Posaconazole-containing solid dispersion and posaconazole-containing formulation containing the same

Abstract

One embodiment of the present invention provides a posaconazole-containing solid dispersion that suppresses the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration of a posaconazole-containing formulation. Alternatively, one embodiment of the present invention provides a posaconazole-containing formulation in which the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration is suppressed. [Solution] A posaconazole-containing solid dispersion according to one embodiment of the present invention comprises posaconazole, hypromellose acetate succinate, and hydroxypropyl cellulose having a viscosity of 6 mPa·s or more and 10 mPa·s or less in a 2% aqueous solution at 20°C and an average molecular weight of 140,000.

Description

Technical Field

[0001] One embodiment of the present invention relates to a posaconazole-containing solid dispersion. Alternatively, one embodiment of the present invention relates to a posaconazole-containing formulation.

Background Art

[0002] Posaconazole (4-(4-{4-[4-({(3R,5R)-5-(2,4-Difluorophenyl)-5-[(1H-1,2,4-triazol-1-yl)methyl]tetrahydrofuran-3-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-[(2S,3S)-2-hydroxypentan-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one) is a drug poorly soluble in water.

[0003] For example, Patent Document 1 describes a solid dispersion containing posaconazole dissolved or molecularly dispersed in a hydroxypropylmethyl-cellulose derivative polymer for the purpose of improving bioavailability. The solid dispersion of Patent Document 1 is produced by the hot melt extrusion (HME) method using hypromellose acetate succinate (HPMCAS) as a polymer. Further, Patent Document 2 describes a sustained-release pharmaceutical composition containing a solid dispersion in which posaconazole is dispersed in a mixture of HPMCAS and hydroxypropyl cellulose (HPC), and external particles containing an enteric polymer and a non-enteric polymer.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

[0005] One embodiment of the present invention aims to provide a posaconazole-containing solid dispersion that suppresses the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration of a posaconazole-containing formulation. Alternatively, one embodiment of the present invention aims to provide a posaconazole-containing formulation in which the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration is suppressed. [Means for solving the problem]

[0006] A posaconazole-containing solid dispersion according to one embodiment of the present invention comprises posaconazole, hypromellose acetate succinate, and hydroxypropyl cellulose having a viscosity of 6 mPa·s or more and 10 mPa·s or less in a 2% aqueous solution at 20°C and an average molecular weight of 140,000.

[0007] The posaconazole-containing solid dispersion may also contain posaconazole dispersed in a molten mixture of hypromellose acetate succinate and hydroxypropyl cellulose.

[0008] The posaconazole-containing solid dispersion may also contain hydroxypropyl cellulose in an amount of 1.2% to 7.0% by mass.

[0009] A posaconazole-containing formulation according to one embodiment of the present invention may include any of the above-mentioned posaconazole-containing solid dispersions and one or more pharmaceutically acceptable additives.

[0010] The posaconazole-containing preparation may also contain 0.79% to 4.80% by mass of hydroxypropyl cellulose. [Effects of the Invention]

[0011] According to one embodiment of the present invention, a posaconazole-containing solid dispersion is provided that suppresses the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration of a posaconazole-containing formulation. Alternatively, according to one embodiment of the present invention, a posaconazole-containing formulation is provided in which the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration is suppressed. [Brief explanation of the drawing]

[0012] [Figure 1] This figure shows the evaluation results of the dissolution properties of the posaconazole-containing solid dispersions of the examples and comparative examples. [Modes for carrying out the invention]

[0013] The posaconazole-containing solid dispersion and posaconazole-containing formulation according to the present invention will be described below with reference to the drawings. However, the posaconazole-containing solid dispersion and posaconazole-containing formulation according to the present invention are not limited to the descriptions of the embodiments and examples shown below. In the drawings referenced in this embodiment and the examples described later, the same parts or parts having similar functions are denoted by the same reference numerals, and repeated descriptions thereof are omitted.

