Solid dispersions containing deramanib

Abstract

Disclosed is a solid dispersion containing the following components (a), (b), and (c). (a) Deramanib; (b) at least one substance selected from the group consisting of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and a vinyl pyrrolidone-vinyl acetate copolymer; and (c) at least one substance selected from the group consisting of hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

Description

Technical Field

[0001] The present invention relates to a solid dispersion containing delamanid and a method for producing the solid dispersion, etc. It should be noted that all the documents described in this specification are incorporated into this specification by reference. Background Art

[0002] Delamanid is a (2R)-2-methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b] Delamanid has excellent bactericidal effects on Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis and atypical mycobacteria (Patent Document 1). In addition, Delamanid is known to be a poorly water-soluble compound with low solubility in water, and research is being conducted to improve solubility and oral absorption (Patent Documents 2 and 3).

[0003]

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: Japanese Patent Application Publication No. 2004-149527

[0007] Patent Document 2: International Publication No. 2007 / 013477

[0008] Patent Document 3: International Publication No. 2019 / 240104 Summary of the invention

[0009] Problem that the invention aims to solve

[0010] As a solubilization method for improving the solubility of poorly water-soluble compounds, various methods such as micronization (nanoparticleization), metastable type (polymorphic), salt, eutectic, amorphous, solubilization using surfactants, oils, etc. can be used. Among them, amorphous form is a formulation technology with high practicality. As a way to improve the instability of amorphous form, there is a solid dispersion technology that is composited with carriers such as polymers. Solid dispersion is "a solid dispersion formed by dispersing one or more active ingredients in a solid state and inactive carriers or their matrix". As a manufacturing method for solid dispersion, there are methods such as coprecipitation, spray drying, and hot melt extrusion. Hot melt extrusion (Hot Melt Extrusion, HME) has many advantages such as continuous process (easy to scale up), solvent-free method (no need for solvent treatment, no solvent residue, etc., which is useful in terms of environment / cost), and can be applied to different drug delivery systems (including particles, tablets, sustained-release tablets, suppositories, stents, ophthalmic implants, and transdermal and transmucosal delivery systems). However, there are the following issues: the process parameters in HME depend on thermodynamics and rheological properties, so high processing temperatures are usually required, which poses a risk of thermal degradation of the drug; if the processing temperature is lowered to suppress this risk, crystalline drugs may remain, etc. Delamanid is a compound with poor thermal stability (melting point: about 195°C (decomposition)), and its melting point is close to its decomposition point, so HME that requires high temperature processing is believed to generate decomposition products and be difficult to manufacture.

[0011] One of the objects of the present invention is to provide a solid dispersion containing delamanid, a method for producing the solid dispersion, a pharmaceutical composition containing the solid dispersion, and an oral solid preparation.

[0012] Methods used to solve problems

[0013] The present inventors have conducted intensive studies to solve the above problems and have found that a solid dispersion having excellent solubility etc. can be obtained by combining delamanid, a specific vinyl polymer and a specific cellulose compound. Based on this finding, the present inventors have conducted further studies and have completed the present invention.

[0014] The present invention includes, for example, the subject matters described in the following items.

[0015] Item 1.

[0016] A solid dispersion comprising the following components (a), (b) and (c).

[0017] (a) Dramani

[0018] (b) at least one selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers and vinyl pyrrolidone-vinyl acetate copolymers

[0019] (c) at least one selected from the group consisting of hypromellose phthalate and hypromellose acetate succinate

[0020] Item 2.

[0021] The solid dispersion according to item 1, wherein the mass ratio of component (a) to component (b) is in the range of 1:1 to 1:20.

[0022] Item 3.

[0023] The solid dispersion according to item 1 or 2, wherein the mass ratio of component (a) to component (b) is in the range of 1:1 to 1:8.

[0024] Item 4.

[0025] The solid dispersion according to any one of items 1 to 3, wherein the mass ratio of component (a) to component (b) is in the range of 1:1 to 1:5.

[0026] Item 5.

[0027] The solid dispersion according to any one of items 1 to 4, wherein the mass ratio of component (a) to component (c) is in the range of 1:1 to 1:10.

[0028] Item 6.

[0029] The solid dispersion according to any one of items 1 to 5, wherein the mass ratio of component (a) to component (c) is in the range of 1:1 to 1:8.

[0030] Item 7.

[0031] The solid dispersion according to any one of items 1 to 6, wherein the mass ratio of component (a) to component (c) is in the range of 1:1 to 1:5.

[0032] Item 8.

[0033] The solid dispersion according to any one of items 1 to 7, wherein the mass ratio of component (a) to component (b) is in the range of 1:1 to 1:5, and the mass ratio of component (a) to component (c) is in the range of 1:1 to 1:5.

[0034] Item 9.

[0035] The solid dispersion according to any one of items 1 to 8, wherein the component (b) contains a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0036] Item 10.

[0037] The solid dispersion according to any one of items 1 to 9, wherein the component (b) contains a vinyl pyrrolidone-vinyl acetate copolymer.

[0038] Item 11.

[0039] The solid dispersion according to any one of Items 1 to 10, wherein the component (c) contains hypromellose phthalate.

[0040] Item 12.

[0041] The solid dispersion according to any one of items 1 to 11, wherein the component (b) contains a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the component (c) contains hypromellose phthalate.

[0042] Item 13.

