Patent Description:
In the development of an orally administered pharmaceutical product, it is generally preferable that an active pharmaceutical ingredient (API) has high oral absorbability. When an active pharmaceutical ingredient is poorly soluble, the oral absorbability may be affected by meals. As a result, administration to patients who are unable to eat sufficiently may be limited. Even in patients who are able to eat, adherence may decrease since the timing of administration is limited. Known techniques to improve the solubility of poorly soluble compounds include salt formation, nanosizing, solid dispersion, solubilization using surfactant and cyclodextrin.

The compound of the formula [I], <NUM>-{<NUM>-[(9R)-<NUM>-hydroxy-<NUM>-(<NUM>-hydroxy-<NUM>-methylbutyloxy)-<NUM>-(trifluoromethyl)-<NUM>-fluoren-<NUM>-yl]-<NUM>-pyrazol-<NUM>-yl}-<NUM>-methylpropanamide, a pharmaceutically acceptable salt thereof, and a monohydrate thereof are described in patent document <NUM> and patent document <NUM>. Patent document <NUM> describes that the compound of the formula [I] and a monohydrate thereof have a pyruvate dehydrogenase kinase (PDHK) inhibitory activity and may become medicaments effective for the prophylaxis and/or treatment of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, diabetic complications, cardiac failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary diseases, brain ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer or pulmonary hypertension. Patent document <NUM> describes a manufacturing method of the compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a monohydrate thereof.

The problem to be solved by the present invention is provision of a pharmaceutical composition containing a compound of the formula [I] with improved pharmacokinetics or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a manufacturing method thereof.

The present inventors have found that an amorphous solid dispersion of a compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof can be obtained using a specific pharmaceutically acceptable polymer, and that the above-mentioned problem can be solved thereby, and completed the present invention.

According to the present invention, an amorphous form of a compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof with improved solubility as compared with crystals thereof can be provided. More specifically, according to the present invention, a solid dispersion capable of stably maintaining a compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof in an amorphous state is provided.

In some embodiments, precipitation of the amorphous solid dispersion of the present invention in an acidic solution is suppressed. Thus, the amorphous solid dispersion is not easily precipitated in the stomach when orally administered.

When a conventional tablet containing a crystal of a compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof is used, the oral absorbability of the compound of the formula [I] is influenced by the diet, and when administered under fasting conditions, the exposure may be reduced as compared with the administration after a meal. In contrast, an amorphous solid dispersion of the compound of the formula [I] according to the present invention shows high solubility in some embodiments regardless of the presence or absence of bile acid at the time of administration. Thus, it is less susceptible to the influence of the diet and shows high oral absorbability even when administered under fasting conditions.

The definitions of the terms in the present specification are as follows.

The "pharmaceutically acceptable salt" may be any salt known in the art that does not accompany excessive toxicity. Specifically, salts with inorganic acids, salts with organic acid, salts with inorganic bases, salts with organic bases
can be mentioned. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following reference documents:.

Pharmaceutically acceptable salts of the compound of the formula [I] can be each obtained by reacting the compound of the formula [I] with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se. A pharmaceutically acceptable salt of the compound of the formula [I] may be formed as a half molecule, one molecule, or two or more molecules of acid or base with respect to one molecule of the compound of the formula [I].

Examples of the salt with inorganic acid include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid and sulfuric acid.

Examples of the salt with organic acid include salts with acetic acid, adipic acid, alginic acid, <NUM>-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, <NUM>-camphorsulfonic acid, carbonic acid, citric acid, edetic acid, ethane-<NUM>,<NUM>-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcinic acid, hydroxy-naphthoic acid, <NUM>-hydroxy-<NUM>-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis (salicylic acid), galactaric acid, naphthalene-<NUM>-sulfonic acid, <NUM>-naphthoic acid, <NUM>,<NUM>-naphthalene disulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid and glutamic acid.

Examples of the salt with inorganic base include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth and ammonium.

Examples of the salt with organic base include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine and lysine.

The compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a monohydrate of the compound of the formula [I] can be synthesized by a known method, for example, the method described in the aforementioned patent document <NUM> or patent document <NUM>.

The compound of the formula [I] or a pharmaceutically acceptable salt thereof may exist as a solvate thereof.

The "solvate" refers to the compound of the formula [I] or a pharmaceutically acceptable salt thereof with which a solvent molecule is coordinated, and also includes hydrates. Such solvates are preferably pharmaceutically acceptable solvates. Such solvates include, for example, hydrate, ethanol solvate, dimethylsulfoxide-solvate of the compound of the formula [I] or a pharmaceutically acceptable salt thereof. Specific examples include hemihydrate, monohydrate, dihydrate or mono ethanol solvate of the compound of the formula [I] or a monohydrate of the compound of the formula [I], <NUM>/<NUM> ethanol solvate of dihydrochloride of the same. Such solvates can be manufactured according to conventional methods.

The solvate is preferably a hydrate of the compound of the formula [I], more preferably a monohydrate of the compound of the formula [I], and is represented by the following structural formula [I-h]:
<CHM>.

The "solid dispersion" means a mixture in which the active pharmaceutical ingredient (hereinafter to be also referred to as "API") is dispersed in a carrier, and is described, for example, in the following references:.

The "carrier" used in the preparation of a solid dispersion is a pharmaceutically acceptable polymer.

Examples of the "pharmaceutically acceptable polymer" include aminoalkylmethacrylate copolymer E, copolyvidone, ethylacrylate methylmethacrylate copolymer, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate, hypromellose, macrogol <NUM>, methylcellulose, ethylene gylcol and vinyl alcohol graft copolymer, polyoxyethylene(<NUM>) polyoxypropylene(<NUM>) glycol, polyvinyl alcohol-acrylic acid-methylmethacrylate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone, polyvinyl alcohol. Preferred polymer is HPMCAS, methylcellulose, copolyvidone, hypromellose, or polyvinyl alcohol.

The "amorphous solid dispersion" means a solid dispersion in which most of the APIs contained in the above-mentioned solid dispersion are amorphous. In the present specification "mostly amorphous" means that not less than <NUM>%, preferably not less than <NUM>%, more preferably not less than <NUM>%, of the compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof is amorphous. Unless particularly specified in the present specification, a solid dispersion means an amorphous solid dispersion.

That API is in an amorphous form can be confirmed, for example, by powder X-ray diffraction. When API is a crystal, peaks peculiar to API is generally observed by powder X-ray diffraction, whereas an amorphous form shows a halo pattern without the specific peak derived from API by powder X-ray diffraction in many cases.

That API is in an amorphous form can also be confirmed by DSC. When API is a crystal, specific peaks are generally observed due to changes in the crystal form, desorption of solvent from solvate, melting, whereas an amorphous form shows a halo pattern without such peaks in many cases.

The amorphous solid dispersion of the present invention can be used as a pharmaceutical composition as it is or in combination with a pharmaceutically acceptable carrier.

Examples of the "pharmaceutically acceptable carrier" include various organic or inorganic carrier substances conventionally used as preparation materials, for example, excipient, disintegrant, binder, fluidizer, lubricant, adsorbent, coating agent for solid preparations, and base, emulsifier, wetting agent, stabilizer, stabilizing agent, dispersing agent, plasticizer, pH modifier, absorption promoter, gelling agent, antiseptic, filler, dissolving agent, solubilizing agent, suspending agent for semisolid preparations. Where necessary, moreover, additives such as preservative, antioxidant, colorant, sweetening agent
may be used.

The pharmaceutical composition of the present invention can be in various dosage forms such as tablet, capsule, powder, granule, and can be manufactured by a conventional method. For example, a pharmaceutical preparation can be prepared through a formulation step such as mixing step, granulation step, tableting step, capsule filling step, coating step. A pharmaceutical preparation containing the amorphous solid dispersion of the present invention is preferably a tablet.

Examples of the "excipient" include lactose, lactose hydrate, sucrose, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, gum arabic, calcium silicate.

Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hypromellose, crystalline cellulose, calcium silicate, silicified microcrystalline cellulose.

A preferred disintegrant is croscarmellose sodium, low-substituted hydroxypropyl cellulose, calcium silicate or silicified microcrystalline cellulose.

Examples of the "binder" include hydroxypropyl cellulose, hypromellose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic.

Examples of the "fluidizer" include light anhydrous silicic acid, magnesium stearate.

Examples of the "lubricant" include magnesium stearate, calcium stearate, talc. A preferred lubricant is magnesium stearate.

Examples of the "base" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil etc.), lower alcohols (ethanol, propanol, propylene glycol, <NUM>,<NUM>-butyleneglycol, phenol etc.), higher fatty acid and ester thereof, waxes, higher alcohol, polyhydric alcohol, hydrocarbons (white petrolatum, liquid paraffin, paraffin etc.), hydrophilic petrolatum, purified lanolin, absorption ointment, hydrolyzed lanolin, hydrophilic ointment, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose derivative (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone etc.), propylene glycol, macrogol (macrogol <NUM> etc.), titanium oxide, triacetin, and combinations of two or more kinds thereof.

Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid.

Examples of the "antioxidant" include sodium sulfite, ascorbic acid.

Examples of the "colorant" include food colors (e.g., Food Color Red No. <NUM> or <NUM>, Food Color yellow No. <NUM> or <NUM> etc.), β-carotene.

Examples of the "sweetening agent" include saccharin sodium, dipotassium glycyrrhizinate, aspartame.

Examples of the "adsorbent" include light anhydrous silicic acid, calcium silicate, microcrystalline cellulose.

A core tablet composed of the amorphous solid dispersion or a combination of the amorphous solid dispersion and a pharmaceutically acceptable carrier of the present invention may be coated. Examples of the coating include sugar coating, film coating.

Examples of the agent used for sugar coating include sucrose, erythritol, maltitol. These agents and the aforementioned pharmaceutically acceptable carrier may be used in combination for the coating.

Examples of the agent used for film coating include methylhydroxyethylcellulose, ethylcellulose, hydroxypropyl cellulose, povidone, carboxymethylcellulose sodium, polyethylene glycol, acrylic polymer, polyvinyl alcohol, hypromellose. These agents and the aforementioned pharmaceutically acceptable carrier may be used in combination for the coating. In addition, a coating agent mixed powder such as Kollicoat (registered trade mark, BASF), OPADRY (registered trade mark, Japan Colorcon) may also be used.

The "solid dispersion tablet" means a tablet formulated using the amorphous solid dispersion of the present invention. The "conventional tablet" means a tablet substantially free of the amorphous solid dispersion of the present invention.

The manufacturing method of the solid dispersion of the present invention is not particularly limited, and solvent method (precipitation, spray drying, freeze-drying, drying under reduced pressure), hot-melt extrusion method, cogrinding method, supercritical method can be mentioned. Among these, preferred is solvent method or hot-melt extrusion method.

The solvent method is a method in which API and a pharmaceutically acceptable polymer are dissolved or dispersed in a solvent, and then the solvent is evaporated. The solvent used for the solvent method is not particularly limited as long as it can dissolve or disperse API and the pharmaceutically acceptable polymer.

Examples of the solvent include water, dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, diethyl ether, dibutyl ether, n-hexane, cyclohexane, n-heptane, benzene, toluene, xylene, acetic acid, propionic acid, ethyl acetate, dimethylformamide, dimethylacetamide. These solvents may be used alone or as a mixed solvent. A preferred solvent is ethanol or acetone. The solvent can be removed, for example, by drying by heating or drying under reduced pressure.

The hot-melt extrusion method is a process of continuously heating, kneading of the starting materials such as API, pharmaceutically acceptable polymer, and extruding the resulting molten material through a temperature controlled extruder. The melting can be performed at, for example, <NUM> - <NUM> (preferably, <NUM> - <NUM>). A general extruder is equipped with barrels and screws in the inside thereof. As the extruder, a twin-screw extruder having two screws is preferred.