[0014] As a result of our investigations, we have found that conventional formulations containing posaconazole-containing solid dispersions exhibit delayed dissolution of posaconazole during the storage period after manufacturing or before administration, compared to immediately after manufacturing. As a result of our investigations, we have for the first time discovered that a solid dispersion containing hydroxypropyl cellulose, which has a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, along with hypromellose acetate succinate as the base of the solid dispersion, can suppress the delayed dissolution of posaconazole during the storage period after manufacturing or before administration.

[0015] In this specification, "delayed dissolution" means that the dissolution rate of posaconazole in a posaconazole-containing formulation stored under specified conditions is reduced compared to a posaconazole-containing formulation immediately after manufacturing.

[0016] [Solid dispersion containing posaconazole] A posaconazole-containing solid dispersion according to one embodiment of the present invention comprises posaconazole, hypromellose acetate succinate (HPMCAS), and hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. In this specification, the average molecular weight of hydroxypropyl cellulose shall be measured by gel permeation chromatography (GPC). HPC-L can be used as the hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. For example, HPC-L from Nippon Soda Co., Ltd. is commercially available as the hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, but is not limited thereto. The posaconazole-containing solid dispersion according to this embodiment contains HPMCAS, which is the base of the solid dispersion, along with hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. This helps to suppress the delayed dissolution of posaconazole during the storage period after manufacturing or until administration of the posaconazole-containing preparation.

[0017] In one embodiment, the posaconazole-containing solid dispersion may contain 1.2% to 7.0% by mass of hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. The posaconazole-containing solid dispersion according to this embodiment may contain, for example, 1.2% or more by mass, 2.4% or more by mass, 3.6% or more by mass, 4.7% or more by mass, and 5.8% to 7.0% by mass of hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. In one embodiment, the posaconazole-containing solid dispersion may include, for example, hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C, and an average molecular weight of 140,000, in amounts of 2.4% to 7.0% by mass, 3.6% to 7.0% by mass, 5.9% to 7.0% by mass, 1.2% to 5.9% by mass, 2.4% to 5.9% by mass, 3.6% to 5.9% by mass, 4.7% to 5.9% by mass, 1.2% to 4.8% by mass, 2.4% to 4.8% by mass, 3.6% to 4.8% by mass, 1.2% to 3.6% by mass, 2.4% to 3.6% by mass, or 1.2% to 2.4% by mass, in an amount of hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C, and an average molecular weight of 140,000.

[0018] The posaconazole-containing solid dispersion contains 1.2% by mass or more of hydroxypropyl cellulose, which has a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. This helps to suppress the delayed dissolution of posaconazole during the storage period after manufacturing or until administration of the posaconazole-containing preparation. On the other hand, if the amount of hydroxypropyl cellulose with a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000 is increased to more than 7.0% by mass, the amount of posaconazole in the posaconazole-containing solid dispersion decreases, or the amount of hypromellose acetate succinate, which is the base of the solid dispersion, decreases, which is undesirable.