[0043] The solid dispersion according to any one of items 1 to 12, wherein the component (b) contains a vinyl pyrrolidone-vinyl acetate copolymer, and the component (c) contains hypromellose phthalate.

[0044] Item 14.

[0045] The solid dispersion according to any one of Items 1 to 13, further comprising vitamin E.

[0046] Item 15.

[0047] The solid dispersion according to item 14, wherein the vitamin E is dl-α-tocopherol.

[0048] Item 16.

[0049] The solid dispersion according to any one of Items 1 to 15, which is a hot melt extrudate or a pulverized product thereof.

[0050] Item 17.

[0051] A pharmaceutical composition comprising the solid dispersion according to any one of items 1 to 16.

[0052] Item 18.

[0053] An oral solid preparation comprising the solid dispersion according to any one of items 1 to 16.

[0054] Item 19.

[0055] The oral solid preparation according to Item 18, which is a tablet or a capsule.

[0056] Item 20.

[0057] A method for producing the solid dispersion described in any one of items 1 to 16, comprising the step of hot-melt extruding a composition containing components (a), (b) and (c).

[0058] Item 21.

[0059] The solid dispersion according to any one of Items 1 to 16, which does not contain xylitol.

[0060] Item 22.

[0061] The solid dispersion according to any one of Items 1 to 16, which contains no sugar alcohol.

[0062] Item 23.

[0063] The solid dispersion according to any one of items 1 to 16, which does not contain xylitol, sorbitol, mannitol and poloxamer.

[0064] Item 24.

[0065] The solid dispersion according to item 9, 11 or 12, wherein the mass ratio of component (a) to component (b) to component (c) is about 1:4:3.

[0066] Item 25.

[0067] The solid dispersion according to item 10, 11 or 13, wherein the mass ratio of component (a) to component (b) to component (c) is about 1:2:2.

[0068] Effects of the Invention

[0069] The solid dispersion containing Delamanid included in the present invention has excellent solubility, etc. In addition, according to the method for producing the solid dispersion of Delamanid included in the present invention, it can be produced by a method with low environmental load and low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 This is a graph showing the change over time in serum concentration after the capsule containing the solid dispersion of Example C was administered to dogs. DETAILED DESCRIPTION

[0071] In this specification, “about” means an error, for example, including a variation within ±10%, within ±5%, or within ±1% of the numerical value thereafter.

[0072] In this specification, “comprising” includes the concepts of “consisting essentially of” and “consisting of”.

[0073] The following describes each embodiment of the present invention in further detail.

[0074] [Solid dispersion]

[0075] The solid dispersion included in the present invention (hereinafter sometimes referred to as the solid dispersion of the present invention) contains: (a) delamanid; (b) at least one selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers and vinyl pyrrolidone-vinyl acetate copolymers; and (c) at least one selected from the group consisting of hypromellose phthalate and hypromellose acetate succinate.

[0076] (ingredient (a))

[0077] In the solid dispersion of the present invention, delamanid is preferably in the form of microcrystalline or amorphous. Specifically, it is preferred that there is no crystalline peak in the powder X-ray diffraction pattern. Powder X-ray diffraction can be measured according to "General Test Methods 2.58 Powder X-ray Diffraction Measurement Method" of the Japanese Pharmacopoeia (18th Revision), for example, under the following conditions.

[0078] Measuring device: X'Pert PRO MPD (Spectris Corporation)

[0079] Optical system: focusing optical system (transmission method)

[0080] Goniometer radius: 240mm

[0081] Tube voltage, tube current: 45kV, 40mA

[0082] Entrance side slit: Soller slit, Soller 0.04 rad

[0083] Divergence slit 1 / 2deg

[0084] Light receiving side slit: Soller slit large Soller 0.04rad

[0085] Anti-scatter slit 5.5mm

[0086] Measuring range: 2θ 3~40deg

[0087] Operation speed: 1.11deg / sec

[0088] Sampling interval: 0.02deg / step

[0089] Wobbled scan: 5 steps, 0.02 degrees

[0090] Delamanid can be produced by a conventional method, for example, the method described in Japanese Patent Application Laid-Open No. 2004-149527, US Patent Application Publication No. 2006 / 094767, and the like.

[0091] (ingredient (b))

[0092] The present inventors have found that by combining component (a) and component (b), the compatibility of the two components is promoted, hot melt kneading is enabled, the fluidity in the melt kneader can be ensured, good manufacturability of the solid dispersion can be achieved, and a solid dispersion showing a solubility higher than that of the delamanid drug substance (jet mill pulverized product) can be obtained.

[0093] In component (b), the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (hereinafter sometimes referred to as component (b1)) contains at least one polyvinyl caprolactam block, at least one polyvinyl acetate block and at least one polyethylene glycol block. The polyethylene glycol may be, for example, PEG6000. The ratio of polyvinyl caprolactam block / polyvinyl acetate block / polyethylene glycol block may be, for example, about 57 / 30 / 13.

[0094] In one embodiment, the component (b1) may be a copolymer represented by the following formula.

[0095]

[0096] (wherein, l, m and n are each independently an integer greater than 1)

[0097] The average molecular weight of component (b1) can be, for example, 10,000 g / mol or more, 50,000 g / mol or more, or 90,000 g / mol or more. The average molecular weight of component (b1) can be, for example, 1,000,000 g / mol or less, 500,000 g / mol or less, 200,000 g / mol or less, or 140,000 g / mol or less. The average molecular weight of component (b1) can be in the range of any combination of the above lower limit and the above upper limit, for example, in the range of 10,000 to 1,000,000 g / mol, preferably in the range of 90,000 to 140,000 g / mol.

