystal may be a crystalline substance composed of quabodepistat and a coformer present in the same crystal lattice at any molar ratio. The cocrystal may exist in multiple crystalline forms (also known as "crystalline polymorphs").

In one embodiment, the coformer is a non-ionizable molecule capable of forming a crystal with quabodepistat. Examples of such non-ionizable molecules include organic acids, amino acids, amines, amides, vanillin, urea, pyridoxine, saccharin, and hydroquinone.

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 non-volatile organic acid, such as an organic acid that does not volatilize at room temperature (15°C to 25°C) and normal pressure. The non-volatile organic acid may also be a water-soluble organic acid.

The amino acid may be a natural amino acid or an unnatural amino acid. Examples of amino acids include proline, lysine, tyrosine, and histidine.

Amines include, for example, aliphatic amines such as meglumine and tromethamine; aromatic amines, etc.

Examples of amides include carboxylic acid amides such as nicotinamide.

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 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.

In the cocrystal, the amount of coformer per 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 coformer per 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 coformer per mole of quabodepistat may be, for example, 0.5 to 2.5 moles.

In yet another embodiment, the composition comprises a solvate of quabodepistat, a salt or cocrystal thereof, a suspending agent, and a dispersion medium.

The solvate may be a solvate formed by quabodepistat, the salt, or the cocrystal and solvent molecules in any molar ratio. Examples of such solvates include hydrates, ethanol solvates, and THF (tetrahydrofuran) 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, monohydrate, 1.5-hydrate, or dihydrate.

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

The concentration of the active ingredient in the composition is not particularly limited, as long as it is an effective concentration depending on the intended use of the composition. The concentration of the active ingredient in the composition, calculated as 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 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 perspective of maintaining good flow properties and prolonged action. The concentration of the active ingredient in the composition, calculated as 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.

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

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.

The average molecular weight of carboxymethylcellulose or its salts is, for example, 5,000 or more, preferably 10,000 or more. The average molecular weight of carboxymethylcellulose or its salts is, for example, 300,000 or less, preferably 250,000 or less. The average molecular weight of carboxymethylcellulose or its salts is, for example, 5,000 to 300,000, preferably 10,000 to 250,000.

The viscosity of a 2% (w/v) aqueous solution of carboxymethylcellulose or its salt 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).

Poloxamers are generally represented by the formula: HO-[ _CH2CH2O ]x-[CH( _CH3 ) _{CH2O ]} y-[ _CH2CH2O ]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. 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 contains poloxamer 338 and/or poloxamer 188.

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.

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, per 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, per 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, per 100 parts by mass of the first suspending agent.

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, first suspending agent, and 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 free form).

The dispersion medium contained in the composition is not particularly limited, so 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. It is preferable that the dispersion medium contains at least water. Examples of such dispersion mediums include water, physiological saline, and solvents containing water and an organic solvent. Examples of the organic solvent include those that are 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.

The dispersion medium is contained in an appropriate amount so that the content of the active ingredient, etc. 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. The amount may be, for example, the amount of composition in a container such as a prefilled syringe, vial, or ampoule.

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

Examples of isotonicity agents 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 composition does not need to contain an isotonicity agent, but if it does contain 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.

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; and carbonates such as sodium carbonate and sodium bicarbonate. 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.

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.

Examples of preservatives include benzoic acid or its salts (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), and benzyl alcohol. The composition may not contain a preservative, but if it does contain a preservative, 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.

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, etc.

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 period of time. The average primary particle size can be measured by laser diffraction scattering 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 period of time. The average secondary particle size can be measured by laser diffraction scattering under conditions of no ultrasonic irradiation. For example, the SALD-3100 or SALD-2300 (manufacturer: Shimadzu Corporation) can be used to measure the average particle size by laser diffraction scattering.

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

The composition preferably exhibits a property in which the viscosity decreases as the shear rate increases, i.e., thixotropy (shear thinning).