[0019] In one embodiment, the posaconazole-containing solid dispersion may contain hypromellose acetate succinate (HPMCAS) with pH solubility of pH 5.5 or higher, pH 6.0 or higher, or pH 6.5 or higher. In one embodiment, the posaconazole-containing solid dispersion may contain two or more combinations selected from these HPMCAS. From the viewpoint of manufacturability, an HPMCAS (AS-LMP) that is soluble at pH 5.5 or higher and has an average particle size of 70 μm to 300 μm as measured by laser diffraction, an HPMCAS (AS-MMP) that is soluble at pH 6.0 or higher and has an average particle size of 70 μm to 300 μm as measured by laser diffraction, or an HPMCAS (AS-HMP) that is soluble at pH 6.5 or higher and has an average particle size of 70 μm to 300 μm as measured by laser diffraction can be used. In one embodiment, AS-MMP is preferred as the HPMCAS. Hypromellose acetate succinate is commercially available, for example, from Shin-Etsu Chemical Co., Ltd. In one embodiment, HPMCAS(AS-LF) that is soluble at pH 5.5 or higher and has an average particle diameter of 10 μm or less and a 90% integrated particle diameter of 20 μm or less as measured by laser diffraction may be used; HPMCAS(AS-MF) that is soluble at pH 6.0 or higher and has an average particle diameter of 10 μm or less and a 90% integrated particle diameter of 20 μm or less as measured by laser diffraction may be used; or HPMCAS(AS-HF) that is soluble at pH 6.5 or higher and has an average particle diameter of 10 μm or less and a 90% integrated particle diameter of 20 μm or less as measured by laser diffraction may be used. Alternatively, in one embodiment, HPMCAS(AS-LG) that exhibits solubility at pH 5.5 or higher and has an average particle size exceeding 300 μm as measured by laser diffraction may be used; HPMCAS(AS-MG) that exhibits solubility at pH 6.0 or higher and has an average particle size exceeding 300 μm as measured by laser diffraction may be used; or HPMCAS(AS-HG) that exhibits solubility at pH 6.5 or higher and has an average particle size exceeding 300 μm as measured by laser diffraction may be used. In one embodiment, the posaconazole-containing solid dispersion may include two or more combinations selected from these HPMCAS.

[0020] In one embodiment, the posaconazole-containing solid dispersion contains 100% to 400% by mass of hypromellose acetate succinate based on 100% by mass of posaconazole.

[0021] In one embodiment, it may contain posaconazole dispersed in a melt of hypromellose acetate succinate and hydroxypropyl cellulose. In this embodiment, posaconazole is in an amorphous form and is included in the posaconazole-containing solid dispersion.

[0022] [Posaconazole-containing formulation] The posaconazole-containing formulation according to this embodiment includes the above-described posaconazole-containing solid dispersion and one or more pharmaceutically acceptable additives. In one embodiment, the posaconazole-containing formulation is provided as a tablet. Alternatively, in one embodiment, the posaconazole-containing formulation may be provided as a film-coated tablet with a film disposed on the surface of the tablet. The posaconazole-containing formulation contains 100 mg of posaconazole per tablet, but the content of posaconazole is not limited thereto and can be arbitrarily changed within the range where a therapeutic effect can be obtained.

[0023] Examples of one or more pharmaceutically acceptable additives included in the posaconazole-containing formulation can include excipients, binders, disintegrants, and lubricants. Examples of excipients can include crystalline cellulose, microcrystalline cellulose phthalate, calcium phosphate, dicalcium phosphate, saccharides (monosaccharides, disaccharides, polysaccharides, sugar alcohols, such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, methyl dextrin, and starch), but are not limited thereto.

[0024] Examples of binders include, but are not limited to, enteric polymers such as hypromellose acetate succinate (HPMCAS), cellulose phthalate acetate, cellulose trimellitate acetate, cellulose acetate succinate, methylcellulose phthalate, ethyl hydroxymethylcellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate maleate, hydroxypropyl methylcellulose trimellitate, carboxymethyl ethylcellulose, polyvinyl butyrate phthalate, polyvinyl acetate phthalate, methacrylic acid / ethyl acrylate copolymer, and methacrylic acid / methyl methacrylate copolymer.

[0025] In one embodiment, when a posaconazole-containing formulation contains hypromellose acetate succinate (HPMCAS) outside the posaconazole-containing solid dispersion, one or more HPMCAS can be selected from the above-mentioned HPMCAS. In one embodiment, it is preferable to use an HPMCAS that is soluble at pH 6.5 or higher, has an average particle diameter of 10 μm or less and a 90% integrated particle diameter of 20 μm or less as measured by laser diffraction, for example, AS-HF from Shin-Etsu Chemical Co., Ltd. can be used. AS-HF is preferred because it can maintain the supersaturated state of posaconazole. In one embodiment, as the hypromellose acetate succinate (HPMCAS) contained outside the posaconazole-containing solid dispersion in the posaconazole-containing formulation, an HPMCAS (AS-HMP) that is soluble at pH 6.5 or higher, has an average particle diameter of 70 μm to 300 μm as measured by laser diffraction, or an HPMCAS (AS-HG) with an average particle diameter exceeding 300 μm may be used. Alternatively, AS-HF may be used in combination with AS-HMP and / or AS-HG.

