Compositions containing quarbundex hispid

Abstract

The present invention provides a composition in the form of a suspension of submicron particles, which can be used as a composition comprising quabodepistat, salts thereof, and the like. As one example of the composition, a composition comprising at least one selected from quabodepistat, salts thereof, co-crystals thereof, and solvates thereof is disclosed. The composition further comprises a suspending agent and a dispersion medium and is in the form of a suspension of submicron particles.

Description

Technical Field

[0001] The present invention relates to a composition comprising at least one selected from quadodepistat, its salts, its eutectics, and their solvates, wherein the composition is in the form of a submicron particle suspension. Background Technology

[0002] Quabordepista is represented by the formula 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolinone-2(1H)-one: , And for Mycobacterium tuberculosis ( Mycobacterium tuberculosis Multidrug-resistant Mycobacterium tuberculosis ( Mycobacterium tuberculosis It has antibacterial activity against mycobacteria and / or nontuberculous mycobacteria (Patent Document (PTL) 1).

[0003] Citation List

[0004] Patent documents

[0005] PTL 1: WO2016 / 031255A. Summary of the Invention

[0006] Technical issues

[0007] One of the problems to be solved by the present invention is to provide a composition in the form of a suspension of submicron particles, which can be used as a composition comprising at least one selected from quambordpistat, its salts, its eutectics, and their solvates.

[0008] Solution to the problem

[0009] The inventors conducted extensive research to address the aforementioned problems. As a result, they discovered a composition in the form of a suspension of submicron particles, which can be used as a composition comprising at least one selected from quambordpistat, its salts, its eutectics, and solvates thereof. This invention was accomplished through further research based on the aforementioned discovery.

[0010] The present invention includes embodiments described in the following entries.

[0011] Item 1

[0012] A composition comprising at least one component selected from quabodepistat, its salts, its eutectics, and their solvates, wherein the composition comprises a suspending agent and a dispersion medium, and wherein the composition is in the form of a submicron particle suspension.

[0013] Item 2

[0014] According to the composition described in item 1, the submicron particles have an average particle size of 500 nm or less.

[0015] Item 3

[0016] The composition according to item 1 or 2, wherein the submicron particles have a polydispersity index of 0.5 or lower.

[0017] Item 4

[0018] The composition according to any one of entries 1 to 3, wherein the suspending agent comprises at least one selected from poloxamer, D-α-tocopherol polyethylene glycol succinate, and polyoxyethylene sorbitol fatty acid ester.

[0019] Item 5

[0020] The composition according to item 4, wherein the suspending agent further comprises polyethylene glycol.

[0021] Item 6

[0022] The composition according to any one of items 1 to 5, wherein the concentration of the component in the composition is from 100 mg / mL to 500 mg / mL in free equivalent.

[0023] Item 7

[0024] The composition according to any one of items 1 to 6, wherein the concentration of the component in the composition is from 200 mg / mL to 500 mg / mL in free equivalent.

[0025] Item 8

[0026] The composition according to any one of entries 1 to 7 is for intramuscular or subcutaneous administration.

[0027] Item 9

[0028] The composition according to any one of entries 1 to 8 is used for application at intervals of 1 week or longer (or 2 weeks or longer).

[0029] Item 10

[0030] The composition described in any of entries 1 to 9 is an injectable formulation.

[0031] Item 11

[0032] The composition according to any one of entries 1 to 10 is used for the prevention and / or treatment of mycobacterial infections.

[0033] Item 11-1

[0034] The composition according to item 11, wherein the mycobacterial infection is caused by Mycobacterium tuberculosis, Mycobacterium leprae, or a nontuberculous mycobacterium.

[0035] Item 11-2

[0036] According to the composition described in item 11, wherein the mycobacterial infection is caused by Mycobacterium tuberculosis (… Mycobacterium tuberculosis ), Mycobacterium africanum ( Mycobacterium africanum m), Bovine Mycobacterium ( Mycobacterium bovis Mycobacterium capsulatum ( ) Mycobacterium capra Mycobacterium sepium ( ) Mycobacterium pinnipedii ), Mycobacterium vulgatum ( Mycobacterium microti Mycobacterium leprae ( Mycobacterium leprae ), Mycobacterium avium ( Mycobacterium avium Intracellular mycobacteria ( Mycobacterium intracellulare Mycobacterium Kansas ( Mycobacterium kansasii ), Mycobacterium marinum ( Marine Mycobacterium Mycobacterium simianum ( Mycobacterium simianum ), Mycobacterium scrofula ( Mycobacterium scrofulaceum ), Mycobacterium chulcei ( Mycobacterium szulgai ), Mycobacterium bufossa ( Mycobacterium xenopis Mycobacterium marmosetum ( Mycobacterium malmoensis Haemophilus ( ) Mycobacterium haemophilus ), Mycobacterium ulcerans ( Mycobacterium ulcerans ), Mycobacterium pyogenes ( Mycobacterium shimoidei ), Mycobacterium tumefaciens ( Mycobacterium fortuitum ), Mycobacterium tectorum ( Mycobacterium chelonae ), Mycobacterium smegmatis ( Mycobacterium smegmatis ) or Mycobacterium aureus ( Mycobacterium aurum Infections caused by ).

[0037] Item 11-3

[0038] The composition according to item 11, wherein the mycobacterial infection is tuberculosis.

[0039] Items 11-4

[0040] The composition described according to any one of entries 1 to 11, 11-1, 11-2 and 11-3 is a sterile composition.

[0041] Item 12

[0042] A pre-filled syringe, vial, or ampoule containing the composition described in any one of entries 1 to 11, 11-1, 11-2, 11-3, and 11-4.

[0043] Item 13

[0044] A method for producing the composition according to any one of entries 1 to 11, 11-1, 11-2, 11-3 and 11-4, the method comprising: Step 1: Mix the components, suspending agent, and dispersion medium to obtain a suspension; and Step 2: Wet milling of the suspension obtained by mixing; and Step 3: Collect the suspension obtained by wet milling.

[0045] Item 14

[0046] According to the method described in entry 13, the wet grinding is performed using a bead mill.

[0047] Item 15

[0048] The method according to item 13 or 14 further includes step 4, namely, sterilizing the collected suspension by irradiation.

[0049] Item 16

[0050] A method for preventing and / or treating mycobacterial infections, the method comprising administering, at intervals of one week or longer, an effective amount of a composition in the form of a suspension of submicron particles intramuscularly or subcutaneously to a subject requiring prevention and / or treatment of mycobacterial infections, the composition comprising at least one component selected from quambordipistat, its salts, its eutectics, and solvates thereof.

[0051] Item 17

[0052] According to the method described in entry 16, the administration is the intramuscular or subcutaneous administration of an effective amount of the composition to the subject at intervals of one month or longer.

[0053] Item 18

[0054] According to the method described in Item 16 or 17, the administration is the administration of an effective amount of the composition to the subject intramuscularly or subcutaneously 1 to 6 times at intervals of 1 to 2 months.

[0055] Item 19

[0056] According to any of the methods described in entries 16 to 18, the mycobacterial infection described is tuberculosis.

[0057] Item 20

[0058] A method for preventing and / or treating latent tuberculosis, the method comprising administering, intramuscularly or subcutaneously, one to three times at intervals of one to two months, an effective amount of a composition in the form of a suspension of submicron particles, the composition comprising at least one component selected from quamboropistat, its salts, its eutectics, and solvates thereof.

[0059] Item 21

[0060] A method for preventing and / or treating mycobacterial infection, the method comprising administering to a subject requiring prevention and / or treatment of said mycobacterial infection an effective amount of the composition according to any one of entries 1 to 10 and 11-4.