The viscosity (VL) of the composition at a shear rate of 0.1 s ^-1 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.

The viscosity (VH) of the composition at any shear rate within the range of 900 to 1000 s ^-1 (e.g., at 900 s ^-1 or 1000 s ^-1 ) is, for example, 0.1 Pa·s or less, preferably 0.05 Pa·s or less, for example, in terms of resistance (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. Note that the viscosity VH of the composition may be the viscosity at which no change in viscosity is observed even when the shear rate is changed within the range of 900 to 1000 s ^-1 .

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

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

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.

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.

Because the composition has a long-lasting effect (e.g., an effective blood concentration is maintained), 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. There is no upper limit, but for example, 2 months, 3 months, 4 months, 5 months, or 6 months. Administration at such a frequency is preferable from the standpoint of patient compliance. The administration period (or treatment period) of the composition can be, for example, 6 months, and it 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 frequently than once every two months or no more frequently 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.

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). The composition is also preferably administered at a daily dose of, for example, 10 to 20 mg, preferably 12 to 18 mg.

The composition is preferably administered so that the injection volume 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 volume 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 volume per administration (or per month) is, for example, 0.5 to 5 mL, 0.5 to 3 mL, or 1 to 2 mL.

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

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, non-tuberculous mycobacteria, etc. Examples of tuberculosis bacteria include Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium microti, etc. Examples of leprae bacteria include Mycobacterium leprae, etc. Examples of non-tuberculous 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.

The composition is preferably a sterile composition or a sterilized composition. Sterilization is preferably by radiation sterilization from the viewpoints of inhibiting particle aggregation and/or maintaining the thixotropy of the composition during long-term storage and preventing particle settling and caking. Examples of radiation sterilization include gamma ray sterilization, electron beam sterilization, and X-ray sterilization.

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 other drugs for preventing or treating mycobacteriosis in addition to the active ingredient, and may be administered as a single composition.

Wet milling techniques can be used to prepare the composition. Preferred wet milling techniques include wet ball milling, high pressure homogenization, high shear homogenization, and bead mills (e.g., Dyno Mill). In addition to the above milling techniques, 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, etc.

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

In Step 1, the order in which the components are mixed is not particularly limited. In one embodiment, Step 1 consists of 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.

In step 2, the wet milling is preferably wet milling using a bead mill or a high-pressure homogenizer. The bead milling method is not particularly limited. In one embodiment, step 2 is a step of adding beads to the suspension and stirring. The bead milling method may be batch, continuous (pass), or circulating. Examples of bead materials include zirconia, alumina, and glass. The bead diameter 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 adjusted appropriately by adjusting the bead size, the rotation speed (circumferential speed) and flow rate (flow velocity) during milling, the milling 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 per 1 L of suspension, preferably 5 to 30 minutes.

In step 3, the method for recovering the suspension obtained by wet milling is not particularly limited. When wet milling is performed using a bead mill, step 3 typically includes a step of removing the beads. In one embodiment, the step of removing the beads is preferably a step of separating and removing the beads using a separator (such as a gap or screen) at the bead mill outlet or by centrifuging 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, 22G or smaller) or a mesh filter (for example, 80 μm mesh).

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

In one embodiment, the composition can be produced by a method comprising, for example, step 1: dry-milling the active ingredient; step 2: mixing the dry-milled active ingredient, suspending agent, and dispersant; and step 3: recovering the suspension obtained by the mixing.

In step 1, the dry grinding is preferably performed using a hammer mill or a jet mill.

In Step 2, the order in which the components are mixed is not particularly limited. In one embodiment, Step 2 consists of 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.

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

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, typically 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.

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, etc. 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 ampoules. For example, the composition can be used as a prefilled syringe by filling it directly into a syringe. It is also preferable to perform the sterilization after filling the composition into the container (particularly a prefilled syringe, vial, or ampoules). Furthermore, the present invention also encompasses a kit containing the container (particularly a prefilled syringe, vial, or ampoules).