For the solid dispersion of the present invention, solid dispersion particles having any particle size can be easily obtained by milling with an appropriate pulverizer.

A pharmaceutical preparation composed of a solid dispersion obtained by the manufacturing method of the present invention, or a pharmaceutical preparation containing a solid dispersion can be safely administered to mammals (e.g., rat, mouse, guinea pig, monkey, bovine, dog, swine, human etc.) orally or parenterally (e.g., intravenously, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, vaginal, or intraperitoneal administration, or directly to the lesion). The dose of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof contained in a pharmaceutical preparation composed of a solid dispersion obtained by the manufacturing method of the present invention, or a pharmaceutical preparation containing the solid dispersion varies depending on the subject of administration, administration route, target disease, symptoms. For example, for oral administration to an adult patient (body weight about <NUM>), a single dose is generally about <NUM> - about <NUM>/kg body weight, preferably about <NUM> - about <NUM>/kg body weight, further preferably about <NUM> - about <NUM>/kg body weight, and this amount is desirably administered once or several times (e.g., three times) per day.

A preferred embodiment of the present invention is described below.

API in the solid dispersion of the present invention is an amorphous compound of the formula [I], <NUM>-{<NUM>-[(9R)-<NUM>-hydroxy-<NUM>-(<NUM>-hydroxy-<NUM>-methylbutyloxy)-<NUM>-(trifluoromethyl)-<NUM>-fluoren-<NUM>-yl]-<NUM>-pyrazol-<NUM>-yl}-<NUM>-methylpropanamide or a pharmaceutically acceptable salt thereof or a monohydrate thereof.

The content of a compound of the formula [I] in the pharmaceutical composition (pharmaceutical preparation) of the present invention varies depending on the dosage form and administration route. For example, it is <NUM> - <NUM> mass % in the case of a pharmaceutical preparation for oral administration.

As a carrier constituting the solid dispersion of the present invention, the aforementioned pharmaceutically acceptable polymers can be mentioned. Among those, preferred are one to four kinds selected from the group consisting of HPMCAS, methylcellulose, hypromellose and polyvinyl alcohol, more preferred is HPMCAS, a mixture of HPMCAS and methylcellulose, or a mixture of HPMCAS, methylcellulose and polyvinyl alcohol.

In the present specification, the "weight ratio of x and y" or "mixing weight ratio of x and y" is shown by "weight of x:weight of y".

When the solid dispersion of the present invention contains HPMCAS, the weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and HPMCAS in the solid dispersion is within the range of from <NUM>:<NUM> to <NUM>:<NUM>, preferably within the range of from <NUM>:<NUM> to <NUM>:<NUM>, more preferably from <NUM>:<NUM> to <NUM>:<NUM>, further preferably from <NUM>:<NUM> to <NUM>:<NUM>, particularly preferably from <NUM>:<NUM> to <NUM>:<NUM>.

When the solid dispersion of the present invention contains methylcellulose, the weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and methylcellulose in the solid dispersion is preferably within the range of from <NUM>:<NUM> to <NUM>:<NUM>, more preferably from <NUM>:<NUM> to <NUM>:<NUM>, further preferably from <NUM>:<NUM> to <NUM>:<NUM>, particularly preferably from <NUM>:<NUM> to <NUM>:<NUM>.

When the solid dispersion of the present invention contains polyvinyl alcohol, the weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and polyvinyl alcohol in the solid dispersion is preferably within the range of from <NUM>:<NUM> to <NUM>:<NUM>, more preferably from <NUM>:<NUM> to <NUM>:<NUM>, further preferably from <NUM>:<NUM> to <NUM>:<NUM>, particularly preferably from <NUM>:<NUM> to <NUM>:<NUM>.

A specific preferred embodiment of the solid dispersion of the present invention is an amorphous solid dispersion of a compound of the formula [I], containing.