[0061] Item 22

[0062] According to the method described in item 21, the mycobacterial infection is caused by Mycobacterium tuberculosis, Mycobacterium leprae, or a nontuberculous mycobacterium.

[0063] Item 23

[0064] According to the method described in entry 21 or 22, the mycobacterial infection is caused by Mycobacterium tuberculosis (… Mycobacterium tuberculosis ), Mycobacterium africanum ( Mycobacterium africanum m), Bovine Mycobacterium ( Mycobacterium bovis Mycobacterium capsulatum ( ) Mycobacterium capra Mycobacterium sepium ( ) Mycobacterium pinnipedii ), Mycobacterium vulgatum ( Mycobacterium microti Mycobacterium leprae ( Mycobacterium leprae ), Mycobacterium avium ( Mycobacterium avium Intracellular mycobacteria ( Mycobacterium intracellulare Mycobacterium Kansas ( Mycobacterium kansasii ), Mycobacterium marinum ( Marine Mycobacterium Mycobacterium simianum ( Mycobacterium simianum ), Mycobacterium scrofula ( Mycobacterium scrofulaceum ), Mycobacterium chulcei ( Mycobacterium szulgai ), Mycobacterium bufossa ( Mycobacterium xenopis Mycobacterium marmosetum ( Mycobacterium malmoensis Haemophilus ( ) Mycobacterium haemophilus ), Mycobacterium ulcerans ( Mycobacterium ulcerans ), Mycobacterium pyogenes ( Mycobacterium shimoidei ), Mycobacterium tumefaciens ( Mycobacterium fortuitum ), Mycobacterium tectorum ( Mycobacterium chelonae ), Mycobacterium smegmatis ( Mycobacterium smegmatis ) or Mycobacterium aureus ( Mycobacterium aurum Infections caused by ).

[0065] Item 24

[0066] According to the method described in entry 21, the mycobacterial infection described therein is tuberculosis.

[0067] Item 25

[0068] Use of the composition described in any of entries 1 to 10 and 11-4 in the preparation of a medicament for the prevention and / or treatment of mycobacterial infections.

[0069] Item 26

[0070] According to the use described in entry 25, the mycobacterial infection is an infection caused by Mycobacterium tuberculosis, Mycobacterium leprae, or a nontuberculous mycobacterium.

[0071] Item 27

[0072] According to the use described in Item 25 or 26, the mycobacterial infection is caused by Mycobacterium tuberculosis ( Mycobacterium tuberculosis ), Mycobacterium africanum ( Mycobacterium africanum m), Bovine Mycobacterium ( Mycobacterium bovis Mycobacterium capsulatum ( ) Mycobacterium capra Mycobacterium sepium ( ) Mycobacterium pinnipedii ), Mycobacterium vulgatum ( Mycobacterium microti Mycobacterium leprae ( Mycobacterium leprae ), Mycobacterium avium ( Mycobacterium avium Intracellular mycobacteria ( Mycobacterium intracellulare Mycobacterium Kansas ( Mycobacterium kansasii ), Mycobacterium marinum ( Marine Mycobacterium Mycobacterium simianum ( Mycobacterium simianum ), Mycobacterium scrofula ( Mycobacterium scrofulaceum ), Mycobacterium chulcei ( Mycobacterium szulgai ), Mycobacterium bufossa ( Mycobacterium xenopis Mycobacterium marmosetum ( Mycobacterium malmoensis Haemophilus ( ) Mycobacterium haemophilus ), Mycobacterium ulcerans ( Mycobacterium ulcerans ), Mycobacterium pyogenes ( Mycobacterium shimoidei ), Mycobacterium tumefaciens ( Mycobacterium fortuitum ), Mycobacterium tectorum ( Mycobacterium chelonae ), Mycobacterium smegmatis ( Mycobacterium smegmatis ) or Mycobacterium aureus ( Mycobacterium aurum Infections caused by ).

[0073] Item 28

[0074] According to the use described in entry 25, the mycobacterial infection described therein is tuberculosis.

[0075] Item 29

[0076] According to the use described in any of entries 25 to 28, the drug is to be administered intramuscularly or subcutaneously 1 to 6 times over a period of 1 week or longer, 1 month or longer, or 1 to 2 months, or intramuscularly or subcutaneously 1 to 3 times over a period of 1 to 2 months.

[0077] Advantages of the invention

[0078] This invention provides a composition in the form of a suspension of submicron particles, which can be used as a composition comprising at least one selected from quabodepistat, its salts, its eutectics, and solvates thereof. The composition may have advantages such as the following: Because the composition exerts its effect rapidly and maintains that effect for a long time (e.g., the composition rapidly reaches and maintains its effective blood concentration), it can be administered at intervals of one week or longer (especially two weeks or longer). This helps improve adherence, thereby increasing the success rate of treatment for mycobacterial infections (including tuberculosis) and inhibiting the emergence of drug-resistant bacteria; - The composition can be used to treat latent mycobacterial infections (especially latent tuberculosis) and to prevent mycobacterial infections in high-risk populations; - By increasing the concentration of the suspension, a therapeutically effective amount of the drug can be administered intramuscularly or subcutaneously; - The composition exhibits excellent long-term storage stability without the submicron particles settling. - The composition causes minimal irritation upon application; and - The composition can be formulated into a compact, easy-to-use formulation. Attached Figure Description

[0079] Figure 1 The plasma concentration curves obtained when the formulation according to Example 4 was injected subcutaneously (SC) into rats at a dose of 50 mg / kg are shown.

[0080] Figure 2 The plasma concentration curves obtained when the formulation according to Example 18 was injected intramuscularly (IM) into rats at a dose of 50 mg / kg are shown.

[0081] Figure 3 The blood concentration curve is obtained when the formulation of Example 19 is injected subcutaneously (SC) into dogs at a dose of 25 mg / kg.

[0082] Figure 4 The effects of the formulation according to Example 19 on inhibiting or reducing the number of lung bacteria in a mouse model of tuberculosis when administered in a single dose or in two divided doses are shown. Detailed Implementation

[0083] In this specification, the term "comprising" includes the concepts of "consistently made up of" and "comprises from".

[0084] The contents of all references described in this specification are incorporated herein by reference.

[0085] The composition of the present invention comprises: Selected from at least one of quarbodpistat, its salts, its eutectic, and their solvates (also referred to below as the "active ingredient"), Suspending agents, and Dispersion medium.

[0086] The active ingredient may be one active ingredient or a combination of two or more active ingredients. The composition is typically a pharmaceutical composition.

[0087] In this specification, quamboropistat (also referred to as “OPC-167832”) means 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, i.e., free form). Quamboropistat can be produced by, for example, the methods described in WO2016 / 031255 (or U.S. Patent Application Publication No. 2017 / 253576). Quamboropistat can be type I or type II crystals as described in JP2020-79206A and JP2021-178818A. Type I crystals refer to crystals that, in powder X-ray diffraction patterns obtained using CuKα radiation as an X-ray source, exhibit 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 exhibit diffraction peaks at 1, 2, 3, 4, 5, 6, or 7 diffraction angles (2θ) selected from 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°. Type II crystals refer to crystals that, in powder X-ray diffraction patterns obtained using CuKα radiation as an X-ray source, exhibit 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 exhibit diffraction peaks at 1, 2, 3, 4, 5, or 6 diffraction angles (2θ) selected from 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°.

[0088] In this specification, "eutectic" means eutectic of quabodepista and co-formed compounds.