The present invention encompasses a method 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 of the method. The present invention encompasses a method 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, which comprises intramuscularly or subcutaneously administering 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, to a subject in need of prevention and/or treatment of latent tuberculosis 1 to 3 times at intervals of 1 to 3 months.

The present invention encompasses the use of the composition for the manufacture of a medicament for the prevention and/or treatment of mycobacteriosis. The respective components of the 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.

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

Examples 1 to 21 and Comparative Example 1
A vehicle solution was prepared by dissolving sodium carboxymethylcellulose (Aqualon CMC 7L2P or Blanose CMC 7LP, 7LF) from Ashland (as shown in Table 1) as a suspending agent, optionally PEG3350 (POLYGLYKOL 3350 S) from CLARIANT or PEG400 (Super Refined PEG400) from CRODA (as shown in Table 1), sodium chloride or mannitol as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer in water (water for injection). The pH was adjusted 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.

The particle size of each of the resulting injectable formulations was measured using the laser diffraction scattering method with a SALD-3100 (manufacturer: Shimadzu Corporation) as the measuring device. Purified water was used as the solvent during measurement. The particle size measured while irradiating the SALD-3100's built-in ultrasound was considered to be the primary particle size, and the particle size measured without ultrasound irradiation was considered to be the secondary particle size.

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℃
・Use a 40 mm flat plate ・Gap: 500 μm (40 mm flat plate)

[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.

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 inter-particle interactions are at work, causing particles to aggregate. The average primary particle size and average secondary particle size in all examples were appropriate for maintaining blood concentrations for more than one month.

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

As shown in Table 3, 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, while 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.

[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.

[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 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 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.

[Test 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 then incubated 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 at 12 mg/kg or 120 mg/kg on the first day of treatment (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 in 5% gum arabic solution and administered orally (PO) at 3.5 mg/kg daily for 28 days starting from the first day of treatment (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 shown in Figure 5, the QBS-LAI (120 mg/kg) group demonstrated a slightly greater reduction in lung viable bacterial counts than the QBS-JM (3.5 mg/kg) group, while the QBS-LAI (12 mg/kg) group demonstrated a therapeutic effect similar to that of the QBS-JM (3.5 mg/kg) group. All quabodepistat-treated groups demonstrated a 1.3-Log to 2.4-Log reduction in lung viable bacterial counts compared with the initial and QBS-LAI-Vehicle groups. Furthermore, although the QBS-LAI (12 mg/kg) group received approximately one-eighth the total dose of the 28-day QBS-JM (3.5 mg/kg) group, it still demonstrated a reduction in lung viable bacterial counts of approximately 1.3 Log compared with the initial group. Subcutaneous administration of the OPC-167832 LAI formulation is expected to produce therapeutic effects comparable to those of oral administration for 28 consecutive days.

Examples 21 to 23
The vehicle solution shown in Table 4 was prepared by dissolving carmellose sodium and PEG3350 as suspending agents, 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. 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.

[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.

[Test Example 7]
Local irritation testing of OPC-167832 LAI formulations. OPC-167832 (Examples 21-23) was administered at a dose of 15 mg/kg in disposable syringes. The positive control substances, 0.425% acetic acid and 1.7% acetic acid, and the negative control substance, saline, were injected subcutaneously or intramuscularly using a 23G needle into male Kbl/JW rabbits while they were manually restrained. On days 7 and 14 after administration, the rabbits were anesthetized by exsanguination via 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 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.

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

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

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 no test-formulation-like substances remained in the control substance not containing OPC-167832 7 days after administration or 14 days after administration. Histopathological examination revealed that Examples 21-23 showed weaker necrosis, partial necrosis/repair reaction, 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 reactions 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.