In this embodiment, the weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and HPMCAS is preferably within the range of from <NUM>:<NUM> to <NUM>:<NUM>. This range is more preferably from <NUM>:<NUM> to <NUM>:<NUM>, further preferably from <NUM>:<NUM> to <NUM>:<NUM>, particularly preferably from <NUM>:<NUM> to <NUM>:<NUM>.

A specific more preferred embodiment of the solid dispersion of the present invention is an amorphous solid dispersion of a compound of the formula [I] containing.

In this embodiment, a preferable weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and HPMCAS is as described above.

In this embodiment, the weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and methylcellulose is preferably within the range of from <NUM>:<NUM> to <NUM>:<NUM>. This range is more preferably from <NUM>:<NUM> to <NUM>:<NUM>, further preferably from <NUM>:<NUM> to <NUM>:<NUM>, particularly preferably from <NUM>:<NUM> to <NUM>:<NUM>.

Another specific more preferred embodiment of the solid dispersion of the present invention is an amorphous solid dispersion of a compound of the formula [I] containing.

In this embodiment, a preferable weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and methylcellulose is as described above.

In this embodiment, the weight ratio of a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof, and polyvinyl alcohol is preferably within the range of from <NUM>:<NUM> to <NUM>:<NUM>. This range is more preferably from <NUM>:<NUM> to <NUM>:<NUM>, further preferably from <NUM>:<NUM> to <NUM>:<NUM>, particularly preferably from <NUM>:<NUM> to <NUM>:<NUM>.

While the present invention is specifically explained in the following by referring to Examples, the present invention is not limited to these Examples. The mixing ratio of each component in the following examples may be increased or decreased by about <NUM>%, preferably about <NUM>%. The monohydrate of the compound of the formula [I] used in the following Examples and Comparative Examples was synthesized according to the method described in the aforementioned patent document <NUM>. As a pharmaceutically acceptable polymer and a pharmaceutically acceptable carrier, the <NPL> or the <NPL> compatible product was used.

A monohydrate of the compound of the formula [I] (<NUM>) and HPMCAS (trade name: AQOAT AS-LF, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were dissolved in acetone (<NUM>). The obtained solution was dried overnight by a vacuum dryer (trade name: DRV320DA, manufactured by ADVANTEC) set at <NUM>, and then sieved through a sieve with an opening of <NUM> to give the solid dispersion granules.

A monohydrate (<NUM>) of the compound of the formula [I] and methylcellulose (trade name: METOLOSE SM-<NUM>, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were dissolved in a mixture (<NUM>) of ethanol: water = <NUM>:<NUM>. The obtained solution was dried overnight by a vacuum dryer (trade name: DRV320DA, manufactured by ADVANTEC) set at <NUM>, and then sieved through a sieve with an opening of <NUM> to give the solid dispersion granules.

A monohydrate (<NUM>) of the compound of the formula [I] and hypromellose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were dissolved in a mixture (<NUM>) of ethanol: water = <NUM>:<NUM>. The obtained solution was dried overnight by a vacuum dryer (trade name: DRV320DA, manufactured by ADVANTEC) set at <NUM>, and then sieved through a sieve with an opening of <NUM> to give the solid dispersion granules.

A monohydrate (<NUM>) of the compound of the formula [I] and HPMCAS (trade name: AQOAT AS-LMP, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were mixed in a glass container. The mixing powder (<NUM>) was processed for <NUM> with a twin screw extruder (trade name: HAKKE MiniCTW, manufactured by Thermo Fisher Scientific) at a kneading unit barrel temperature <NUM> and screw speed <NUM> rpm to give a cylinder-shaped moldings. The obtained moldings were milled by a powermill (trade name: new PowerMill, manufactured by OSAKA CHEMICAL Co. ) at rotating speed <NUM>,<NUM> rpm to give the solid dispersion granules.

A monohydrate (<NUM>) of the compound of the formula [I] and methylcellulose (trade name: METOLOSE SM-<NUM>, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were mixed in a glass container. This mixed powder (<NUM>) was processed for <NUM> with a twin screw extruder (trade name: HAKKE MiniCTW, manufactured by Thermo Fisher Scientific) at a kneading unit barrel temperature <NUM> and screw speed <NUM> rpm to give a cylinder-shaped moldings. The obtained moldings were milled by a PowerMill (trade name: new PowerMill, manufactured by OSAKA CHEMICAL Co. ) at rotating speed <NUM>,<NUM> rpm to give the solid dispersion granules.