[0026] Examples of binders include, but are not limited to, non-enteric polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone (povidone), poly(vinylpyrrolidone / vinyl acetate) (copovidone), polyvinylcaprolactam / polyvinyl acetate / polyethylene glycol graft copolymer, polyethylene glycol / polyvinyl alcohol graft copolymer, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, polyvinyl alcohol, partially saponified polyvinyl alcohol, macrogol glycerol hydroxystearate, polyethylene glycol, and maltodextrin.

[0027] Examples of binders include, but are not limited to, gum arabic, alginic acid, starch, agar, carrageenan calcium, cellulose derivatives such as ethylcellulose, methylcellulose, and sodium carboxymethylcellulose, crystalline cellulose, dextrin, gelatin, gum arabic, guar gum, and sodium alginate.

[0028] Examples of disintegrants include, but are not limited to, low-substituted hydroxypropylcellulose, croscarmellose sodium, hydroxypropylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose, carboxymethylcellulose calcium, crospovidone, sodium starch glycolate, corn starch, carboxymethyl starch, hydroxypropyl starch, potato starch, corn starch, and modified starch.

[0029] Examples of lubricants include, but are not limited to, stearic acid and its pharmaceutically acceptable salts or esters (e.g., magnesium stearate, calcium stearate, sodium stearyl fumarate, or other metal stearates), talc, waxes (e.g., microcrystalline wax), glycerides, light mineral oils, polyethylene glycol, silicic acid or its derivatives or salts (e.g., silicates, silicon dioxide, colloidal silicon dioxide and its polymers, magnesium aluminosilicate and / or magnesium aluminometasilicate), sucrose fatty acid esters, and hydrogenated vegetable oils (e.g., hydrogenated castor oil).

[0030] In one embodiment, the posaconazole-containing formulation may contain 0.79% to 4.80% by mass of hydroxypropyl cellulose per tablet, having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. The posaconazole-containing solid dispersion according to this embodiment may contain, for example, 0.79% to 1.59% to 2.39% to 3.18% to 4.80% by mass of hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. In one embodiment, the posaconazole-containing formulation is, for example, 1.59% by weight or more and 4.80% by weight or less, 2.39% by weight or more and 4.80% by weight or less, 3.18% by weight or more and 4.80% by weight or less, 0.7 9 mass% or more and 3.98 mass% or less, 1.59 mass% or more and 3.98 mass% or less, 2.39 mass% or more and 3.98 mass% or less, 3.18 mass% or more and 3.98 mass% or less, 0.79 mass% or more and 3.18 quality It may also contain hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C, with an average molecular weight of 140,000, in amounts of % or less, 1.59% to 3.18% by mass, 2.39% to 3.18% by mass, 0.79% to 2.39% by mass, 1.59% to 2.39% by mass, or 0.79% to 1.59% by mass or less, in an amount of 1.59% by mass or less, and an average molecular weight of 140,000.

[0031] [Method for producing a solid dispersion containing posaconazole] In this embodiment, the posaconazole-containing solid dispersion can be produced by a molten metal extrusion (HME) method. In one embodiment, posaconazole, hypromellose acetate succinate (HPMCAS), and hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000 are mixed. The mixture is heated to melt the posaconazole and soften the hypromellose acetate succinate (HPMCAS) and the hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000. The molten material is mixed and homogenized, and the posaconazole-containing solid dispersion according to this embodiment can be produced by cooling while extruding. Since the posaconazole is melted by heating, the posaconazole used as a raw material may be in amorphous or crystalline form. Regardless of the form of posaconazole used, a solid dispersion containing amorphous posaconazole can be obtained by manufacturing using the HME method. In one embodiment, the steps of melting posaconazole by heating, softening hypromellose acetate succinate (HPMCAS) and hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s and an average molecular weight of 140,000 in a 2% aqueous solution at 20°C, and mixing and homogenizing the molten material are not particularly limited in temperature, as long as the manufacturing conditions allow for amorphous posaconazole. The obtained posaconazole-containing solid dispersion can be pulverized and, if necessary, granulated to obtain the posaconazole-containing solid dispersion used in the formulation according to this embodiment.