[0098] In one embodiment, the component (b1) preferably contains Soluplus (trademark) produced by BASF.

[0099] In the component (b), the vinyl pyrrolidone-vinyl acetate copolymer (hereinafter sometimes referred to as the component (b2)) is not particularly limited as long as it is a copolymer containing at least vinyl pyrrolidone (usually 1-vinyl-2-pyrrolidone) and vinyl acetate as polymerization components. The copolymerization ratio (mass ratio) of vinyl pyrrolidone to vinyl acetate may be, for example, in the range of 1:9 to 9:1, in the range of 2:8 to 8:2, or in the range of 3:7 to 7:3. The copolymerization ratio (mass ratio) of vinyl pyrrolidone to vinyl acetate may be, for example, in the range of 4:6 to 8:2, or in the range of 5:5 to 7:3.

[0100] In the component (b2), the arrangement of monomers is not particularly limited, and may be any of a random copolymer, an alternating copolymer, a block copolymer, and a graft copolymer. In one embodiment, the component (b2) is preferably a random copolymer.

[0101] The average molecular weight of component (b2) can be, for example, more than 10000 g / mol, more than 20000 g / mol, more than 30000 g / mol, more than 40000 g / mol or more than 45000 g / mol. The average molecular weight of component (b2) can be, for example, less than 1000000 g / mol, less than 500000 g / mol, less than 100000 g / mol or less than 70000 g / mol. The average molecular weight of component (b2) can be in the range of any combination of the above lower limit and the above upper limit, for example, in the range of 10000 to 1000000 g / mol, preferably in the range of 45000 to 70000 g / mol.

[0102] In one embodiment, component (b2) preferably contains copovidone, for example, Kollidon (trademark) VA64 from BASF.

[0103] In one embodiment, component (b) preferably contains component (b1). In another embodiment, component (b) preferably contains component (b2). In another embodiment, component (b) is preferably a combination of component (b1) and component (b2). In this combination, the mass ratio of component (b1) to component (b2) is not particularly limited, but is, for example, in the range of 0.5:1 to 10:1, preferably in the range of 1:1 to 6:1.

[0104] (ingredient (c))

[0105] The present inventors have found that a solid dispersion having even better solubility can be obtained by further combining component (c) with components (a) and (b).

[0106] In component (c), hydroxypropyl methylcellulose phthalate (hereinafter sometimes referred to as component (c1)) is a polymer compound obtained by half-ester bonding of phthalic acid and hydroxypropyl cellulose. Hydroxypropyl methylcellulose phthalate is preferably "Hypromellose Phthalate" recorded in the drug entry (chemical drugs, etc.) of the Japanese Pharmacopoeia (Eighteenth Revision). Hydroxypropyl methylcellulose phthalate is commercially available, for example, from Shin-Etsu Chemical Co., Ltd. under the trade names HPMCP (trademark) HP-55, HP-55S and HP-50. In the present invention, any of these commercially available products can be used. In one embodiment, the hydroxyl group of the hydroxypropyl methylcellulose phthalate is preferably substituted with at least 21 to 35% by mass (e.g., 21 to 27% by mass or 27 to 35% by mass) of carboxybenzoyl groups. In this embodiment, it is preferred that the hydroxyl groups of hypromellose phthalate are substituted with 18 to 24% by mass of methoxy groups, 5 to 10% by mass of hydroxypropoxy groups, and 21 to 35% by mass of carboxybenzoyl groups.

[0107] In component (c), hydroxypropyl methylcellulose acetate succinate (hereinafter sometimes referred to as component (c2)) is a polymer compound obtained by ester-bonding acetic acid and succinic acid to hydroxypropyl cellulose. Hydroxypropyl methylcellulose acetate succinate is preferably "Hypromellose acetate succinate" recorded in the drug entry (chemical drugs, etc.) of the Japanese Pharmacopoeia (18th revision). As hydroxypropyl methylcellulose acetate succinate, for example, it is commercially available from Shin-Etsu Chemical Co., Ltd. under the trade names Shin-Etsu AQOAT (trademark) AS-LF, AS-MF and AS-HF. In the present invention, any of these commercially available products can be used. Hydroxypropyl methylcellulose acetate succinate preferably has its hydroxyl group substituted by 20 to 26% by mass of methoxy, 5 to 10% by mass of hydroxypropoxy, 5 to 14% by mass of acetyl and 4 to 18% by mass of succinyl.

[0108] In one embodiment, the component (c) preferably contains the component (c1) (for example, the component (c1) alone or a combination of the component (c1) and the component (c2)).

[0109] In the solid dispersion of the present invention, the content of component (a) can be, for example, 1% by mass or more, 5% by mass or more, or 10% by mass or more. The content of component (a) can be, for example, 30% by mass or less, 25% by mass or less, or 20% by mass or less. The content of component (a) can be, for example, in the range of any combination of the above lower limit and the above upper limit, for example, in the range of 1 to 30% by mass.

