Delamanid-containing composition

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

Delamanid-containing compositions

[0001] The present invention relates to compositions comprising delamanid or a salt thereof, such as compositions in the form of a suspension of submicron particles.

[0002] Delamanid has the following formula: and has excellent bactericidal activity against Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis, and atypical mycobacteria (Patent Documents 1 to 3).

[0003] Delamanid is sold as DELTYBA® Tablets 50 mg, a tablet containing the free form of delamanid, to be taken orally twice daily (200 mg daily). It is believed to exert its antibacterial effect by inhibiting the biosynthesis of mycolic acids, which are specific to tuberculosis bacteria.

[0004] Patent Publication No. 2004-149527 International Publication No. 2005 / 042542 International Publication No. 2007 / 013477

[0005] Tuberculosis treatment involves combining multiple effective drugs to improve efficacy and prevent the emergence of drug-resistant bacteria. Treatment for multidrug-resistant tuberculosis, which uses delamanid, previously required 18 months or more of treatment, but in recent years, clinical trial results have been reported for regimens that allow treatment to be completed in 6 or 9 months. However, because this is still a long-term treatment, problems remain, including treatment failure due to poor adherence, such as missed doses, and the resulting emergence of drug-resistant bacteria.

[0006] Improving adherence is expected to improve the success rate of treatment, suppress the increase of resistant bacteria, and shorten the treatment period. To improve adherence, it is effective to provide a simple treatment method, and a dosage form with long intervals, such as one week or more or one month or more, is desirable. Inexpensive, small, lightweight, and easy to use devices may also be required.

[0007] Delamanid is a poorly soluble drug, and its suspensions tend to settle over time, causing caking, making redispersion difficult. If vigorous shaking is required for redispersion, this presents a problem for clinical convenience.

[0008] One of the problems that the present invention aims to solve is to provide a composition in the form of a suspension of submicron particles that is useful as a composition containing delamanid or a salt thereof.

[0009] As a result of intensive research conducted by the present inventors to solve the above problems, they discovered a composition in the form of a suspension of submicron particles that is useful as a composition containing delamanid or a salt thereof, and further research led to the completion of the present invention.