[Test Example 8]
Dog PK study of OPC-167832 LAI formulation and post-study 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 manually restrained 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 anesthetized by intravenous administration of 25 mg/mL/kg thiopental sodium via the carotid artery and euthanized. The subcutaneous injection site (skin and subcutaneous tissue) was then excised and fixed in 20% neutral buffered formalin. After embedding in paraffin according to standard procedures, HE-stained tissue specimens were prepared, and the injection site was evaluated by histopathological examination using the average value of three animals.
The plasma OPC-167832 concentrations of the collected blood samples were measured using LC-MS/MS. As shown in Figure 6, the blood concentration of OPC-167832 was dependent on the particle size of the microparticles, and the plasma OPC-167832 concentration was sustained up to 56 days after administration.

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

As shown in Table 8, histopathological examination after administration of Examples 21 and 22 revealed no necrosis, partial necrosis/repair reaction, or fibrosis suggestive of subcutaneous damage, and only an immune reaction was observed, making the irritation tolerable.

Examples 24 to 26
The vehicle solution shown in Table 9 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. 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 of the bead mill, the suspension was collected. 3.5 mL of the injection formulation was filled into vials, stoppered, and sealed with an aluminum cap. The vials were then irradiated with gamma rays at 25-35 kGy. The stability tests shown in Table 10 were then performed.

[Test Example 9]
The stability of Examples 24 to 26 was evaluated by storing them at 40°C and 50°C for one month. 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 that had not been irradiated with gamma rays were also evaluated in the stability test.

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 changes in particle size or viscosity. It was also found that the crystalline form in the injectable formulation did not change from the active pharmaceutical ingredient when exposed to bead milling or gamma rays.

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.

Example 28
A vehicle solution was prepared by dissolving carmellose sodium and PEG3350 as suspending agents, 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 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 (22)

A composition comprising at least one component selected from quabodepistat, its salts and cocrystals, and solvates thereof,
The composition comprises a suspending agent and a dispersion medium, the composition being in the form of a suspension of microparticles. 2. The composition of claim 1, wherein the viscosity at a shear rate of 0.1 ^s is 0.2 to 200 Pa s, and the viscosity at any shear rate within the range of 900 to 1000 ^s is 0.1 Pa s or less. The composition described in 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. 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. The composition of claim 3, wherein the suspending agent further comprises polyethylene glycol. The composition of claim 1, wherein the concentration of the component in the composition is 100 to 500 mg/mL in terms of the free form. The composition of claim 1, wherein the concentration of the component in the composition is 200 to 500 mg/mL in terms of the free form. The composition described in claim 1 is for intramuscular or subcutaneous administration. The composition of claim 1, administered at intervals of one month or more. The composition of claim 1 is an injectable formulation. The composition according to claim 1, which is used for the prevention and/or treatment of mycobacteriosis. A pre-filled syringe containing the composition described in any one of claims 1 to 11. 10. A method for producing the composition of claim 1, comprising:
Step 1 of mixing the ingredients, suspending agent, and dispersion medium;
Step 2: wet-pulverizing the suspension obtained by the mixing;
and step 3 recovering the suspension obtained by said wet milling. The method according to claim 13, wherein the wet milling is carried out using a bead mill or a high-pressure homogenizer. 10. A method for producing the composition of claim 1, comprising:
Step 1: dry-milling the ingredients;
Step 2: mixing the dry-milled components, a suspending agent, and a dispersion medium;
and step 3 recovering the suspension obtained by said mixing. The method of claim 15, wherein the dry milling is performed using a hammer mill, jet mill, or pin mill. The method of any one of claims 13 to 16, further comprising step 4 of sterilizing the recovered suspension by radiation. 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 microparticles 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. The method of claim 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. The method of claim 18, wherein the administration comprises administering an effective amount of the composition intramuscularly or subcutaneously to the subject 1 to 4 times at intervals of 2 to 3 months. The method of any one of claims 18 to 20, wherein the mycobacterial disease is tuberculosis. A method for preventing and/or treating latent tuberculosis, comprising administering 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, 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.