[0110] The mass ratio of component (a) to component (b) is not particularly limited. The mass ratio of component (a) to component (b) may be less than 1:1 (for example, in the range of 1:0.1 to 1:0.9), usually 1:1 or more (meaning that component (b) / component (a) is 1 / 1 or more), preferably 1:1.5 or more, and more preferably 1:2 or more. The mass ratio of component (a) to component (b) may be, for example, 1:20 or less (meaning that component (b) / component (a) is 20 / 1 or less), 1:15 or less, 1:10 or less, 1:8 or less, or 1:5 or less. The mass ratio of component (a) to component (b) is within the range formed by any combination of the above lower limit and the above upper limit, for example, within the range of 1:1 to 1:20, preferably within the range of 1:1 to 1:8, more preferably within the range of 1:1 to 1:5, further preferably within the range of 1:2 to 1:5, further more preferably within the range of 1:2 to 1:4, or about 1:2 or about 1:4. When component (b) contains component (b1), the mass ratio of component (a) to component (b) is preferably about 1:4, and when component (b) contains component (b2), the mass ratio of component (a) to component (b) is preferably about 1:2.

[0111] The mass ratio of component (a) to component (c) may be less than 1:1 (for example, in the range of 1:0.1 to 1:0.9), and is usually 1:1 or more (meaning that component (c) / component (a) is 1 / 1 or more), preferably 1:1.5 or more, and more preferably 1:2 or more. The mass ratio of component (a) to component (c) may be, for example, 1:10 or less (meaning that component (c) / component (a) is 10 / 1 or less), 1:8 or less, or 1:5 or less. The mass ratio of component (a) to component (c) is within the range formed by any combination of the above lower limit and the above upper limit, for example, within the range of 1:1 to 1:10, preferably within the range of 1:1 to 1:8, more preferably within the range of 1:1 to 1:5, further preferably within the range of 1:1 to 1:4, further more preferably within the range of 1:2 to 1:4, and particularly preferably about 1:2 or about 1:3. When component (b) contains component (b1), the mass ratio of component (a) to component (c) is preferably about 1:3, and when component (b) contains component (b2), the mass ratio of component (a) to component (c) is preferably about 1:2.

[0112] In one embodiment, the mass ratio of component (a) to component (b) to component (c) is preferably in the range of 1:1 to 8:1 to 8, more preferably in the range of 1:1 to 5:1 to 5, further preferably in the range of 1:1.5 to 5:1.5 to 5, further preferably in the range of 1:2 to 4:2 to 4, or about 1:2:2 or about 1:4:3. When component (b) contains component (b1), the mass ratio of component (a) to component (b) to component (c) is preferably about 1:4:3, and when component (b) contains component (b2), the mass ratio of component (a) to component (b) to component (c) is preferably about 1:2:2.

[0113] (Other ingredients)

[0114] The solid dispersion of the present invention may further contain other ingredients. Examples of other ingredients include antioxidants, pH-independent water-soluble polymers other than component (b), plasticizers, etc. Other ingredients may be used alone or in combination of two or more.

[0115] As antioxidants, for example, vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, soybean lecithin, ascorbyl palmitate, cysteine ​​hydrochloride, ascorbic acid, citric acid, isoascorbic acid, sodium nitrite, sodium sulfite, sodium thioglycolate, sodium thiomalate, etc. can be cited. In one embodiment, the antioxidant preferably contains vitamin E, and further preferably contains vitamin E and butylated hydroxytoluene (for example, the mass ratio of vitamin E to butylated hydroxytoluene is 15:1 to 1:1). According to this embodiment, the generation of decomposition products during storage (especially when stored at a high temperature such as about 60°C) can be suppressed.

[0116] Vitamin E includes, for example, natural and synthetic vitamin E such as d-α-tocopherol, d-δ-tocopherol, d-α-tocopherol acetate, d-α-tocopherol succinate, dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, dl-α-tocopherol nicotinate, etc. Preferred vitamin E is dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate and dl-α-tocopherol nicotinate, and more preferably vitamin E is dl-α-tocopherol.

[0117] The amount of the antioxidant (e.g., vitamin E) formulated in the solid dispersion of the present invention is generally 0.001 parts by mass or more, preferably 0.01 parts by mass or more, and more preferably 0.03 parts by mass or more, relative to 1 part by mass of delamanid. The amount of the above-mentioned antioxidant (e.g., vitamin E) is generally 1 part by mass or less, preferably 0.8 parts by mass or less, and more preferably 0.5 parts by mass or less, relative to 1 part by mass of delamanid. The amount of the above-mentioned antioxidant (e.g., vitamin E) is within the range formed by any combination of the above lower limit and the above upper limit, for example, relative to 1 part by mass of delamanid, generally in the range of 0.001 to 1 part by mass, preferably in the range of 0.01 to 0.8 parts by mass, and more preferably in the range of 0.03 to 0.5 parts by mass.

[0118] Examples of the pH-independent water-soluble polymer compound other than the component (b) include hydroxypropyl cellulose, hypromellose, polyvinyl pyrrolidone, polyethylene glycol, and cyclodextrin.

[0119] Examples of the plasticizer include triethyl citrate, glycerin, glycerol fatty acid esters, medium-chain fatty acid triglycerides, triacetin, castor oil, propylene glycol, and polysorbate.

[0120] Other components other than the component (b), such as the pH-independent water-soluble polymer compound and the plasticizer, may be blended in the solid dispersion in the same amount as that of the antioxidant.