[0010] The present invention encompasses the following embodiments. [Item 1] A composition comprising delamanid or a salt thereof, the composition comprising a suspending agent and a dispersion medium and in the form of a suspension of submicron particles, the suspending agent comprising at least one selected from the group consisting of poloxamer and D-α-tocopherol polyethylene glycol succinate. [Item 2] The composition according to Item 1, wherein the average particle size of the submicron particles is 1,000 nm or less. [Item 3] The composition according to Item 1 or 2, wherein the polydispersity index of the submicron particles is 0.5 or less. [Item 4] The composition according to any of Items 1 to 3, wherein the poloxamer is poloxamer 338. [Item 5] The composition according to any of Items 1 to 4, wherein the suspending agent further comprises polyethylene glycol. [Item 6] The composition according to Item 5, wherein the average molecular weight of the polyethylene glycol is 1,000 or more. [Item 7] The composition according to any of Items 1 to 6, wherein the concentration of delamanid or a salt thereof in the composition is 100 to 500 mg / mL, calculated as the free form. [Item 8] The composition according to any one of Items 1 to 7, wherein the concentration of delamanid or a salt thereof in the composition is 200 to 500 mg / mL calculated as the free form. [Item 9] The composition according to any one of Items 1 to 8, which is used for intramuscular or subcutaneous administration. [Item 10] The composition according to any one of Items 1 to 9, which is administered at intervals of one week or more, two weeks or more, or one month or more. [Item 11] The composition according to any one of Items 1 to 10, which is an injectable formulation. [Item 12] The composition according to any one of Items 1 to 11, which is used for the prevention and / or treatment of mycobacteriosis. [Item 12-1] The composition according to Item 12, wherein the mycobacteriosis is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 12-2] 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 12. The composition according to Item 12, wherein the mycobacterial disease is an infection caused by Mycobacterium chelonae, Mycobacterium smegmatis, or Mycobacterium aurum. [Item 12-3] The composition according to Item 12, wherein the mycobacterial disease is tuberculosis. [Item 12-4] The composition according to any one of Items 1 to 12, 12-1, 12-2, and 12-3, which is a sterile composition. [Item 13] A pre-filled syringe, vial, or ampoule containing the composition according to any one of Items 1 to 12, 12-1, 12-2, 12-3, and 12-4. [Item 14] A method for producing the composition according to any one of Items 1 to 12, 12-1, 12-2, 12-3, and 12-4, comprising: Step 1 of mixing delamanid or a salt thereof, 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. [Item 15] The method according to Item 14, wherein the wet milling is wet milling using a bead mill. [Item 16] The method according to Item 14 or 15, further comprising step 4 of sterilizing the recovered suspension by radiation.[Item 17] 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 comprising delamanid or a salt thereof at intervals of one week or more to a subject in need of prevention and / or treatment of mycobacteriosis. [Item 18] The method of Item 17, 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 19] The method of Item 17 or 18, 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 20] The method of any of Items 17 to 19, wherein the mycobacteriosis is tuberculosis. [Item 21] A method for preventing and / or treating latent tuberculosis, comprising administering intramuscularly or subcutaneously an effective amount of a composition in the form of a suspension of submicron particles comprising delamanid or a salt thereof 1 to 3 times at intervals of 1 to 2 months to a subject in need of prevention and / or treatment of latent tuberculosis. [Item 22] A method for preventing and / or treating mycobacteriosis, comprising administering an effective amount of the composition according to any one of Items 1 to 11 and 12-4 to a subject in need of prevention and / or treatment of mycobacteriosis. [Item 23] The method according to Item 22, wherein the mycobacteriosis is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 24] 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 of Item 22, wherein the mycobacterial disease is tuberculosis. [Item 26] Use of the composition of any of Items 1 to 11 and 12-4 for the manufacture of a medicament for the prevention and / or treatment of mycobacterial disease. [Item 27] ​​The use of Item 26, wherein the mycobacterial disease is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria.[Section 28] 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 26, wherein the mycobacterial disease is tuberculosis. [Item 30] The use according to any of Items 26 to 29, 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.

[0011] The present invention provides a composition in the form of a suspension of submicron particles, which is useful as a composition containing delamanid or a salt thereof. The composition may have the following advantages, for example: - Rapid onset of action and prolonged duration of action (e.g., effective blood concentrations are quickly reached and sustained), allowing administration at intervals of one week or more (particularly one month or more), contributing to improved adherence, improved treatment success rates, and suppression of the development of resistant bacteria. - Highly concentrated suspensions allow for intramuscular or subcutaneous administration of an effective therapeutic dose. - Submicron particles do not settle, providing excellent long-term storage stability. - Low irritation upon administration. - Small, easy-to-use formulations are possible.

[0012] Figure 1 shows the blood concentration profile of the LAI formulation of Example 2 administered intramuscularly (IM) or subcutaneously (SC) to rats at a dose of 50 mg / kg. Figure 2 shows the effect of the LAI formulation of Example 4 administered subcutaneously (SC) to a mouse tuberculosis infection model at a dose of 30 mg / kg or 300 mg / kg on reducing the number of viable bacteria in the lungs. Figure 3 shows the blood concentration profile of the LAI formulation of Example 17 administered intramuscularly (IM) to dogs at a dose of 10 mg / kg.

[0013] In this specification, the term "comprise" encompasses the concepts of "essentially consist of" and "consist of."

[0014] All documents mentioned herein are incorporated herein by reference.

[0015] The compositions of the present invention comprise delamanid or a salt thereof (also referred to as the "active ingredient"), a suspending agent, and a dispersion medium. The compositions are typically pharmaceutical compositions.

[0016] As used herein, delamanid refers to (2R)-2-methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b]oxazole (non-salt form, free form).