[0089] In this specification, "solvent" means solvate of quabodepistat, solvate of quabodepistat salt, or solvate of eutectic of quabodepistat and co-formation.

[0090] In one embodiment, the composition comprises quambordipista, a suspending agent, and a dispersing medium.

[0091] In another embodiment, the composition comprises a salt of quamborpitol, a suspending agent, and a dispersion medium. There are no particular limitations on the quamborpitol salt, as long as it is a pharmaceutically acceptable salt. Examples include salts of quambopistar with inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; salts of quambopistar with organic bases such as alkylamines (e.g., methylamine, diethylamine, trimethylamine, and triethylamine), alkanolamines (e.g., ethanolamine, diethanolamine, triethanolamine, and tri(hydroxymethyl)methylamine), cycloalkanamines (e.g., dicyclohexylamine), alkylene diamines (e.g., ethylenediamine and N,N'-diphenylmethylethylenediamine), guanidine, pyridine, methylpyridine, and choline; salts of quambopistar with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; and salts of quambopistar 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.

[0092] In yet another embodiment, the composition comprises a eutectic of quambordiprexat and co-formation, a suspending agent, and a dispersion medium.

[0093] The eutectic can be a crystalline material in which quabodpistat and the co-formation coexist in the same lattice in any molar ratio. The eutectic can exist as multiple crystal forms (also known as "polymorphs").

[0094] In one embodiment, the co-formation is a non-ionized molecule capable of forming crystals with quambordipishta. Examples of such non-ionized molecules include organic acids, amino acids, amines, amides, vanillin, urea, pyridoxine, saccharin, and hydroquinone.

[0095] Examples of organic acids include carboxylic acids, ascorbic acid, and phenols. Examples of 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. Available organic acids can be non-volatile organic acids, such as organic acids that do not volatilize at room temperature (15°C to 25°C) and normal pressure. Available non-volatile organic acids can be water-soluble organic acids.

[0096] Amino acids can be natural or non-natural. Examples of amino acids include proline, lysine, tyrosine, and histidine.

[0097] Examples of amines include aliphatic amines such as meglumine and tromethamine, as well as aromatic amines.

[0098] Examples of amides include carboxylic acid amides, such as nicotinamide.

[0099] The co-formulated compound can be used alone or in combination of two or more. In a preferred embodiment, the co-formulated compound is a non-volatile organic acid or an amino acid. The non-volatile organic acid is preferably a carboxylic acid, more preferably benzoic acid, which is optionally substituted at at least one position selected from hydroxyl, amino, and carboxyl groups at the ortho, meta, and para positions, and even more preferably 2,5-dihydroxybenzoic acid or salicylic acid.

[0100] In the eutectic, the co-formed product is present in an amount of, for example, 0.5 mol or more, preferably 0.8 mol or more, more preferably 0.9 mol or more, and even more preferably 1 mol or more, relative to 1 mol of quabordepistat. In the eutectic, the co-formed product is present in an amount of, for example, 2.5 mol or less, preferably 2 mol or less, more preferably 1.5 mol or less, and even more preferably 1 mol or less, relative to 1 mol of quabordepistat. In the eutectic, the co-formed product may be, for example, 0.5 to 2.5 mol relative to 1 mol of quabordepistat.

[0101] In yet another embodiment, the composition comprises: Solvates of quabodepicta, solvates of quabodepicta salts, or solvates of quabodepicta eutectic; Suspending agents; and Dispersion medium.

[0102] The solvate can be a solvate formed by quambopistat, a salt of quambopistat, or a eutectic of quambopistat with solvent molecules in any molar ratio. Examples of such solvates include hydrates, ethanol solvates, and THF (tetrahydrofuran) solvates. The solvate can exist, for example, as a solvate in which 0.5 to 2 solvent molecules are bound to 1 quambopistat molecule, such as in the form of a hemihydrate, monohydrate, 1.5-hydrate, or dihydrate.

[0103] The eutectic or solvate of quabodepistat can be, for example, those described in WO2021 / 230198A.

[0104] The composition may contain any concentration of the active ingredient, provided that the concentration is effective for the intended use of the composition. The concentration of the active ingredient in the composition, in free equivalent form, is, for example, 100 mg / mL or higher, preferably 150 mg / mL or higher, more preferably 200 mg / mL or higher, even more preferably 250 mg / mL or higher, even more preferably 300 mg / mL or higher. The concentration of the active ingredient in the composition, in free equivalent form, may be, for example, 400 mg / mL or lower, or 450 mg / mL or lower; however, from the viewpoint of maintaining efficacy over a long period while maintaining good flowability, the concentration is preferably 500 mg / mL or lower. The concentration of the active ingredient in the composition, in free equivalent form, is, for example, 100 to 500 mg / mL, preferably 200 to 500 mg / mL, more preferably 300 to 500 mg / mL.

[0105] There are no particular limitations on the suspending agents contained in the composition, as long as they are pharmaceutically acceptable and can achieve the desired viscosity. Examples of suspending agents include polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, D-α-tocopherol polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol (also known as "macrogol"), hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium dioctyl sulfosuccinate (DOSS).

[0106] Poloxamer is usually represented by the following formula: HO-[CH2CH2O] x -[CH(CH3)CH2O] y -[CH2CH2O] z-H (where x is 2 to 150, y is 15 to 70, and z is 2 to 150). Examples of poloxamer include poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and mixtures of two or more thereof. The average molecular weight of poloxamer is, for example, 2000 or higher, preferably 3000 or higher, more preferably 4000 or higher, and even more preferably 5000 or higher. For example, the average molecular weight of poloxamer is, for example, 6000 or higher, 6500 or higher, 7000 or higher, or 7500 or higher. The average molecular weight of poloxamer is, for example, 20000 or lower, preferably 19000 or lower, more preferably 18000 or lower. The average molecular weight of poloxamer is, for example, 2000 to 20000 or lower. The average molecular weight can be measured according to the method described in USP-NF (e.g., USP42-NF37, 2019 edition). In one embodiment, the suspending agent preferably contains poloxamer 338 and / or poloxamer 188.

[0107] Examples of D-α-tocopherol polyethylene glycol (PEG) succinates include D-α-tocopherol PEG1000 succinate.

[0108] Polyoxyethylene sorbitol fatty acid esters are usually represented by the following formula:

[0109] Where a + b + c + d is 20 (e.g., 15 to 25), and R is C 11-17 Alkyl or C 11-17 Alkenyl group.

[0110] Examples of polyoxyethylene dehydrated sorbitol fatty acid esters include polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, and mixtures thereof. In one embodiment, the suspending agent preferably comprises polysorbate 20.

[0111] The average molecular weight of polyethylene glycol (PEG) is, for example, 100 or higher, preferably 150 or higher, more preferably 200 or higher. The average molecular weight of PEG is, for example, 10,000 or lower, preferably 8,000 or lower, more preferably 5,000 or lower. The average molecular weight of PEG is, for example, from 100 to 10,000. The average molecular weight can be measured according to the methods described in USP-NF (e.g., USP42-NF37, 2019 edition). Examples of PEG include PEG200, PEG300, PEG400, PEG600, PEG3350, PEG4000, PEG6000, PEG8000, and mixtures of two or more of these. PEG3350 and / or PEG400 are preferred.

[0112] The suspending agent can be used alone or in combination of two or more. In one embodiment, when the suspending agent contains at least one selected from poloxamer, D-α-tocopherol polyethylene glycol succinate, and polyoxyethylene sorbitan fatty acid ester as a first suspending agent, it preferably further contains PEG as a second suspending agent to adjust the viscosity to the desired level.