A monohydrate (<NUM>) of the compound of the formula [I] and hypromellose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were mixed in a glass container. This mixed powder (<NUM>) was processed for <NUM> with a twin screw extruder (trade name: HAKKE MiniCTW, manufactured by Thermo Fisher Scientific) at a kneading unit barrel temperature <NUM> and screw speed <NUM> rpm to give a cylinder-shaped moldings. The obtained moldings were milled by a powermill (trade name: new PowerMill, manufactured by OSAKA CHEMICAL Co. ) at rotating speed <NUM>,<NUM> rpm to give the solid dispersion granules.

A monohydrate (<NUM>) of the compound of the formula [I] and polyvinyl alcohol (trade name: JL-05E, manufactured by JAPAN VAM & POVAL CO. ) (<NUM>) were mixed in a glass container. This mixed powder (<NUM>) was processed for <NUM> with a twin screw extruder (trade name: HAKKE MiniCTW, manufactured by Thermo Fisher Scientific) at a kneading unit barrel temperature <NUM> and screw speed <NUM> rpm to give a cylinder-shaped moldings. The obtained moldings were milled by a powermill (trade name: new PowerMill, manufactured by OSAKA CHEMICAL Co. ) at rotating speed <NUM>,<NUM> rpm to give the solid dispersion granules.

A monohydrate (<NUM>) of the compound of the formula [I] and HPMCAS (trade name: AQOAT AS-LG, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were dissolved in acetone (<NUM>). Methylcellulose (trade name: METOLOSE SM-<NUM>, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) was added thereto and the mixture was stirred for <NUM> or longer. This solution was added to a mixture of calcium silicate (trade name: Florite RE, manufactured by Tomita Pharmaceutical Co. ) (<NUM>), light anhydrous silicic acid (trade name: Aerosil <NUM>, manufactured by NIPPON AEROSIL) (<NUM>) and croscarmellose sodium (trade name: Ac-Di-Sol, manufactured by FMC Health and Nutrition) (<NUM>), and granulated by a high-shear granulator (trade name: FM-VG-<NUM>, manufactured by POWREX). The obtained granules were dried by a vacuum dryer (trade name: VOD-<NUM>, manufactured by IKEDA SCIENTIFIC Co. ) set at <NUM> until the residual acetone concentration became not more than <NUM>%, and then milled through a screen mill (trade name: QC-U5, manufactured by Quadro Engineering) with an opening of <NUM>. This operation was repeated twice, and the combined granules (<NUM>) were blended with magnesium stearate (trade name: Parteck LUB MST, manufactured by Merck) (<NUM>) and then compressed to give a core tablet (mass <NUM>, hardness about 100N, caplet form (<NUM>. The obtained core tablets (<NUM>) were coated with a water dispersion containing a mixture (trade name: OPADRY, manufactured by Japan Colorcon) (<NUM>) of polyvinyl alcohol, titanium oxide, macrogol, and talc in a coating machine (trade name: HCT-LABO, manufactured by Freund) to give the tablet containing <NUM> of the compound of the formula [I] per tablet.