[0017] In one embodiment, the composition comprises delamanid, a suspending agent, and a dispersion medium.

[0018] In another embodiment, the composition comprises a salt of delamanid, a suspending agent, and a dispersion medium. The salt of delamanid is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salts, salts with inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); tri(lower)alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidinium, methylparaben ... Examples of such salts include salts with organic bases such as methyl amine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkyl-morpholines (e.g., N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO); salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and glutamic acid. Here, "(lower) alkyl" means "alkyl having 1 to 6 carbon atoms."

[0019] 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.

[0020] The suspending agent contained in the composition includes at least one selected from the group consisting of poloxamer and D-α-tocopherol polyethylene glycol succinate.

[0021] 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.

[0022] Examples of D-α-tocopherol polyethylene glycol (PEG) succinate esters include D-α-tocopherol PEG1000 succinate esters.

[0023] The suspending agent may be a single agent or a combination of two or more agents. In one embodiment, the suspending agent preferably comprises at least one agent selected from the group consisting of poloxamer and D-α-tocopherol polyethylene glycol succinate as a first suspending agent, and polyethylene glycol (PEG) as a second suspending agent. The average molecular weight of 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.

[0024] 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.

[0025] When the first suspending agent contains poloxamer 338, it is preferable that the first suspending agent is 15 mg / mL or more and the second suspending agent is 10 mg / mL or more, and 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 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.

[0026] 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).

[0027] 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.

[0028] 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, and even more preferably 0.5 mL or more. The dispersion medium may also be contained so that the total volume of the composition is 7 mL or less, preferably 6 mL or less, more preferably 5 mL or less, even more preferably 4 mL or less, even more preferably 3 mL or less, and particularly preferably 2 mL or less. Furthermore, the dispersion medium may be contained so that the total volume of the composition is 0.2 to 5 mL or 3 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.

[0029] The composition may further contain optional additives. Such additives are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include isotonicity agents, buffers, pH adjusters, preservatives, excipients, lubricants, fluidizers, disintegrants, binders, surfactants, flavoring agents, and odor-correcting agents. The additives may be used alone or in combination of two or more.

[0030] Examples of isotonicity agents include alkali metal chlorides such as sodium chloride and potassium chloride; sugar alcohols such as arabitol, mannitol, sorbitol, xylitol, and maltitol; sugars such as glucose, maltose, sucrose, fructose, trehalose, and lactose; and glycerin and erythritol. In one embodiment, the isotonicity agent preferably comprises mannitol. The concentration of the isotonicity agent in the composition is, for example, 1 to 100 mg / mL, preferably 5 to 60 mg / mL. In the composition, the w / w ratio of delamanid or a salt thereof to the isotonicity agent is, for example, 1:1 to 30:1, preferably 8:1 to 25:1, and more preferably 12:1 to 20:1.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] The average particle size of the submicron particles is, for example, 1000 nm or less, preferably 700 nm or less, more preferably 500 nm or less, and even 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, or 50 nm or more. The average particle size of the submicron particles is, for example, 10 to 1000 nm. Submicron particles with an average particle size of 100 nm or less can be called nanoparticles. This average particle size range is preferable in that the effect is rapidly exerted and lasts for a long time.

[0036] The polydispersity index of the submicron particles is, for example, 0.5 or less, preferably 0.45 or less, more preferably 0.4 or less, and even more preferably 0.35 or less. The polydispersity index of the submicron particles may be, for example, 0 or more, 0.01 or more, or 0.05 or more. The polydispersity index of the submicron particles is, for example, 0 to 0.5.

[0037] 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.

[0038] The composition preferably exhibits a property of decreasing viscosity with increasing shear rate, i.e., thixotropy (shear thinning).

[0039] 0.1s of the composition -1 The viscosity (VL) at a shear rate of 100 Pa·s or less is, for example, 200 Pa·s or less, preferably 150 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, 10 Pa·s or less, preferably 8 Pa·s or less, and more preferably 5 Pa·s or less. 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 200 Pa·s.