[0113] The amount of the second suspending agent relative to 100 parts by weight of the first suspending agent is, for example, 10 parts by weight or more, preferably 15 parts by weight or more, more preferably 20 parts by weight or more. The amount of the second suspending agent relative to 100 parts by weight of the first suspending agent is, for example, 200 parts by weight or less, preferably 150 parts by weight or less, more preferably 100 parts by weight or less. The amount of the second suspending agent relative to 100 parts by weight of the first suspending agent is, for example, 10 to 200 parts by weight.

[0114] When the first suspending agent contains poloxamer 338, preferably the first suspending agent is present at an amount of 20 mg / mL or more, and the second suspending agent is present at an amount of 5 mg / mL or more; and equally preferably, the first suspending agent is present at an amount of 25 mg / mL or more, and the second suspending agent is present at an amount of 0 mg / mL or more. When the first suspending agent contains poloxamer 188, preferably the first suspending agent is present at an amount of 50 mg / mL or more, and the second suspending agent is present at an amount of 20 mg / mL or more. When the first suspending agent contains D-α-tocopherol polyethylene glycol succinate, preferably the first suspending agent is present at an amount of 50 mg / mL or more, and the second suspending agent is present at an amount of 0 mg / mL or more. When the first suspending agent contains polysorbate 20, preferably the first suspending agent is present at an amount of 30 mg / mL or more, and the second suspending agent is present at an amount of 30 mg / mL or more.

[0115] The concentration of the suspending agent in the composition is, for example, 10 mg / mL or higher, preferably 15 mg / mL or higher, more preferably 20 mg / mL or higher. The concentration of the suspending agent is, for example, 150 mg / mL or lower, preferably 120 mg / mL or lower, more preferably 100 mg / mL or lower. 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 suitably combined with the concentration of the active ingredient in the composition (e.g., 100 to 500 mg / mL in free equivalent).

[0116] There are no particular limitations on the dispersion medium contained in the composition, as long as it is pharmaceutically acceptable and capable of dispersing the active ingredient. Such dispersion media can be used alone or in combination of two or more. The dispersion medium preferably 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 like methanol, ethanol, propanol, and isopropanol, ketones like acetone, ethers like tetrahydrofuran, amides like dimethylformamide, and mixtures of these organic solvents. The organic solvent is preferably an alcohol, more preferably ethanol. In the solvent containing water and an organic solvent, the proportion of water is, for example, 50% by mass or higher and less than 100% by mass, preferably 60% by mass or higher and less than 100% by mass, more preferably 70% by mass or higher and less than 100% by mass (e.g., 70 to 99% by mass). In a preferred embodiment, the dispersion medium is water. Purified water, sterile purified water, and water for injection are particularly preferred.

[0117] The composition contains an appropriate amount of the dispersion medium, such that the content ratio of the active ingredient, etc., in the composition falls within the aforementioned range. For example, the composition may contain a certain amount of the dispersion medium, such 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, still more preferably 0.6 mL or more, particularly preferably 0.7 mL or more, even more preferably 0.8 mL or more, and most preferably 0.9 mL or more. Furthermore, for example, the composition may contain a certain amount of the dispersion medium, such that the total volume of the composition is 1 mL or more, 1.5 mL or more, 2 mL or more, or 2.5 mL or more. Furthermore, the composition may contain a certain amount of the dispersion medium, such 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, particularly preferably 2.5 mL or less, and even more preferably 2 mL or less. For example, the composition may contain an amount of the dispersion medium such that the total amount 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 the composition contained in a container such as a pre-filled syringe, vial, or ampoule.

[0118] The composition may also contain optional additives. There are no particular limitations on such additives, as long as they are pharmaceutically acceptable. Examples include isotonic agents, buffers, pH adjusters, and preservatives. Such additives may be used alone or in combination of two or more.

[0119] Examples of isotonic 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 glycerol. The concentration of the isotonic agent in the composition is, for example, 1 to 50 mg / mL, preferably 5 to 40 mg / mL.

[0120] Examples of buffers include phosphates such as sodium phosphate, sodium dihydrogen phosphate, sodium 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 buffer in the composition is, for example, from 0.01 to 1.5 mg / mL, preferably from 0.1 to 1 mg / mL.

[0121] The pH adjuster may be an acidic pH adjuster or an alkaline pH adjuster. Examples of acidic pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, and citric acid. Examples of alkaline pH adjusters include sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide. The pH adjuster is typically added in an appropriate amount according to the desired pH of the composition.

[0122] Examples of preservatives include benzoic acid or its salts (e.g., alkali metal salts such as sodium salts), parabens (e.g., alkyl esters such as methyl, ethyl, propyl, and butyl esters), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and benzyl alcohol. The composition may be preservative-free; however, when the composition contains 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.

[0123] 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, for example, contain a suspending agent on their surface.

[0124] The average particle size of the submicron particles is, for example, 500 nm or less, preferably 400 nm or less, more preferably 300 nm or less. The average particle size of the submicron particles is, for example, 10 nm or greater, 20 nm or greater, 30 nm or greater, 40 nm or greater, 50 nm or greater, 60 nm or greater, 70 nm or greater, 80 nm or greater, 90 nm or greater, or 100 nm or greater. The average particle size of the submicron particles is in the range of, for example, 10 to 500 nm, 50 to 400 nm, or 100 to 300 nm. The average particle size of the submicron particles can be 300 nm or greater, for example, 300 to 500 nm. Submicron particles with an average particle size of 100 nm or less can also be specifically referred to as nanoparticles. Such an average particle size range is preferred because it allows for a rapid increase in blood drug concentration, rapid onset of action, and maintenance of effect over a long period.

[0125] The polydispersity index of the submicron particles is, for example, 0.5 or less, preferably 0.45 or less, and more preferably 0.4 or less. The polydispersity index of the submicron particles can be, for example, 0.01 or greater, 0.05 or greater, or 0.1 or greater. The polydispersity index of the submicron particles is in the range of, for example, 0.01 to 0.5.

[0126] The aforementioned average particle size and polydispersity index can be measured using dynamic light scattering, for example, with a sample diluted with water at the desired dilution factor (e.g., 10 times). For measuring the average particle size by dynamic light scattering, an ELSZneo (manufactured by Otsuka Electronics Co., Ltd.) can be used, for example.

[0127] The composition may exhibit the property that its viscosity does not change (or remains substantially constant) with shear rate, i.e., it may exhibit Newtonian behavior; or the composition may exhibit the property that its viscosity decreases with increasing shear rate, i.e., thixotropy (shear thinning).

[0128] When the average particle size of the submicron particles is 300 nm or larger, the composition preferably exhibits thixotropy, more preferably satisfies the following conditions (A) and (B), and even more preferably satisfies (A), (B) and (C).

[0129] (A) From the perspective of, for example, resistance (slippage) and manufacturability during injection, the composition in 0.1s -1The viscosity (VL) at the shear rate is, for example, 10 Pa·s or less, preferably 8 Pa·s or less, 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, from 0.005 to 10 Pa·s.

[0130] (B) The composition is in the range of 900 to 1000 s -1 At shear rates within the range (e.g., at 900 s), -1 Or 1000 s -1 The viscosity (VH) of the composition is, for example, 0.5 Pa·s or lower, preferably 0.2 Pa·s or lower, more preferably 0.15 Pa·s or lower, and may be 0.1 Pa·s or lower. The viscosity VH of the composition is, for example, 0.001 Pa·s or higher, preferably 0.005 Pa·s or higher. The viscosity VH of the composition is in the range of, for example, 0.001 to 0.5 Pa·s. The viscosity VH of the composition may be in the range of 900 to 1000 s⁻¹. -1 The viscosity at the time point in the range where no viscosity change was observed even when the shear rate changed was within the range.