A monohydrate (<NUM>) of the compound of the formula [I] and HPMCAS (trade name: AQOAT AS-LG, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were dissolved in acetone (<NUM>). Methylcellulose (trade name: METOLOSE SM-<NUM>, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) was added thereto and the mixture was stirred for <NUM> or longer. This solution was added to a mixture of calcium silicate (trade name: Florite RE, manufactured by Tomita Pharmaceutical Co. ) (<NUM>), light anhydrous silicic acid (trade name: Aerosil <NUM>, manufactured by NIPPON AEROSIL) (<NUM>) and croscarmellose sodium (trade name: Ac-Di-Sol, manufactured by FMC Health and Nutrition) (<NUM>), and granulated by a high-shear granulator (trade name: FM-VG-<NUM>, manufactured by POWREX). The granules were dried by a vacuum dryer (trade name: VOD-<NUM>, manufactured by IKEDA SCIENTIFIC Co. ) set at <NUM> until the residual acetone concentration became not more than <NUM>%, and then milled through a screen mill (trade name: QC-U10, manufactured by Quadro Engineering) with an opening of <NUM> to give solid dispersion granules. This operation was repeated <NUM> times, and the combined granules (<NUM>) were blended with magnesium stearate (trade name: Parteck LUB MST, manufactured by Merck) (<NUM>) and then compressed to give a core tablet (mass <NUM>, diameter <NUM>). The obtained core tablets (<NUM>) were coated with a water dispersion containing a mixture (trade name: OPADRY, manufactured by Japan Colorcon) (<NUM>) of polyvinyl alcohol, titanium oxide, macrogol, and talc in a coating machine (trade name: HCT-LABO, manufactured by Freund) to give the tablet containing <NUM> of the compound of the formula [I] per tablet.

A monohydrate (<NUM>) of the compound of the formula [I], HPMCAS (trade name: AQOAT AS-LF, manufactured by Shin-Etsu Chemical Co. ) <NUM>, methylcellulose <NUM> (trade name: METOLOSE SM-<NUM>,manufactured by Shin-Etsu Chemical Co. ), polyvinyl alcohol (trade name: JL-05E, manufactured by JAPAN VAM & POVAL CO. ) (<NUM>) and calcium silicate (trade name: Florire RE, manufactured by Tomita Pharmaceutical Co. ) (<NUM>) were mixed in a high-shear granulator (trade name: MECHANOMILL, manufactured by OKADA SEIKO CO. This mixed powder (<NUM>) was processed with a twin screw extruder (trade name: HAKKE MiniCTW, manufactured by Thermo Fisher Scientific) at a kneading unit barrel temperature <NUM> and screw speed <NUM> rpm to give a cylinder-shaped moldings. This operation was performed <NUM> times, and the combined moldings were milled by a powermill (trade name: new PowerMill, manufactured by OSAKA CHEMICAL Co. ) at rotating speed <NUM>,<NUM> rpm. The obtained milled granules (<NUM>) were mixed with low-substituted hydroxypropyl cellulose (trade name: L-HPC LH-B1, manufactured by Shin-Etsu Chemical Co. ) (<NUM>), silicified microcrystalline cellulose (trade name: PROSOLV SMCC <NUM>, manufactured by JRS Pharma) (<NUM>) and magnesium stearate (trade name: Parteck LUB MST, manufactured by Merck) (<NUM>), and then compressed to give a core tablet (mass <NUM>, diameter <NUM>). The obtained core tablets (<NUM>) were coated with a water dispersion containing a mixture (trade name: OPADRY, manufactured by Japan Colorcon) (<NUM>) of hypromellose, titanium oxide, lactose hydrate, macrogol <NUM>, and triacetin in a coating machine (trade name: HCT-LABO, manufactured by Freund) to give the tablet containing <NUM> of the compound of the formula [I] per tablet.

A monohydrate (<NUM>) of the compound of the formula [I], HPMCAS (trade name: AQOAT AS-LF, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) and methylcellulose (trade name: METOLOSE SM-<NUM>, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) were mixed in a bag, and sieved through a sieve with an opening of <NUM>. This mixed powder (<NUM>) was processed for <NUM> with a twin screw extruder (trade name: HAKKE MiniCTW, manufactured by Thermo Fisher Scientific) at a kneading unit barrel temperature <NUM> and screw speed <NUM> rpm to give a cylinder-shaped moldings. This operation was performed twice, and the obtained moldings were milled by a powermill (trade name: new PowerMill, manufactured by OSAKA CHEMICAL Co. ) at rotating speed <NUM>,<NUM> rpm. The obtained milled granules (<NUM>) were mixed with low-substituted hydroxypropyl cellulose (trade name: L-HPC LH-B1, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) and magnesium stearate (trade name: Parteck LUB MST, manufactured by Merck) (<NUM>), and then compressed to give a core tablet (mass <NUM>, diameter <NUM>). The obtained core tablets (<NUM>) were coated with a water dispersion containing a mixture (trade name: OPADRY, manufactured by Japan Colorcon) (<NUM>) of hypromellose, titanium oxide, lactose hydrate, macrogol <NUM>, and triacetin together with dummy tablets (<NUM>) in a coating machine (trade name: HCT-LABO, manufactured by Freund) to give the tablet containing <NUM> of the compound of the formula [I] per tablet.