[0032] [Method for manufacturing posaconazole-containing preparations] The posaconazole-containing solid dispersion according to this embodiment can be mixed with one or more pharmaceutically acceptable additives described above, and the resulting tablets can be manufactured by compressing the mixture. In this specification, "tablet" refers to a tablet obtained by compression molding the posaconazole-containing solid dispersion and one or more pharmaceutically acceptable additives, and is intended to be a tablet without a film or printing on its surface.

[0033] A coating composition can be prepared by combining the additives described above to manufacture film-coated tablets. A film coating solution can be prepared by dissolving or dispersing the coating composition in a pharmaceutically acceptable solvent, and a film can be formed on the surface of the tablet by applying the film coating solution to the tablet by a conventional method and allowing the solvent to drain off. For example, a film can be formed by a spray coating method in which the film coating solution is sprayed onto the tablet. In addition, if necessary, markings may be printed on the surface of the film.

[0034] [Evaluation of elution properties] In this specification, the dissolution properties of posaconazole in posaconazole solid dispersions and formulations may be evaluated in accordance with Dissolution Test Method No. 2 (Paddle Method) of the 18th Edition of the Japanese Pharmacopoeia.

[0035] [Evaluation of amorphous morphology] In this specification, the amorphous form of posaconazole contained in a posaconazole solid dispersion or formulation can be evaluated by powder X-ray diffraction (XRD). In this specification, "amorphous" means that no peaks originating from crystalline components are detected in the diffraction pattern obtained by powder X-ray diffraction. "No peaks detected" in the diffraction pattern means that a broad halo pattern is observed relative to the baseline, and no prominent peaks originating from crystalline components are observed. [Examples]

[0036] [Comparative Example 1] 15 g of posaconazole and 45 g of hypromellose acetate succinate (AS-MMP, Shin-Etsu Chemical Co., Ltd.) were placed in a twin-screw extruder (HAAKE MiniLab II, Thermo Scientific) and a hot-melt extruded product was obtained at 170°C and a screw rotation speed of 100 rpm. The obtained hot-melt extruded product was pulverized using a fine grinder (Labomill LM-05-1, Dalton Co., Ltd.) at a diameter of 0.5 mm and a rotation speed of 12,000 rpm to obtain the posaconazole-containing solid dispersion of Comparative Example 1.

[0037] [Comparative Example 2] A posaconazole-containing solid dispersion of Comparative Example 2 was obtained by the same manufacturing method as for Comparative Example 1, except that the amount of posaconazole was changed to 20 g and the amount of hypromellose acetate succinate (AS-MMP, Shin-Etsu Chemical Co., Ltd.) was changed to 80 g.

[0038] [Comparative Example 3] A posaconazole-containing solid dispersion of Comparative Example 3 was obtained by the same manufacturing method as for Comparative Example 1, except that 0.75 g of hypromellose acetate succinate (AS-HMP, Shin-Etsu Chemical Co., Ltd.) was further added.

[0039] [Comparative Example 4] A posaconazole-containing solid dispersion of Comparative Example 4 was obtained by the same manufacturing method as in Comparative Example 3, except that the amount of hypromellose acetate succinate (AS-HMP, Shin-Etsu Chemical Co., Ltd.) was changed to 4.5 g.

[0040] [Example 1] The posaconazole-containing solid dispersion of Example 1 was obtained by the same manufacturing method as in Comparative Example 1, except that 4.5 g of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), which has a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, was further added and the HPC-L was placed inside the solid dispersion.