[0131] (C) The viscosity ratio of the composition, VL / VH, is, for example, 1.1 or greater, preferably 2 or greater, more preferably 5 or greater, and even more preferably 10 or greater.

[0132] The viscosity at the stated shear rate can be measured at 25°C, for example, using a rotational rheometer such as Discovery Hybrid rheometer-2 (DHR-2), Discovery Hybrid Rhiometer-3 (DHR-3), or Discovery Hybrid Rhoemeter-20 (DHR-20) (manufactured by TA Instruments).

[0133] The composition has a pH of, for example, 5 or higher at room temperature (e.g., 25°C), preferably 5.5 or higher, more preferably 6 or higher. The composition may optionally have a pH of 6.5 or higher at room temperature (e.g., 25°C). The composition has a pH of, for example, 9 or lower at room temperature (e.g., 25°C), preferably 8.5 or lower, more preferably 8 or lower. The composition may optionally have a pH of 7.5 or lower at room temperature (e.g., 25°C). The composition has a pH of, for example, 5 to 9 at room temperature (e.g., 25°C), preferably 6 to 8.

[0134] There are no particular limitations on the route of administration of the composition. The composition is preferably administered intramuscularly or subcutaneously. Examples of subjects administering the composition include mammals, such as humans. Subjects administering the composition may be patients requiring prevention and / or treatment of mycobacterial infections. The composition for intramuscular or subcutaneous administration is also preferably used in combination with an oral composition comprising at least one selected from quambordpistat, its salts, its cocrystals, and their solvates, and such combination therapy may be effective in patients at an early stage of initiating prevention and / or treatment of mycobacterial infections.

[0135] Because the composition exhibits a sustained effect (e.g., maintaining effective blood drug concentrations), it is suitable for use as a long-acting injectable (LAI) formulation, thereby reducing the frequency of administration. For example, the composition can be administered at intervals of 1 week or longer, 2 weeks or longer, 3 weeks or longer, 4 weeks or longer, or 1 month or longer. Longer dosing intervals are preferred. While there is no particular upper limit, the interval can be, for example, 2 months, 3 months, 4 months, 5 months, or 6 months. This dosing frequency is preferred from the perspective of patient medication adherence. The administration period (or treatment period) can be, for example, 6 months or less. In one embodiment, the composition is preferably administered subcutaneously at a frequency of once a month or less, or once every two months or less. In another embodiment, the composition is preferably administered intramuscularly at a frequency of once every two months or less, or once every three months or less. The composition can also be administered in combination with another composition in the form of a suspension of submicron particles, the other composition comprising at least one component selected from quarbodpistat, its salts, its cocrystals, and their solvates, and also comprising a suspending agent and a dispersion medium. Because LAI formulations work rapidly, they can also be administered in combination with another formulation (e.g., one that provides a longer-lasting effect but has a slower onset of action than the LAI formulation), and this combination may be effective in the early stages of treatment. Combining LAI formulations with oral formulations is also preferred.

[0136] The composition is preferably administered at a daily dose of, for example, 10 mg or higher or 12 mg or higher (or a monthly dose of, for example, 300 mg or higher or 360 mg or higher). The composition is preferably administered at a daily dose of, for example, 20 mg or lower or 18 mg or lower (or a monthly dose of, for example, 600 mg or lower or 540 mg or lower). The composition is preferably administered at a daily dose of, for example, 10 to 20 mg, more preferably 12 to 18 mg.

[0137] The composition is preferably administered in an injection volume of, for example, 0.5 mL or more, or 1 mL or more per dose (or per month). Alternatively, the composition is administered in an injection volume of, 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 per dose (or per month). The composition is preferably administered in an injection volume of, for example, 0.5 to 5 mL, 0.5 to 3 mL, or 1 to 2 mL per dose (or per month).

[0138] The composition is typically an injectable formulation. The composition is an injectable formulation administered using an 18-30G (specification) or 20-30G (specification) needle.

[0139] The composition is preferably used for the prevention and / or treatment of mycobacterial infections (including latent mycobacterial infections). Mycobacterial infections are caused by, for example, Mycobacterium tuberculosis, Mycobacterium leprae, or nontuberculous mycobacteria. Examples of Mycobacterium tuberculosis include Mycobacterium tuberculosis (Mycobacterium tuberculosis). Mycobacterium tuberculosis ), Mycobacterium africanum ( Mycobacterium africanum m), Bovine Mycobacterium ( Mycobacterium bovis Mycobacterium capsulatum ( ) Mycobacterium capra Mycobacterium sepium ( ) Mycobacterium pinnipedii ) and Mycobacterium vulgatum ( Mycobacterium microti Examples of Mycobacterium leprae include Mycobacterium leprae ( ). Mycobacterium leprae Examples of nontuberculous mycobacteria include Mycobacterium avium ( ). Mycobacterium avium Intracellular mycobacteria ( Mycobacterium intracellulare Mycobacterium Kansas ( Mycobacterium kansasii ), Mycobacterium marinum ( Marine Mycobacterium Mycobacterium simianum ( Mycobacterium simianum ), Mycobacterium scrofula ( Mycobacterium scrofulaceum ), Mycobacterium chulcei ( Mycobacterium szulgai ), Mycobacterium bufossa ( Mycobacterium xenopis Mycobacterium marmosetum ( Mycobacterium malmoensis Haemophilus ( ) Mycobacterium haemophilus ), Mycobacterium ulcerans ( Mycobacterium ulcerans ), Mycobacterium pyogenes ( Mycobacterium shimoidei ), Mycobacterium tumefaciens ( Mycobacterium fortuitum ), Mycobacterium tectorum ( Mycobacterium chelonae ), Mycobacterium smegmatis ( Mycobacterium smegmatis ) and Mycobacterium aureus ( Mycobacterium aurum In a preferred embodiment, the mycobacterial infection is tuberculosis (including latent tuberculosis). The tuberculosis may be multidrug-resistant tuberculosis. The tuberculosis may be pulmonary tuberculosis.

[0140] The composition is preferably a sterile composition or a sterilized composition. From the perspective of inhibiting particle aggregation and / or reducing the viscosity of the composition, the sterilization is preferably irradiation sterilization. Examples of irradiation sterilization include gamma-ray sterilization, electron beam sterilization, and X-ray sterilization.

[0141] The composition may be used in combination with another preventive or therapeutic agent for mycobacterial infections. In this specification, the term "combined use" is intended to include both simultaneous and separate administration (e.g., sequential administration). In one embodiment, in addition to the active ingredient, the composition may also contain one or more other therapeutic or preventive agents for mycobacterial infections and may be administered as a single composition.

[0142] The preferred method for preparing the composition is wet milling. Preferred wet milling methods include wet ball milling, high-pressure homogenization, high-shear homogenization, and bead milling (e.g., Dyno-Mill). In addition to the above-described milling methods, other low-energy and high-energy mills (e.g., roller mills) can also be used. Other preparation methods include controlled crystallization.

[0143] In one embodiment, the composition can be prepared by a method including, for example, the following steps: Step 1: mixing the active ingredient, suspending agent and dispersion medium; Step 2: wet milling the suspension obtained by mixing; and Step 3: collecting the suspension obtained by wet milling.