[0121] In one embodiment, the solid dispersion of the present invention preferably does not contain xylitol, more preferably does not contain xylitol, sorbitol and mannitol, and further preferably does not contain sugar alcohol.

[0122] In one embodiment, the solid dispersion of the present invention preferably does not contain poloxamer (a block copolymer consisting of a polyoxypropylene chain and two polyoxyethylene chains sandwiching the polyoxypropylene chain).

[0123] In one embodiment, the solid dispersion of the present invention preferably does not contain xylitol, sorbitol, mannitol and poloxamer.

[0124] The solid dispersion of the present invention is preferably a hot melt extrudate or a pulverized product thereof, and is preferably produced by the manufacturing method described below. The pulverized product is usually particles, sometimes also referred to as solid dispersion particles, molten particles, etc. The size of the pulverized product is not particularly limited, but for example, it is a size that passes through a sieve with an aperture of 500 μm (30 mesh) or an aperture of 425 μm (36 mesh), preferably a size that passes through a sieve with an aperture of 355 μm (42 mesh), an aperture of 300 μm (50 mesh), an aperture of 250 μm (60 mesh), an aperture of 212 μm (70 mesh), an aperture of 180 μm (83 mesh), an aperture of 160 μm (93 mesh), an aperture of 150 μm (100 mesh), an aperture of 12 The size of the sieve is 5 μm (119 mesh), 106 μm (140 mesh), 100 μm (149 mesh), 90 μm (166 mesh), 75 μm (200 mesh), 63 μm (235 mesh), 53 μm (280 mesh), 45 μm (330 mesh), 38 μm (390 mesh), 32 μm (440 mesh) or 25 μm (500 mesh). The particle size can be adjusted by passing through any two of the above sieves, and the size of the above pulverized product is, for example, 25 to 500 μm, preferably 53 to 150 μm, and more preferably 75 to 106 μm.

[0125] [Method for producing solid dispersion]

[0126] The method for producing a solid dispersion included in the present invention (hereinafter sometimes referred to as the method for producing a solid dispersion of the present invention) preferably includes a step of hot melt extrusion (HME) of a composition containing components (a), (b) and (c). The above composition may contain components other than components (a), (b) and (c), and may contain "other components" recorded in the above "solid dispersion" item. HME is typically a method characterized by mixing raw materials uniformly, heating to melt and extruding, and then cooling, and can be carried out using conventional methods and devices (e.g., a stirrer, a mixer, etc. having a heat source).

[0127] For HME, for example, an extruder having a screw in a barrel (cylinder) (eg, a single-screw extruder, a twin-screw extruder, a twin-screw extruder, etc.) can be used. Among them, a twin-screw extruder is preferred.

[0128] The extruder consists of the following five main parts: hopper (inlet structure), motor (controls the rotation of the screw), screw (the main power supply device for material shearing and movement), barrel (contains the screw and provides temperature control) and die (exit) (controls the shape and size of the extruded product).

[0129] Raw materials are fed from the hopper of the extruder into the device maintained at a suitable heating and melting temperature, and the screw is rotated to melt and knead the solid matter of the raw materials uniformly. Alternatively, the raw materials may be mixed in advance before being fed into the device as required.

[0130] The conditions such as pressure, temperature, powder supply speed, die diameter, screw shape, screw speed in the manufacturing method of the present invention vary according to the type of extruder, etc., and are preferably combined in a manner to reach a decomposition temperature of the raw material or less. In particular, it is necessary to appropriately set the heating temperature from the perspective of stability issues such as decomposition and modification of the raw material. The heating temperature is preferably below 190°C, more preferably below 185°C, and further preferably below 180°C. The heating temperature is generally above 150°C, preferably above 155°C, and more preferably above 160°C. The heating temperature can be within the range of any combination of the above lower limit and the above upper limit, for example, within the range of 150 to 190°C, preferably within the range of 160 to 190°C. The screw speed is preferably above 10rpm, more preferably above 15rpm, and further preferably above 20rpm. The screw speed is preferably below 250rpm, more preferably below 200rpm, further preferably below 150rpm, and further more preferably below 100rpm. The screw rotation speed may be within a range formed by arbitrarily combining the above lower limit and the above upper limit, for example, within a range of 20 to 250 rpm.

[0131] The preferred method for producing the solid dispersion of the present invention comprises the steps of preparing a composition (mixture) by mixing component (a), component (b) and component (c) and additives as required, and hot-melt extruding the composition. In the hot-melt extrusion step, the composition is preferably supplied to a twin-screw extruder and treated at a screw speed of 20 to 250 rpm and a treatment temperature of 160 to 190°C.

[0132] The method for producing the solid dispersion of the present invention preferably further comprises the step of pulverizing the hot melt extrudate. As long as a suitable pulverizer is used for pulverization, solid dispersion particles with any particle size can be simply obtained, which can be directly used as powders, fine granules, granules, etc. It is also possible to prepare oral preparations such as pharmaceutical compositions or oral solid preparations containing the solid dispersion of the present invention by appropriately adding pharmaceutical preparation components (additives) to the solid dispersion of the present invention (or solid dispersion particles) and performing the preparation step.