[0040] 900 to 1000s of the composition -1Any value within the range (e.g. 900s -1 or 1000s -1 The viscosity at a shear rate (VH) of the composition may be, for example, 0.5 Pa·s or less, preferably 0.2 Pa·s or less, more preferably 0.15 Pa·s or less, and even more preferably 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. -1 The viscosity may be the point at which no change in viscosity is observed even when the shear rate is changed within the range.

[0041] 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.

[0042] 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).

[0043] 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.

[0044] The route of administration 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 a composition for oral administration containing delamanid or a salt thereof, and such combination may be effective for patients in the early stages of prevention and / or treatment of mycobacteriosis.

[0045] Because the composition has a long-lasting effect (e.g., maintains an effective blood concentration), it is suitable for use as a long-acting injection (LAI) formulation, enabling reduced administration frequency. The composition is administered, for example, at intervals of one week or more, two weeks or more, three weeks or more, four weeks or more, one month or more, or two months or more. The longer the administration interval, the more preferable. There is no particular upper limit, but for example, two months, three months, four months, five months, or six months. Administration at such a frequency is preferred from the viewpoint of patient compliance. The administration period (or treatment period) of the composition can be, for example, six months, with administration being preferably one to six times every six months, more preferably one to three times every six months, even more preferably one or two times every six months, and particularly preferably once every six months. The composition can also be administered in combination with a composition in the form of a microparticle suspension containing delamanid or a salt thereof. Because the LAI formulation acts rapidly, it can be administered in combination with other LAI formulations (e.g., formulations that have a long duration of action but a slower onset of action than the LAI formulation), which may be effective in the early stages of treatment.The LAI formulation can also be used in combination with an orally administered formulation.

[0046] The compositions may be single or multiple doses containing, for example, about 100 to about 500 mg / mL, preferably about 200 to about 400 mg / mL, of delamanid given once per month or once every 2-3 months.

[0047] The composition is preferably administered at a monthly dose of, for example, 500 mg or more, 800 mg or more, 1000 mg or more, or 1200 mg or more. The composition is also preferably administered at a monthly dose of, for example, 2500 mg or less, 2000 mg or less, or 1800 mg or less. Furthermore, the composition is preferably administered at a monthly dose of, for example, 500 to 2500 mg.

[0048] The composition is preferably administered so that the injection amount per administration (or per month) is, for example, 1 mL or more, 2 mL or more, or 3 mL or more. The composition is also preferably administered so that the injection amount per administration (or per month) is, for example, 7 mL or less, 6.5 mL or less, 6 mL or less, 5.5 mL or less, or 5 mL or less. Furthermore, the composition is preferably administered so that the injection amount per administration (or per month) is, for example, 3 to 7 mL or 3 to 5 mL.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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 bead milling the suspension obtained by the mixing, and step 3 of recovering the suspension obtained by the bead mill.

[0055] 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.

[0056] 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.

[0057] 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).

[0058] 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.

[0059] 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.

[0060] 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).

[0061] The present invention includes a method for preventing and / or treating mycobacteriosis, comprising administering an effective amount of the composition to a subject in need of mycobacteriosis prevention and / or treatment. The corresponding configurations described for the composition can be employed for each component of the method. The present invention includes 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 delamanid or a salt thereof to a subject in need of mycobacteriosis prevention and / or treatment 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 includes a method for preventing and / or treating latent tuberculosis, comprising intramuscularly or subcutaneously administering an effective amount of a composition in the form of a suspension of submicron particles containing delamanid or a salt thereof to a subject in need of mycobacteriosis prevention and / or treatment 1 to 3 times at intervals of 1 to 2 months.

[0062] 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.

[0063] 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.