[0144] In step 1, there is no particular restriction on the order in which each component is mixed. In one embodiment, step 1 includes mixing the components other than the active ingredient to obtain a mediator solution, and mixing the mediator solution with the active ingredient.

[0145] In step 2, the wet milling is preferably performed using a bead mill or a high-pressure homogenizer, more preferably a bead mill. There are no particular limitations on the bead milling method. In one embodiment, step 2 is the addition of beads to the suspension and stirring. The bead milling can be performed in any of intermittent, continuous (through), or cyclic modes. Examples of bead materials include zirconium oxide, alumina, and glass. The bead diameter is, for example, 0.1 to 5 mm, preferably 0.2 to 3 mm. The average particle size obtained by bead milling can be appropriately adjusted by factors such as bead size, rotational speed (circumferential speed) and flow rate during the milling process, and milling time. There are no particular limitations on the high-pressure homogenizer method. The processing pressure (or the final achievable pressure) is, for example, 2000 bar or higher, preferably 2000 to 4000 bar, more preferably 2000 to 3000 bar. The processing time is, for example, 1 to 60 minutes per liter of suspension, preferably 5 to 30 minutes.

[0146] In step 3, there are no particular limitations on the method for collecting the suspension obtained by wet milling. When wet milling is performed using a bead mill, step 3 typically includes a bead removal step. In one embodiment, the bead removal step is preferably a step of separating and removing the beads by means of a separator (e.g., a gap or screen) at the bead mill outlet or by centrifugal separation of the bead mill, or a step of separating and removing the beads using a needle (e.g., 22G or smaller) or a mesh filter (e.g., an 80 µm screen) with an aperture size smaller than the bead size.

[0147] Step 3 preferably includes a method of filling a container with the suspension obtained after wet milling (or, in the case of bead milling, the suspension obtained after removing the beads). In one embodiment, a filling device can be used, such as a valve-type piston pump, a peristaltic pump, a mass flow system, or a time-pressure system. There are no particular limitations on the container, examples of which include ampoules, vials, and pre-filled syringes, with pre-filled syringes being preferred.

[0148] The composition is preferably a sterilized composition or a sterile composition. In this case, in addition to steps 1, 2, and 3, the preparation method preferably includes step 4 of sterilizing the suspension (e.g., a suspension obtained by wet milling, typically a suspension in a container). From the perspective of suppressing particle aggregation, the sterilization is preferably irradiation sterilization. Examples of irradiation sterilization include gamma-ray sterilization, electron beam sterilization, and X-ray sterilization.

[0149] This invention includes a container (also referred to as a main container) containing the composition. Examples of containers include syringes such as pre-filled syringes, vials, ampoules, bottles, and cartridges. The material of these containers is not particularly limited and can be glass or plastic. In one embodiment, the container is a pre-filled syringe, vial, or ampoule. For example, the composition can be used as a pre-filled syringe by filling a syringe with the composition as is. Sterilization after filling the container (particularly a pre-filled syringe, vial, or ampoule) with the composition is also preferred. Furthermore, this invention includes a medicine box containing the container (particularly a pre-filled syringe, vial, or ampoule).

[0150] This invention includes a method for preventing and / or treating mycobacterial infections, the method comprising administering an effective amount of the composition to a subject requiring prevention and / or treatment of a mycobacterial infection. Each component of the method may employ the corresponding element described for the composition. This invention also includes a method for preventing and / or treating mycobacterial infections (e.g., tuberculosis), the method comprising administering, intramuscularly or subcutaneously, one to six times at intervals of one week or longer, preferably one month or longer, more preferably one to two months, to a subject requiring prevention and / or treatment of a mycobacterial infection (e.g., tuberculosis), the composition comprising at least one component selected from quambordpistat, its salts, its eutectics, and their solvates. Furthermore, the present invention includes a method for preventing and / or treating latent tuberculosis, the method comprising administering, at intervals of 1 to 3 times, intramuscularly or subcutaneously, an effective amount of a composition in the form of a suspension of submicron particles to a subject requiring prevention and / or treatment of latent tuberculosis, the composition comprising at least one component selected from quambordipistat, its salts, its eutectics, and solvates thereof.

[0151] This invention includes the use of the composition in the preparation of a medicament for the prevention and / or treatment of mycobacterial infections. Each component in the method may employ the corresponding element described for the composition. In one embodiment, the medicament is preferably administered intramuscularly or subcutaneously 1 to 6 times at intervals of 1 week or longer, 1 month or longer, or 1 to 2 months, or intramuscularly or subcutaneously 1 to 3 times at intervals of 1 to 2 months.

[0152] Example

[0153] The invention is described in more detail below. The invention is not limited to the embodiments described below. The term "QS" stands for "appropriate amount ( quantum sufficit The abbreviation for ")" means sufficient quantity.

[0154] Examples 1 to 18 and Comparative Examples 1 to 2

[0155] As shown in Table 1, poloxamer 338 (Kolliphor P338) and poloxamer 188 (Kolliphor P188) obtained from BASF, D-α-tocopherol polyethylene glycol (PEG) 1000 succinate (TPGS) or polysorbate 20 obtained from Sigma-Aldrich, alone or together with PEG 3350 (POLYGLYKOL 3350S) obtained from CLARIANT and / or PEG 400 (Super Refined PEG400) obtained from CRODA, were dissolved in water (water for injection) as an isotonic agent (mannitol) and as a buffer (sodium dihydrogen phosphate monohydrate). The resulting solution was adjusted to pH 7.0 with sodium hydroxide solution to prepare the media solution. The active ingredient, quarbodepistat (OPC-167832), and the prepared media solution were weighed and mixed in vials to prepare a suspension. Additionally, 3 g of the suspension was added to each vial. 0.2 mm zirconia beads were prepared, and a stir bar was placed in the vial. The vial containing the stir bar was stirred on a stirrer and bead milled (1500 rpm, 24 hours). All operations after suspending the active ingredient in the media solution were performed at a temperature of 10°C or lower. A diameter smaller than [missing information] was used. The milled suspension was collected using an injection needle (29G or smaller) with 0.2 mm zirconia beads or an 80 µm nylon mesh filter. This yielded the injectable formulations shown in Table 1.

[0156] Each injectable formulation thus obtained was diluted 10-fold with water for injection. The particle size of the diluted formulations was measured using an ELSZneo (manufactured by Otsuka Electronics Co., Ltd.) as the measuring device. The particle size was measured by dynamic light scattering and is shown in Table 2 based on scattering intensity. When the measurement results obtained using the ELSZneo indicated that the obtained particles were microparticles, the particle size was measured by laser diffraction / scattering using a SALD-3100 (manufactured by Shimadzu Corporation) as the measuring device. Purified water was used as the measuring solvent. The particle size was measured while the built-in sonication of the SALD-3100 was applied.

[0157] In addition, the viscosity of some injectable formulations was measured using a Discovery Hybrid Rheometer (DHR)-2 (manufactured by TA Instruments). The viscosity measurement conditions are as follows.

[0158] - Shear rate: 10 -3→ 1000 (1 / s)

[0159] - Temperature measured: 25℃

[0160] - Use a 40 mm conical plate or a 40 mm flat plate

[0161] - Gap: 50 μm (40 mm cone plate) or 500 μm (40 mm flat plate)

[0162] Table 1

[0163] Experimental Example 1

[0164] The average particle size and polydispersity index of each embodiment were measured using ELSZneo. The results are shown in Table 2.

[0165] Table 2

[0166] As shown in Table 2, suspensions with an average particle size of less than 500 nm could be prepared in all examples. On the other hand, uniform suspensions could not be prepared in the comparative examples.