[0133] [Drug composition]

[0134] The pharmaceutical composition included in the present invention (hereinafter sometimes referred to as the pharmaceutical composition of the present invention) contains the above-mentioned solid dispersion. The amount of the above-mentioned solid dispersion in the pharmaceutical composition of the present invention is not particularly limited, but for example, it can be in the range of 50 to 90% by mass. In addition to the above-mentioned solid dispersion, the pharmaceutical composition of the present invention may also contain other active ingredients and / or additives. As additives, there is no particular limitation as long as they are pharmaceutically acceptable additives, and examples thereof include excipients, disintegrants, binders, fluidizers, lubricants, preservatives, stabilizers, isotonic agents, dissolution aids, coating agents, colorants, suspending agents, surfactants, sweeteners, flavors, preservatives, pH adjusters, etc. The additives can be used alone or in combination of two or more. The amount of other active ingredients and / or additives in the pharmaceutical composition of the present invention is not particularly limited, but for example, it can be in the range of 10 to 50% by mass.

[0135] Examples of the excipient include lactose, anhydrous lactose, refined white sugar, white sugar, D-mannitol, D-sorbitol, xylitol, erythritol, dextrin, crystalline cellulose, microcrystalline cellulose, corn starch, potato starch, anhydrous calcium hydrogen phosphate, and the like.

[0136] Examples of the disintegrant include sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, cross-linked povidone, low-substituted hydroxypropyl cellulose, and partially α-starch.

[0137] Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, pregelatinized starch, syrup, and maltose.

[0138] Examples of the fluidizing agent include light anhydrous silicic acid, calcium silicate, synthetic aluminum silicate, hydrous silicon dioxide, calcium stearate, magnesium aluminometasilicate, and talc.

[0139] Examples of the lubricant include magnesium stearate, calcium stearate, magnesium silicate, magnesium oxide, talc, hydrogenated oil, sucrose fatty acid ester, and sodium stearyl fumarate.

[0140] Examples of the coating agent include hypromellose, polyvinyl alcohol, polysorbate, polyethylene glycol, and talc.

[0141] Examples of the coloring agent include yellow ferric oxide, brown ferric oxide, ferric oxide, titanium oxide, food blue No. 1, food red No. 2, food red No. 3, and food yellow No. 4.

[0142] Examples of the suspending agent include polysorbate, polyethylene glycol, gum arabic, glycerin, sucrose fatty acid ester, gelatin, and the like.

[0143] Examples of the sweetener include aspartame, sucralose, saccharin, saccharin sodium, maltose, and fructose.

[0144] Examples of the surfactant include sodium lauryl sulfate, polysorbate, and polyoxyethylene hydrogenated castor oil.

[0145] The form of the pharmaceutical composition of the present invention is not particularly limited. For example, it can be preferably used in a solid state (granular, tablet, capsule, etc.), granular or liquid (suspension, etc.) form. As an example of the pharmaceutical composition of the present invention, the above-mentioned solid dispersion and additives as needed can be filled in a capsule and used in the form of a capsule. As another example of the pharmaceutical composition of the present invention, the above-mentioned solid dispersion and additives as needed can also be mixed and tableted and used in the form of a tablet. As another example of the pharmaceutical composition of the present invention, the above-mentioned solid dispersion can also be dispersed in water and used in the form of a suspension.

[0146] [Oral preparations]

[0147] The oral preparation included in the present invention (hereinafter sometimes referred to as the oral preparation of the present invention) contains the above-mentioned solid dispersion. The amount of the above-mentioned solid dispersion in the oral preparation of the present invention is not particularly limited, for example, it can be in the range of 50 to 90% by mass. In addition to the above-mentioned solid dispersion, the oral preparation of the present invention may also contain other active ingredients and / or additives. As additives, the substances described in the above-mentioned "pharmaceutical composition" item and exemplified as "additives" can be used. The amount of other active ingredients and / or additives in the oral preparation of the present invention is not particularly limited, for example, it can be in the range of 10 to 50% by mass. As the oral preparation of the present invention, oral solid preparations such as tablets, capsules, powders, and granules can be listed. In one embodiment, the oral preparation of the present invention is preferably a tablet or a capsule. Tablets include, for example, plain tablets, film-coated tablets, sugar-coated tablets, caplets, and chewable tablets.

[0148] The above-mentioned components (properties, structures, functions, etc.) described in the various embodiments of the present invention can be arbitrarily combined when defining the subject matter included in the present invention. That is, the present invention includes all the subject matter consisting of all combinations of the components that can be combined as described in this specification.

[0149] Example

[0150] The present invention will be described in more detail below, but the present invention is not limited to the following examples.

[0151] [Examples A1 to A11]

[0152] Delamanid (hammer mill pulverized product, Otsuka Pharmaceutical Co., Ltd.), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus (trademark), BASF), hydroxypropyl methylcellulose phthalate (HPMCP (trademark) HP-50, Shin-Etsu Chemical Co., Ltd.), dl-α-tocopherol (a type of vitamin E, therefore sometimes referred to as VE hereinafter) (Fujifilm Wako Pure Chemical Industries, Ltd.) used as needed, and butylated hydroxytoluene (BHT) used as needed were placed in a polyethylene bag in the amounts shown in Tables 1 to 4 and mixed for several minutes.

[0153] For this mixed powder, a twin screw extruder (Pharma 11 twin screw extruder, Thermo Fisher Scientific) equipped with a die head of 1 mm diameter was used, and the barrel temperature of the kneading section was set to 160-180°C, and the extrusion speed was 40-80 rpm to form a rod-shaped molded body. The molded body was cooled at room temperature and finely pulverized using a pulverizer (tablet pulverizer HTF-35, Daido Chemical Industry Co., Ltd.) to pass through a 53 μm sieve to obtain particles (solid dispersion particles).