[0064] Examples 1 to 16 and Comparative Examples 1 and 2: As the suspending agent shown in Table 1, Poloxamer 338 (Kolliphor P338) obtained from BASF, Poloxamer 188 (Kolliphor P188) obtained from BASF, or D-α-tocopherol polyethylene glycol (PEG) 1000 succinate (TPGS) obtained from Sigma-Aldrich, and / or PEG 3350 (POLYGLYKOL 3350 S) obtained from CLARIANT or PEG 400 (Super Refined PEG 400) obtained from CRODA, mannitol as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer were dissolved in water (water for injection) and adjusted to pH 7.0 with sodium hydroxide solution to prepare a vehicle solution. The active ingredient (delamanid) and the prepared vehicle solution were weighed and mixed in a vial 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 crushed 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 formulation shown in Table 1 was obtained.

[0065] Each of the resulting injection formulations was diluted 10-fold with water for injection, and the particle size of the diluted solution was measured using an ELSZneo measuring device (manufacturer: Otsuka Electronics Co., Ltd.) The particle sizes in Table 2 were measured by dynamic light scattering and are shown based on scattering intensity.

[0066] 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)

[0067]

[0068] [Test Example 2] The particle size of each example was measured using ELSZneo. The results are shown in Table 2.

[0069]

[0070] As shown in Table 2, suspensions of less than 500 nm could be prepared in all Examples, whereas in Comparative Examples 1 and 2, homogeneous suspensions could not be prepared because delamanid floated on the vehicle solution.

[0071] Test Example 2 The viscosities of Examples 1 to 4, 7, 8, and 10 to 14 were measured using a rheometer. The results are shown in Table 3.

[0072]

[0073] 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 PEG3350 was added (Examples 2, 4, 10, 12, and 14), resulting in reduced sliding properties and excellent manufacturability.

[0074] Test Example 3: PK study of delamanid LAI formulation in rats. Using the formulation of Example 2, an injectable formulation with an average particle size of 167.9 nm was prepared by bead milling for 48 hours. The injectable formulation was injected into the calf muscle or subcutaneously on the back of male SD rats at a dose of 50 mg / kg. To evaluate the blood distribution of delamanid 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 delamanid concentrations were measured by LC-MS / MS. The results are shown in Figure 1. The blood delamanid concentration reached its peak one day after administration, remained high for 28 days, and was detectable even after 84 days.

[0075] Test Example 4: In vivo experiment on the therapeutic effect of delamanid LAI formulation. BALB / c mice were inoculated transtracheally with 698 CFU of Mycobacterium tuberculosis Kurono strain and allowed to stand for 2 weeks to create an experimental mouse tuberculosis model. The LAI formulation of Example 4 was administered subcutaneously (SC) to the back of the mice once on the day treatment started, at 30 mg / kg or 300 mg / kg (shown as "DLM-LAI (30 mg / kg)" and "DLM-LAI (300 mg / kg)" in Figure 2). As a control, a suspension of delamanid spray-dried powder was prepared using 5% gum arabic solution and orally (PO) administered daily for 28 days starting from the day treatment started, at 2 mg / kg (shown as "DLM-SD (2 mg / kg)" in Figure 2). 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 cultured 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 (indicated as "Initial" in Figure 2 ) and in the group that received a single subcutaneous (SC) injection of a vehicle solution (combined with the formulation of Example 4, excluding delamanid) on the day of treatment (indicated as "DLM-LAI-Vehicle" in Figure 2 ). As shown in Figure 2, the DLM-LAI (300 mg / kg) group demonstrated a greater reduction in lung viable bacterial counts than the DLM-SD (2 mg / kg) group, and the DLM-LAI (30 mg / kg) group demonstrated an effect comparable to that of the DLM-SD (2 mg / kg) group. All delamanid-treated groups demonstrated a 2-Log to 3-Log reduction in lung viable bacterial counts compared to the Initial and DLM-LAI-Vehicle groups. Subcutaneous (SC) administration of delamanid LAI formulations is expected to produce therapeutic effects equivalent to or greater than those achieved by oral (PO) administration for 28 consecutive days.