[0041] [Comparative Example 5] A posaconazole-containing solid dispersion of Comparative Example 5 was obtained by the same manufacturing method as in Example 1, except that hydroxypropyl cellulose was replaced with 4.5 g of hydroxypropyl cellulose (Klucel® EF Pharm, Ashland) having a viscosity of 300 mPa·s to 600 mPa·s in a 10% aqueous solution at 25°C and an average molecular weight of 80,000.

[0042] [Comparative Example 6] A posaconazole-containing solid dispersion of Comparative Example 6 was obtained by the same manufacturing method as in Example 1, except that hydroxypropyl cellulose was replaced with 4.5 g of hydroxypropyl cellulose (Klucel fusion®, Ashland) having a viscosity of 75 mPa·s to 250 mPa·s in a 5% aqueous solution at 25°C and an average molecular weight of 115,000.

[0043] [Comparative Example 7] A posaconazole-containing solid dispersion of Comparative Example 7 was obtained by the same manufacturing method as in Example 1, except that hydroxypropyl cellulose was replaced with 4.5 g of hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.) having a viscosity of 150 mPa·s to 400 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 700,000.

[0044] [Comparative Example 8] A posaconazole-containing solid dispersion of Comparative Example 8 was obtained by the same manufacturing method as for Comparative Example 1, except that 4.5 g of hypromellose (TC-5® R, Shin-Etsu Chemical Co., Ltd.), which has a viscosity of 6 mPa·s in a 2% aqueous solution at 20°C and a substitution degree type of 2910, was further added.

[0045] [Comparative Example 9] A posaconazole-containing solid dispersion of Comparative Example 9 was obtained by the same manufacturing method as Comparative Example 1, except that 4.5 g of mannitol (mannitol P, Mitsubishi Corporation Foodtech Co., Ltd.) was further added.

[0046] [Comparative Example 10] A posaconazole-containing solid dispersion of Comparative Example 10 was obtained by the same manufacturing method as for Comparative Example 1, except that 4.5 g of stearic acid (plant-derived, NOF Corporation) was further added.

[0047] [Comparative Example 11] A posaconazole-containing solid dispersion of Comparative Example 11 was obtained by the same manufacturing method as for Comparative Example 1, except that 4.5 g of macrogol 4000 (NOF Co., Ltd.) was further added.

[0048] The posaconazole-containing solid dispersions of Example 1 and Comparative Examples 1-11 were stored for one week under open conditions at 25°C and 90% relative humidity.

[0049] [Evaluation of elution properties] Using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), dissolution tests were conducted on the posaconazole-containing solid dispersions of Example 1 and Comparative Examples 1-11 immediately after manufacturing and after storage, under the conditions of 75 rpm for 60 minutes, using 900 ml of dissolution test solution 2 (containing 0.3% polysorbate 80 (Kanto Chemical Co., Ltd.)) as the test solution, in accordance with Dissolution Test Method 2 (Paddle Method) of the 18th Edition of the Japanese Pharmacopoeia. The dissolution tests were performed twice using 100 mg of each posaconazole-containing solid dispersion as a sample, and the average value was taken as the dissolution rate of the posaconazole-containing solid dispersions of Example 1 and Comparative Examples 1-11. The dissolution rates of the posaconazole-containing solid dispersions of Example 1 and Comparative Examples 1-11 immediately after manufacturing and after storage are shown in Figure 1.