[0154] [Example A12]

[0155] Particles were prepared in the same manner as in Example A11 except that hypromellose phthalate was changed to hypromellose acetate succinate (Shin-Etsu AQOAT (trademark) AS-LF, Shin-Etsu Chemical Co., Ltd.).

[0156] [Comparative Example A1]

[0157] Particles were prepared in the same manner as in Example A1 except that hypromellose phthalate and dl-α-tocopherol (VE) were not added.

[0158] [Comparative Example A2]

[0159] Particles were prepared in the same manner as in Example A3 except that hypromellose phthalate and dl-α-tocopherol (VE) were not added.

[0160] [Comparative Example A3]

[0161] Particles were prepared in the same manner as in Example A11 except that hypromellose phthalate, dl-α-tocopherol (VE) and butylated hydroxytoluene (BHT) were not added.

[0162] [Comparative Example A4]

[0163] The same operation as in Example A1 was carried out except that the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and dl-α-tocopherol were not added. As a result, delamanid was decomposed during the molding process, and a molded body could not be obtained.

[0164] [Examples B1 to B5]

[0165] Delamanid (hammer mill pulverized product, Otsuka Pharmaceutical Co., Ltd.), vinyl pyrrolidone-vinyl acetate copolymer (Kollidon (trademark) VA64, BASF), hypromellose phthalate (HPMCP (trademark) HP-50, Shin-Etsu Chemical Co., Ltd.) and dl-α-tocopherol (VE) (Fujifilm Wako Pure Chemical Industries, Ltd.) were placed in a polyethylene bag in the amounts shown in Table 5 and mixed for several minutes.

[0166] For this mixed powder, a twin screw extruder (Pharma 11 twin screw extruder, Thermo Fisher Scientific Co., Ltd.) equipped with a die head of 1 mm diameter was used, and the barrel temperature of the kneading section was set to 160-170°C, and the extrusion speed was 40 rpm to form a rod-shaped molded body. The molded body was cooled at room temperature and finely pulverized using a pulverizer (tablet pulverizer HTF-35, Daido Chemical Co., Ltd.) to pass through a 53 μm sieve to obtain particles (solid dispersion particles).

[0167] [Example C]

[0168] 40 g of delamanid (hammer mill product, Otsuka Pharmaceutical Co., Ltd.), 160 g of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus (trademark), BASF), 120 g of hydroxypropyl methylcellulose phthalate (HPMCP (trademark) HP-50, Shin-Etsu Chemical Co., Ltd.) and 9.6 g of dl-α-tocopherol (VE) (Fujifilm Wako Pure Chemical Industries, Ltd.) were placed in a polyethylene bag and mixed for several minutes.

[0169] For this mixed powder, a twin screw extruder (Pharma 11 twin screw extruder, Thermo Fisher Scientific Co., Ltd.) equipped with a die head of 1 mm diameter was used, and the barrel temperature of the kneading section was set to 180°C, and a molding process was performed at an extrusion speed of 40 rpm to obtain a rod-shaped molded body. The molded body was cooled at room temperature and finely pulverized using a pulverizer (tablet pulverizer HTF-35, Daido Chemical Co., Ltd.) to pass through a 53 μm sieve to obtain particles (solid dispersion particles).

[0170] [Test Example 1 (Solubility)]

[0171] The solubility of the particles of Examples A1 to A12 and Comparative Examples A1 to A3 was examined by the following method 1 or 2.

[0172] (Method 1)

[0173] Add 100 mL of 0.3 mass % sodium lauryl sulfate aqueous solution to a 100 mL beaker and stir with a magnetic stirrer (rotation speed: 500 rpm). Separately weigh the particles of the embodiment and the comparative example in an agate mortar so that the amount of delamanid reaches 5 mg, and add several mL of the test solution in the beaker. After dispersing for about 1 minute, the dispersion is put into a beaker. After 5 minutes, 10 minutes, 20 minutes and 30 minutes from the time the dispersion is put in, take out 6 mL of the liquid in the beaker as a sample, and filter the liquid with a filter membrane with a pore size of less than 0.5 μm. Remove the initial filtrate 2 mL and use the subsequent filtrate 4 mL as the sample solution. Determine the absorbance of the sample solution at a wavelength of 335 nm.

[0174] (Method 2)

[0175] A sample solution was prepared in the same manner as in Method 1 except that a 0.1% by mass sodium lauryl sulfate aqueous solution was used as the test solution, and the absorbance at a wavelength of 335 nm was measured.

[0176] Tables 1 to 4 show the solubility results of the particles of Examples A1 to A12 and Comparative Examples A1 to A3.

[0177] [Table 1]

[0178]

[0179] [Table 2]

[0180]

[0181] [Table 3]

[0182]

[0183] [Table 4]

[0184]

[0185] Table 5 shows the solubility results of the particles of Examples B1 to B5.