[0076] Examples 17-18 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 (shown in Table 4) were dissolved in water (water for injection) and the pH was adjusted to 7.0 with sodium hydroxide solution to prepare a vehicle solution. Delamanid 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, 0.3 mm diameter zirconia beads were placed in the grinding container to achieve an 80% filling rate. The peripheral speed was set to 2.5 m / s and the flow rate to 50 mL / min. After 80 minutes of bead milling, the suspension was collected. Five mL of the suspension and vehicle solution were filled into vials, which were then stoppered and sealed with aluminum caps. The samples were then irradiated with gamma rays at 25-35 kGy.

[0077]

[0078] [Test Example 5] The particle sizes of Examples 17 and 18 were measured using ELSZneo. The results are shown in Table 5.

[0079]

[0080] Test Example 6 The viscosities of Examples 17 and 18 were measured using a rheometer. The results are shown in Table 6.

[0081]

[0082] Test Example 7: Muscle Irritation Test of Delamanid LAI Formulations. Examples 17 and 18 were administered at a dose of 40 mg / kg (delamanid), along with Comparative Example 3, the positive control (0.425% acetic acid aqueous solution, 1.7% acetic acid aqueous solution), and the negative control (physiological saline) at 0.4 mL / kg in disposable syringes. Male Kbl / JW rabbits were manually restrained and injected intramuscularly with a 23G 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 injection site (skin and subcutaneous tissue) in the thigh was then excised, and the excised muscles were fixed in 10% neutral buffered formalin. After embedding in paraffin according to standard procedures, HE-stained tissue specimens were prepared and subjected to histopathological examination. Muscle irritation was evaluated using the average value of three rabbits.

[0083] Grade of findings (score). -: None (1), ±: slight (2), +: mild (3), 2+: moderate (4), 3+: marked (5).

[0084] Table 7 shows intramuscular retention and muscle irritation. Visual observation at autopsy revealed that test formulation-like substances remained in Examples 17-18 7 and 14 days after administration, whereas no test formulation-like substances remained in Comparative Example 3 or the control substance, which did not contain delamanid, 7 or 14 days after administration. Histopathological examination revealed that Examples 17-18 showed weaker necrosis, partial necrosis / repair reaction, and fibrosis than the positive controls, 0.425% acetic acid aqueous solution and 1.7% acetic acid aqueous solution, and the irritation was within an acceptable range. Furthermore, immune responses such as foam cell aggregates and mononuclear cell infiltration were observed in Examples 17-18, but the irritation in both cases was within an acceptable range.

[0085] Test Example 8 Dog PK Test of Delamanid LAI Formulation and Post-Test Histopathological Examination Example 17 was dispensed into a disposable syringe at a dose of 10 mg / kg of delamanid, and while a male dog was restrained manually, the drug was injected into the right upper quadrant of the thigh muscle using a 23 G 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. The animal was restrained, the blood collection site was disinfected with rubbing alcohol, and 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 dogs were anesthetized by exsanguination via the carotid artery under anesthesia with 25 mg / mL / kg thiopental sodium administered intravenously through the cephalic vein. The injection site (skin and subcutaneous tissue) was then excised from the thigh, and the excised muscle was fixed in 20% neutral buffered formalin. After embedding in paraffin, HE-stained tissue specimens were prepared and histopathologically evaluated for the injection site, using the average value from three dogs. The plasma concentrations of delamanid in each blood sample were measured using LC-MS / MS. As shown in Figure 3, the plasma delamanid concentrations reached their peak 6 hours after administration, and were maintained for more than one month in the dogs.

[0086] Grade of findings (score). -: None (1), ±: slight (2), +: mild (3), 2+: moderate (4), 3+: marked (5).

[0087] As shown in Table 8, the histopathological examination after administration of Example 17 revealed only an immune reaction, and no necrosis, partial necrosis / repair reaction, or fibrosis suggestive of muscle damage was observed, indicating that the irritation was tolerable.