[0050] In Figure 1, the posaconazole-containing solid dispersion of Comparative Example 1, which contained only posaconazole and hypromellose acetate succinate, showed a decrease in the posaconazole elution rate after storage compared to immediately after manufacturing. Similarly, in the posaconazole-containing solid dispersions of Comparative Examples 2-4, which added hypromellose acetate succinate in different amounts and grades, the decrease in posaconazole elution rate after storage compared to immediately after manufacturing could not be suppressed. On the other hand, the posaconazole-containing solid dispersion of Example 1, which contained hydroxypropyl cellulose (HPC-L) with a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, was found to be able to suppress the decrease in posaconazole elution rate after storage compared to immediately after manufacturing. However, in the posaconazole-containing solid dispersions of Comparative Examples 5-7, which had other grades of hydroxypropyl cellulose added, it was not possible to suppress the decrease in the dissolution rate of posaconazole after storage compared to immediately after manufacturing. Furthermore, in the posaconazole-containing solid dispersion of Comparative Example 8 with added hypromellose, the posaconazole-containing solid dispersion of Comparative Example 9 with added mannitol, the posaconazole-containing solid dispersion of Comparative Example 10 with added stearic acid, and the posaconazole-containing solid dispersion of Comparative Example 11 with added macrogol 4000, it was not possible to suppress the decrease in the dissolution rate of posaconazole after storage compared to immediately after manufacturing.

[0051] As shown in Figure 1, only the posaconazole-containing solid dispersion of Example 1, which contained hydroxypropyl cellulose (HPC-L) with a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, was able to suppress the decrease in posaconazole elution rate after storage compared to immediately after manufacturing. On the other hand, other grades of hydroxypropyl cellulose were found not to suppress the decrease in posaconazole elution rate after storage compared to immediately after manufacturing. This effect of specific hydroxypropyl cellulose in posaconazole-containing solid dispersions is a novel finding that has not been reported before and represents an effect that could not be predicted from conventional technology.

[0052] [Comparative Example 12] 300 g of posaconazole and 900 g of hypromellose acetate succinate (AS-MMP, Shin-Etsu Chemical Co., Ltd.) were placed in a twin-screw extruder (Process 11, Thermo Scientific) and a hot-melt extruded product was obtained at approximately 150°C and a screw rotation speed of 200 rpm. The obtained hot-melt extruded product was pulverized using a fine grinder (Labomill LM-05-1, Dalton Co., Ltd.) at a diameter of 0.5 mm and a rotation speed of 12,000 rpm to obtain a posaconazole-containing solid dispersion. 320 g of the obtained posaconazole-containing solid dispersion, 4 g of hypromellose acetate succinate (AS-HF, Shin-Etsu Chemical Co., Ltd.) with an average particle size of 10 μm or less and a 90% cumulative particle size of 20 μm or less, 58.4 g of crystalline cellulose (PH-102, Asahi Kasei Corporation), 20 g of croscarmellose sodium (Aczisol®, FMC International), 48 g of hydroxypropyl cellulose (HPC SSL-SFP, Nippon Soda Co., Ltd.), 4 g of hydrated silicon dioxide (Carplex® #80, DSL. Japan Co., Ltd.), and 1.6 g of magnesium stearate (Shokubutsu, Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag and compressed into tablets using a rotary tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) to obtain a 570 mg tablet of Comparative Example 12. A film coating solution was prepared by suspending 285 g of Opadry (registered trademark, Colorcon) in 1140 g of water. This film coating solution was used to coat the obtained uncoated tablets using a coating machine (HC-LABO20, Freund Industrial Co., Ltd.) to obtain a posaconazole-containing formulation (627 mg).

[0053] [Example 2] The posaconazole-containing formulation of Example 2 (627 mg) was obtained by the same manufacturing method as in Comparative Example 12, except that 15 g of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), which has a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, was further added to the posaconazole-containing solid dispersion, and the amount was changed to 54.4 g of crystalline cellulose (PH-102, Asahi Kasei Corporation).

[0054] [Example 3] The posaconazole-containing formulation of Example 3 (627 mg) was obtained by the same manufacturing method as in Example 2, except that 30 g of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), which has a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, was used, and 50.4 g of crystalline cellulose (PH-102, Asahi Kasei Corporation) was used.