[0186] [Table 5]

[0187]

[0188] [Test Example 2 (Purity of Delamanid)]

[0189] The particles obtained in Examples A8 to A10 were placed in a glass container, the outer layer was sealed with an aluminum bag, and then stored at 60°C for 2 weeks. The obtained particles were used as samples to investigate the purity of Delamanid. For the purity of Delamanid, a column (ACQUITY UPLC (trademark) BEH C18, Waters Japan) was connected to UPLC (ultra-high performance liquid chromatography, ACQUITY UPLC / TUV system, Waters Japan), the sample cooler was set to 15°C, the column oven was set to 40°C, and the measuring wavelength of the detector was set to 254nm. 2.0 μL of a sample solution prepared to 1.0 mg / mL was injected and analyzed in isocratic mode. The spectrum after the measurement was analyzed, and the purity of Delamanid was shown as area percentage. The results are shown in Table 6.

[0190] [Table 6]

[0191]

[0192] From Table 6, it can be confirmed that the storage stability of Delamanid at high temperature is improved by adding dl-α-tocopherol.

[0193] [Test Example 3 (Concentration in dog serum)]

[0194] Male beagle dogs (about 30 months old, weighing 8-12 kg, Nosan: Beagle, Nalk Co., Ltd.) were forcibly orally administered a gelatin capsule filled with 50 mg of the particles of Example C as delamanid, and immediately after that, 40 mL of water was forcibly administered. About 50 g of feed CD-5 (Japan Clea Co., Ltd.) was fed 30 minutes before administration, and fasted until the last blood collection. In addition, the same study was conducted using a capsule containing 50 mg of delamanid in a commercially available tablet (deltyba (registered trademark) tablet 50 mg) filled in a gelatin capsule.

[0195] Blood was collected before administration and at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration, and the amount of blood collected was about 1 mL (n=6). The obtained blood was centrifuged at 3000 rpm for 10 minutes to obtain serum. The concentration of delamanid in the serum was measured by LC-MS. The results are shown in Figure 1 .

[0196] [Preparation Examples 1 to 16]

[0197] The formulations of Preparation Examples 1 to 16 are shown in Tables 7 and 8.

[0198] [Table 7]

[0199]

[0200] [Table 8]

[0201]

[0202] According to the formulations of Tables 7 and 8, the components except magnesium stearate were mixed in a polyethylene bag, and magnesium stearate was added and further mixed. The mixed powder was tableted using a rotary tablet press (Clean Press, Kikusui Seisakusho Co., Ltd.) equipped with a die for capsule tablets (18.0×10.8 mm) at a tableting pressure of 20 kN to prepare capsule tablets containing 100 mg of delamanid per tablet.

[0203] For the capsule tablets of Preparation Examples 5, 7 and 16, a film coating liquid prepared by dissolving and suspending hydroxypropyl methylcellulose, PEG6000, titanium oxide, talc and yellow ferric oxide in the formulation of Table 9 in purified water was sprayed on the capsule tablets in a film coater (POWREX COATER PRC-GTXmini, POWREX Co., Ltd.) to prepare film-coated tablets.

[0204] [Table 9]

[0205]

Claims

1. A solid dispersion comprising the following components (a), (b) and (c): (a) Dramani; (b) at least one selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers and vinyl pyrrolidone-vinyl acetate copolymers; (c) at least one selected from the group consisting of hypromellose phthalate and hypromellose acetate succinate.

2. The solid dispersion according to claim 1, wherein The mass ratio of component (a) to component (b) is in the range of 1:1 to 1:

20.

3. The solid dispersion according to claim 1, wherein The mass ratio of component (a) to component (b) is in the range of 1:1 to 1:

8.

4. The solid dispersion according to claim 1, wherein The mass ratio of component (a) to component (b) is in the range of 1:1 to 1:

5.

5. The solid dispersion according to claim 1, wherein The mass ratio of component (a) to component (c) is in the range of 1:1 to 1:

10.

6. The solid dispersion according to claim 1, wherein The mass ratio of component (a) to component (c) is in the range of 1:1 to 1:

8.

7. The solid dispersion according to claim 1, wherein The mass ratio of component (a) to component (c) is in the range of 1:1 to 1:

5.

8. The solid dispersion according to claim 1, wherein The mass ratio of component (a) to component (b) is in the range of 1:1 to 1:5, and the mass ratio of component (a) to component (c) is in the range of 1:1 to 1:

5.

9. The solid dispersion according to claim 1, wherein The component (b) contains a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

10. The solid dispersion according to claim 1, wherein Component (b) contains a vinyl pyrrolidone-vinyl acetate copolymer.

11. The solid dispersion according to claim 1, wherein Ingredient (c) contains hypromellose phthalate.

12. The solid dispersion according to claim 1, wherein The component (b) contains a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the component (c) contains hypromellose phthalate.

13. The solid dispersion according to claim 1, wherein The component (b) contains vinyl pyrrolidone-vinyl acetate copolymer, and the component (c) contains hypromellose phthalate.

14. The solid dispersion according to claim 1, wherein Also contains vitamin E.

15. The solid dispersion according to claim 14, wherein Vitamin E is dl-α-tocopherol. 16 . The solid dispersion according to claim 1 , which is a hot melt extrudate or a pulverized product thereof.

17. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 16.

18. An oral solid preparation comprising the solid dispersion according to any one of claims 1 to 16. The oral solid preparation according to claim 18, which is a tablet or a capsule.

20. A method for producing the solid dispersion according to any one of claims 1 to 16, comprising the step of hot-melt extruding a composition comprising components (a), (b) and (c).

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