[0167] Experimental Example 2

[0168] The viscosities of Examples 1 through 6, 8 and 9 were measured using a rheometer. The results are shown in Table 3.

[0169] Table 3

[0170] As shown in Table 3, in the formulations with added PEG (Examples 2, 4, 6, 8, and 9), at 0.1 s -1 The decrease in viscosity at low shear rates indicates reduced sliding resistance and improved manufacturability.

[0171] Experimental Example 3

[0172] An injectable formulation with an average primary particle size of 125.6 nm was prepared according to the formulation in Example 4. The injectable formulation was administered subcutaneously to the dorsal region of male SD rats at a dose of 50 mg / kg. To assess hematogenous transfer of OPC-167832 after administration, blood samples were collected at 0.083, 1, 3, 6, 9, 14, 21, 28, 42, 56, 70, and 84 days post-administration, and serum OPC-167832 concentrations were measured by LC-MS / MS. Figure 1 The results are shown.

[0173] The blood concentration reached its maximum 0.083 days after OPC-167832 administration, and the serum drug level was maintained for 21 days or longer.

[0174] Test Example 4

[0175] The injectable formulation according to Example 18, with an average particle size of 293.8 nm, was administered to the calf muscles of male SD rats at a dose of 50 mg / kg. To assess hematogenous transfer of OPC-167832 after administration, blood samples were collected at 0.083, 1, 3, 6, 9, 14, 21, 28, 42, 56, 70, and 84 days post-administration, and serum OPC-167832 concentrations were measured by LC-MS / MS. Figure 2 The results are shown.

[0176] The blood concentration of OPC-167832 reached its maximum 6 days after administration, and the serum drug level was maintained for 42 days or longer.

[0177] Example 19 and Comparative Example 3

[0178] As shown in Table 4, poloxamer 338 and PEG3350 as suspending agents, mannitol as an isotonic 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 mediator solution. The active ingredient, quarbodepistat (OPC-167832), and the mediator solution were weighed and mixed in vials to prepare a suspension. Furthermore, 3 g of the suspension was added to each vial. 0.2 mm zirconia beads were prepared and a stir bar was placed in a vial. The vial containing the stir bar was stirred with a stirrer and bead milled (1500 rpm, 24 hours). All operations after suspending the active ingredient in the media solution were performed at 10°C or lower. A pore size smaller than [missing information] was used. The milled suspension was collected using an injection needle (29G or smaller) with 0.2 mm zirconia beads or an 80 µm nylon mesh filter to obtain Example 19 as shown in Table 4. Comparative Example 3 was prepared by dissolving the additive in water for injection and adjusting the solution to pH 7.0 with sodium hydroxide solution. Each vial was filled with 3.5 mL of Example 19 or Comparative Example 3, then capped and crimped with an aluminum cap. Subsequently, γ-irradiation was performed at 25–35 kGy.

[0179] Table 4

[0180] Experimental Example 5

[0181] The average particle size and polydispersity index of each embodiment were measured using ELSZneo. The results are shown in Table 5.

[0182] Table 5

[0183] Experimental Example 6

[0184] Local irritation study of OPC-167832 LAI formulation

[0185] The formulation of Example 19 was subcutaneously injected into manually restrained rabbits at a dose of 15 mg / kg (based on OPC-167832) using a 23G injection needle.

[0186] The formulation of Comparative Example 3, the 0.425% aqueous acetic acid solution and the 1.7% aqueous acetic acid solution as positive controls, and the physiological saline solution as a negative control were each drawn into a disposable syringe at a volume of 0.4 mL / kg. Male Kbl / JW rabbits were manually restrained, and the solutions were injected subcutaneously using a 23G needle.

[0187] On days 7 and 14 post-administration, animals were euthanized by exsanguination from the abdominal aorta under anesthesia induced by intravenous administration of 2.5% sodium thiopental solution (2 mL / kg) via the ear vein. The subcutaneous application site (skin and subcutaneous tissue) was then excised, and the excised subcutaneous tissue was fixed in 10% neutral buffered formalin. After paraffin embedding according to standard procedures, hematoxylin and eosin (HE) stained tissue samples were prepared for histopathological examination. Local irritation at the application site was assessed using the mean of three individuals.

[0188] Table 6

[0189] Result rating (score)

[0190] -: None (1), ±: Slight (2), +: Mild (3), 2+: Moderate (4), 3+: Significant (5).

[0191] Table 6 shows subcutaneous retention and subcutaneous irritation. Based on gross observation at autopsy, test formulation material residues were observed at 7 and 14 days post-application when Example 19 was administered. In contrast, no test formulation material residues were observed at 7 and 14 days post-application when the control material without OPC-167832 was administered. Histopathological examination showed that Example 19 was weaker in any aspect of necrosis, partial necrosis / repair response, and fibrosis compared to the positive controls (i.e., 0.425% acetic acid and 1.7% acetic acid), and irritation was within acceptable limits. Immunological responses such as foam cell aggregates and mononuclear cell infiltration were observed when Example 19 was administered, but irritation was within acceptable limits.

[0192] Experimental Example 7

[0193] Canine pharmacokinetic study and post-study histopathological examination of OPC-167832 LAI formulation

[0194] Example 19 was administered via aspiration at a dose of 25 mg / kg (based on OPC-167832) into a disposable syringe. Male dogs were manually restrained, and Example 19 was subcutaneously injected into the dorsal region of the dog using a 23G needle. Blood was collected at a total of 12 time points: 2 hours and 6 hours post-administration, and on days 1, 3, 6, 9, 14, 21, 28, 35, 42, and 56 post-administration. Specifically, after restraining the animal and disinfecting the blood collection site with rubbing alcohol, approximately 2 mL of blood was collected from the cephalic vein using a heparinized vacuum blood collection tube (Venoject® II vacuum blood collection tube, Terumo Corporation). After all blood collection was completed, the animal was euthanized by exsanguination from the carotid artery under anesthesia induced by administration of 25 mg / mL / kg sodium thiopental into the cephalic vein. The subcutaneous application site (skin and subcutaneous tissue) was then excised, and the excised subcutaneous tissue was fixed with 20% neutral buffered formalin. After paraffin embedding using standard methods, HE-stained tissue samples were prepared, and the application site was evaluated by histopathological examination using the average of three individuals.

[0195] Using the collected blood samples, the concentration of OPC-167832 in the plasma was measured by LC-MS / MS. As a result, as... Figure 3 As shown, the maximum plasma drug concentration of OPC-167832 was found to be reached in plasma 9 days after administration, and it was confirmed that the plasma concentration of OPC-167832 in dogs was maintained for 1 month or longer.

[0196] Table 7

[0197] Result rating (score): -: None (1), ±: Slight (2), +: Mild (3), 2+: Moderate (4), 3+: Significant (5).

[0198] As shown in Table 7, no necrosis, focal necrosis / repair response, or fibrosis indicative of subcutaneous injury was observed in histopathological examination following the application of Example 19; only an immune response was observed, and the irritation was within acceptable limits.

[0199] Experimental Example 8

[0200] The injectable formulation of Example 19 was diluted 10-fold and 100-fold with a carrier solution. The 100-fold diluted formulation was subcutaneously injected into the dorsal region of female mice at doses of 6 and 20 mg / kg based on OPC-167832, while the 10-fold diluted formulation was subcutaneously injected into the dorsal region of female mice at doses of 60 and 120 mg / kg. To assess hematopoiesis of OPC-167832 after administration, blood samples were collected from the tail vein at 0.083, 1, 3, 7, 14, 21, and 28 days post-administration, and plasma concentrations of OPC-167832 were measured. The results are shown in Table 8. Dose-dependent plasma concentrations were observed.