[0088] Examples 19-21: Poloxamer 338 and PEG 3350 as suspending agents, mannitol as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer (shown in Table 9) were dissolved in water (water for injection) and the pH was adjusted to 7.0 with sodium hydroxide solution to prepare a vehicle solution. Delamanid 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, zirconia beads were placed in the grinding container to achieve an 80% filling rate. The peripheral speed, flow rate, and grinding time were set to achieve a particle size of approximately 500 nm in Example 19, approximately 600 nm in Example 20, and approximately 400 nm in Example 21, and the suspension was collected by bead milling. 5 mL of the suspension was filled into vials, stoppered, and then sealed with an aluminum cap. This was followed by gamma irradiation at 25-35 kGy.

[0089]

[0090] The stability of Examples 19 to 21 was evaluated by storing them at 40° C. In the stability test, particle size and viscosity were measured with an average value of n=3.

[0091]

[0092] As shown in Table 10, no change in particle size or viscosity or particle settling was observed, and the product was stable.

[0093] Example 22: Poloxamer 338 and PEG 3350, shown in Table 11, as suspending agents, mannitol as an isotonicity agent, and sodium dihydrogen phosphate monohydrate as a buffer were dissolved in water (water for injection) and the pH was adjusted to 7.0 with sodium hydroxide solution to prepare a vehicle solution. Delamanid and the vehicle solution were weighed and mixed in a beaker to prepare a suspension. Using a Labostar Mini MGF015 (Ashizawa Finetech Co., Ltd.), zirconia beads were placed in a grinding container to achieve an 85% filling rate. The bead mill was run for 240 minutes at a flow rate of 0.3 L / min and a peripheral speed of 12 m / s, and the suspension was collected. 5 mL of the suspension was filled into a vial, which was then stoppered and sealed with an aluminum cap. The vial was then subjected to gamma irradiation at 25-35 kGy.

[0094]

[0095] Example 22 was stored at 40°C and 50°C to evaluate its stability. In the stability test, particle size and viscosity were measured as an average value of n = 3. Particle size measurements in this stability test were performed using a Zetasizer (Malvern Panalytical). A solution prepared by diluting the vehicle solution 100 times with purified water was used as a dispersion medium, and the suspension was diluted 200 times or more with the dispersion medium to measure particle size.

[0096]

[0097] As shown in Table 12, no significant changes in particle size or viscosity or particle settling were observed, and the solution was stable.

Claims

1. A composition comprising delamanid or a salt thereof, said composition comprising a suspending agent and a dispersion medium, and being in the form of a suspension of submicron particles, said suspending agent comprising at least one selected from the group consisting of poloxamer and D-α-tocopherol polyethylene glycol succinate.

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 poloxamer is poloxamer 338.

5. The composition of claim 1, wherein the suspending agent further comprises polyethylene glycol.

6. The composition according to claim 5, wherein the average molecular weight of the polyethylene glycol is 1000 or more.

7. The composition according to claim 1, wherein the concentration of delamanid or a salt thereof in the composition is 100 to 500 mg / mL in terms of the free form.

8. The composition according to claim 1, wherein the concentration of delamanid or a salt thereof in the composition is 200 to 500 mg / mL in terms of the free form.

9. The composition of claim 1, which is administered intramuscularly or subcutaneously.

10. The composition of claim 1, administered at intervals of one week or more.

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

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

13. A pre-filled syringe, vial, or ampoule containing the composition of any one of claims 1 to 12.

14. A method for producing the composition of claim 1, comprising: step 1 of mixing delamanid or a salt thereof, 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.

15. The method according to claim 14, wherein the wet milling is wet milling using a bead mill.

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

17. 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 comprising delamanid or a salt thereof.

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

19. The method of claim 17, 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.

20. The method of any one of claims 17 to 19, wherein the mycobacterial disease is tuberculosis.

21. A method for preventing and / or treating latent tuberculosis, comprising administering an effective amount of a composition in the form of a suspension of submicron particles comprising delamanid or a salt thereof 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.