[0055] [Evaluation of amorphous morphology] The crystalline form of posaconazole in the posaconazole-containing formulations of Comparative Example 12, Example 2, and Example 3 was evaluated by XRD. The measurement results are shown in Table 1. (XRD conditions) X-ray diffractometer: D8 ADVANCE (Bruker Corporation) Measurement conditions: Tube: Cu, Tube Voltage: 40kV, Tube Current: 40mA, Divergence Slit: 0.3°, Solar Slit: 2.5°, Scanning Range: 2°~30° [Table 1] [Table 1]

[0056] In the diffraction patterns of the posaconazole-containing formulations of Comparative Example 12, Example 2, and Example 3, no peaks originating from posaconazole crystals were observed, and as shown in Table 1, it was determined that the posaconazole maintained its amorphous form.

[0057] The posaconazole-containing formulations of Examples 2-3 and Comparative Example 12 described above were stored for one week under open conditions at 25°C and 90% relative humidity.

[0058] [Evaluation of elution properties] Using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), dissolution tests were conducted on the posaconazole-containing preparations of Examples 2-3 and Comparative Example 12 immediately after manufacturing and after storage, under the conditions of 75 rpm for 30 minutes, using 900 ml of Dissolution Test Solution 2 (containing 0.3% polysorbate) as the test solution, in accordance with Dissolution Test Method 2 (Paddle Method) of the 18th Edition of the Japanese Pharmacopoeia. The dissolution test was performed twice using one tablet of each posaconazole-containing preparation as a sample, and the average value was taken as the dissolution rate of the posaconazole-containing preparations of Examples 2-3 and Comparative Example 12. Table 2 shows the dissolution rates of the posaconazole-containing preparations of Examples 2-3 and Comparative Example 12 immediately after manufacturing (Initial) and after storage.

[0059] [Table 2] [Table 2]

[0060] The results in Table 2 show that increasing the amount of hydroxypropyl cellulose added, which has a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000, further suppresses the decrease in the dissolution rate of posaconazole in posaconazole-containing formulations after storage compared to immediately after manufacturing.

[0061] [Effect of reducing maximum torque during the production of posaconazole-containing solid dispersions] The inventors' investigations revealed that when producing a posaconazole-containing solid dispersion, adding hydroxypropyl cellulose with a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000 reduces the maximum torque of the twin-screw extruder. Using a twin-screw extruder (Pharma 11, Thermo Scientific), the maximum torque was measured when producing the posaconazole-containing solid dispersions of Comparative Example 1 and Example 1, with the screw rotation speed and feed rate of the twin-screw extruder fixed and the set temperature of the twin-screw extruder changed. For the posaconazole-containing solid dispersion of Comparative Example 1, the maximum torque at a set temperature of 135°C exceeded 95%, so the screw rotation speed was changed to 400 rpm when producing the solid dispersion at a set temperature of 125°C. The measurement results for Comparative Example 1 and Example 1 are shown in Tables 3 and 4, respectively.

[0062] [Table 3] [Table 3]

[0063] [Table 4] [Table 4]

[0064] Comparing the results in Table 3 and Table 4, the addition of hydroxypropyl cellulose with a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000 reduced the maximum torque during the production of the solid dispersion. This suggests that adding hydroxypropyl cellulose with a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000 may enable the production of solid dispersions at lower temperatures and shorten the production time.

Claims

1. A posaconazole-containing solid dispersion comprising posaconazole, hypromellose acetate succinate, and hydroxypropyl cellulose having a viscosity of 6 mPa·s to 10 mPa·s in a 2% aqueous solution at 20°C and an average molecular weight of 140,000.

2. The posaconazole-containing solid dispersion according to claim 1, comprising the posaconazole dispersed in a molten mixture of the hypromellose acetate succinate and the hydroxypropyl cellulose.

3. The posaconazole-containing solid dispersion according to claim 1, wherein the posaconazole-containing solid dispersion contains 1.2% by mass or more and 7.0% by mass or less of the hydroxypropyl cellulose.

4. A posaconazole-containing formulation comprising a posaconazole-containing solid dispersion according to any one of claims 1 to 3, and one or more pharmaceutically acceptable additives.

5. The posaconazole-containing preparation according to claim 4, wherein the posaconazole-containing preparation contains 0.79% by mass or more and 4.80% by mass or less of the hydroxypropyl cellulose.

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