[0201] Table 8

[0202] Examples 20 and 21

[0203] As shown in Table 9, poloxamer 338 and PEG3350 as suspending agents, mannitol as an isotonic 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 mediator solution. OPC-167832 and the mediator solution were weighed and mixed in a beaker to prepare the formulation. Using a DYNO-MILL MULTI LAB (Willy A. Bachofen AG) equipped with a stirrer pan and a 600 mL grinding chamber, the mediator solution was prepared... Zirconia beads of 0.2 mm were placed in a grinding chamber to achieve an 80% filling rate. The circumferential speed was set to 10 m / s and the flow rate to 50 mL / min. Bead milling was performed, and the suspension was collected. 3.5 mL of the injectable formulation was filled into a vial, capped, and crimped with an aluminum cap to obtain Example 20. Example 20 was irradiated with gamma rays at 25-35 kGy to obtain Example 21.

[0204] Table 9

[0205] Experimental Example 9

[0206] Examples 20 and 21 were stored at 40°C for 1 month and 3 months, respectively, to evaluate their stability. In the stability study, the average particle size and viscosity were measured as averages with n=3.

[0207] The average particle size was measured using a Zetasizer (Malvern Panalytical). To prepare the diluent for measurement using the Zetasizer, the mediator solution was diluted 100-fold with purified water. Each injectable formulation was diluted to the optimal concentration using the diluent before measurement. Viscosity was measured using a rheometer.

[0208] Crystal form analysis was also performed using an Empyrean multi-purpose X-ray diffractometer (Malvern Panalytical).

[0209] Table 10

[0210] The stability of the injectable formulations of Examples 20 and 21 was evaluated after storage at 40°C for one and three months. As shown in Table 10, the injectable formulations showed no changes in particle size or viscosity, nor any particle sedimentation, after storage at 40°C for one and three months, indicating that the formulations were stable. It was also confirmed that bead milling or gamma-ray irradiation did not alter the crystal form of the active pharmaceutical ingredient in the injectable formulations.

[0211] Experimental Example 10

[0212] In vivo therapeutic efficacy study of the LAI formulation of OPC-167832

[0213] By using 460 CFU of Mycobacterium tuberculosis ( Mycobacterium tuberculosis A mouse model of tuberculosis was established by intratracheal inoculation of BALB / c mice with *S. kurundinella* and allowing infection to progress for 2 weeks. The LAI formulation of Example 19 was diluted with a carrier solution without active agent to 4 mg / mL or 40 mg / mL, and the resulting formulation was administered subcutaneously (SC) to the dorsal region of the mice at a total dose of 12 mg / kg, 40 mg / kg, or 120 mg / kg on the day of treatment initiation, or twice subcutaneously (SC) on the day of treatment initiation and two weeks after treatment initiation. Figure 4 The product is labeled as "QBS-LAI 12 mg / kg". 1”, QBS-LAI 40 mg / kg 1”, QBS-LAI 120 mg / kg 1”, QBS-LAI 6 mg / kg 2”, QBS-LAI 20mg / kg 2” and “QBS-LAI 60 mg / kg” 2”). As a comparative control, a suspension of quambordpistat jet mill powder was prepared using a 5% gum arabic solution and administered orally (PO) at 3.5 mg / kg daily for 28 consecutive days from the start of treatment (at 2”). Figure 4 The substance was labeled as "QBS-PO (3.5 mg / kg)". 28). To confirm the reduction in the number of viable bacteria in the lungs, mice were euthanized under anesthesia by exsanguination from the inferior vena cava on the second day after the completion of 28 days of treatment, and the lungs were aseptically excised. The excised lungs were placed in homogenization tubes containing 2 mL of sterile water and homogenized using a multi-bead shaker. The homogenate was serially diluted, and 0.1 mL of each dilution was spread onto 7H11 agar plates containing 0.4% activated charcoal. The plates were incubated until colonies appeared, and the number of viable bacteria in the lungs after treatment was counted. As a control for assessing the effect of reducing the number of viable bacteria in the lungs, the number of viable bacteria in the lungs of the time group was measured in the same manner (in Figure 4 The lung bacteria count (referred to as "Initial") in the group that received two subcutaneous (SC) injections of a carrier solution without the active agent of Example 19 on the treatment start date and two weeks after the treatment start date. Figure 4 The winning bid was for "LAI-media". 2") and the number of viable lung bacteria (in the group that received oral administration of 5% gum arabic solution for 28 days from the start of treatment) Figure 4 The winning bid was for "PO-medium". 28”). As a result, such as Figure 4 As shown, QBS-LAI 6 mg / kg Group 2 and QBS-LAI 12 mg / kg Group 1 showed the same or slightly lower lung bacterial counts as the initial group, indicating an inhibitory effect on the increase of lung bacterial counts. Other LAI treatment groups showed a reduction in lung bacterial counts compared to the initial group, thus confirming a bactericidal effect. Even at QBS-PO 3.5 mg / kg Compared to the reduction in lung bacterial count observed in 28 groups, QBS-LAI 60 mg / kg 2. It also exhibits strong bactericidal effects. QBS-LAI 40 mg / kg Group 1 showed improvement with QBS-PO 3.5 mg / kg 28 groups showed a reduction in lung bacterial count, while QBS-LAI 120 mg / kg Group 1 with QBS-PO 3.5 mg / kg The 28 groups showed a more significant reduction in lung bacteria count. (QBS-LAI 120 mg / kg) Group 1 (single administration) and QBS-LAI 60 mg / kg The reduction in lung bacteria counts observed in the two groups (administered in two separate doses) was almost comparable. Subcutaneous (SC) administration of the QBS LAI submicron formulation, with only one or two treatments, is expected to provide comparable or greater therapeutic effects than that achieved with continuous oral administration for 28 days.

Claims

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

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

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

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

5. The composition according to claim 4, wherein the suspending agent further comprises polyethylene glycol.

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

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

8. The composition according to claim 1, for intramuscular or subcutaneous administration.

9. The composition according to claim 1, for use at intervals of one week or longer.

10. The composition according to claim 1, wherein it is an injectable formulation.

11. The composition according to claim 1, for the prevention and / or treatment of mycobacterial infection.

12. A pre-filled syringe, vial, or ampoule containing the composition according to any one of claims 1 to 11.

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

14. The method of claim 13, wherein the wet grinding is performed using a bead mill.

15. The method according to claim 13 or 14, further comprising step 4, namely, sterilizing the collected suspension by irradiation.

16. A method for preventing and / or treating mycobacterial infection, the method comprising administering, at intervals of one week or longer, an effective amount of a composition in the form of a suspension of submicron particles intramuscularly or subcutaneously to a subject requiring prevention and / or treatment of mycobacterial infection, the composition comprising at least one component selected from quambordpistat, its salts, its eutectics, and solvates thereof.

17. The method of claim 16, wherein the administration is the intramuscular or subcutaneous administration of an effective amount of the composition to the subject at intervals of one month or longer.

18. The method of claim 16, wherein the administration is to administer an effective amount of the composition to the subject intramuscularly or subcutaneously 1 to 6 times at intervals of 1 to 2 months.

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

20. A method for preventing and / or treating latent tuberculosis, the method comprising administering, intramuscularly or subcutaneously, one to three times at intervals of one to two months, an effective amount of a composition in the form of a suspension of submicron particles, the composition comprising at least one component selected from quamboropistat, its salts, its eutectics, and solvates thereof.

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