A monohydrate (<NUM>) of the compound of the formula [I], HPMCAS (trade name: AQOAT AS-LF, manufactured by Shin-Etsu Chemical Co. ) (<NUM>), methylcellulose (trade name: METOLOSE SM-<NUM>, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) and magnesium stearate (trade name: Parteck LUB MST, manufactured by Merck) (<NUM>) were mixed by a V-type diffusion mixer (trade name: V-<NUM>, manufactured by TOKUJU CORPORATION). This mixed powder was processed with a dry granulator (trade name: TF-MINI, manufactured by Freund) and a screen mill (trade name: QC-U5, manufactured by Quadro Engineering) to give granules with a specific volume <NUM>/g. The obtained granules (<NUM>) were processed with a twin screw extruder (trade name: Nano-<NUM>, manufactured by Leistriz) at a maximum temperature <NUM> and screw speed <NUM> rpm to give a cylinder-shaped moldings. The obtained moldings were milled by an impact mill (trade name: SAMF, manufactured by NARA MACHINERY CO. ) at rotating speed <NUM> rpm. The obtained milled granules (<NUM>) were blended with low-substituted hydroxypropyl cellulose (trade name: L-HPC LH-B1, manufactured by Shin-Etsu Chemical Co. ) (<NUM>) and magnesium stearate (trade name: Parteck LUB MST, manufactured by Merck) (<NUM>), and then compressed to give a core tablet (mass <NUM>, diameter <NUM>). The obtained core tablets (<NUM>) were coated with a water dispersion containing a mixture (trade name: OPADRY, manufactured by Japan Colorcon) (<NUM>) of hypromellose, titanium oxide, lactose hydrate, macrogol <NUM>, and triacetin in a coating machine (trade name: HCT-LABO, manufactured by Freund) to give the tablet containing <NUM> of the compound of the formula [I] per tablet.

A monohydrate (particle size D90 <NUM>) (<NUM>) of the compound of the formula [I] micronized by an impact mill (trade name: SAMF, manufactured by NARA MACHINERY CO. ), lactose hydrate (trade name: Pharmatose <NUM>, manufactured by DFE Pharma) (<NUM>) and carmellose calcium (trade name: ECG-<NUM>, manufactured by GOTOKU CHEMICAL CO. ) (<NUM>) were mixed, a solution of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda Co. ) (<NUM>) and purified water (<NUM>) was added thereto, and the mixture was granulated by a high-shear granulator (trade name: FM-VG-<NUM>, manufactured by POWREX). The obtained granules were dried to loss on drying <NUM>% in a fluid bed granulator (trade name: FD-MP-<NUM>, manufactured by POWREX) set to charge air temperature <NUM>, and milled by a screen mill with an opening of <NUM> (trade name: QC-U10, manufactured by Quadro Engineering) to give granules. This operation was repeated twice, and the obtained granules (<NUM>) and magnesium stearate (trade name: Parteck LUB MST, manufactured by Merck) (<NUM>) were blended, and then compressed to give a core tablet (mass <NUM>, hardness about 70N, diameter <NUM>). The obtained core tablets (<NUM>) were coated with a water dispersion containing a mixture (trade name: OPADRY, manufactured by Japan Colorcon) (<NUM>) of hypromellose, titanium oxide, lactose hydrate, macrogol <NUM>, and triacetin in a coating machine (trade name: HCT-LABO, manufactured by Freund) to give the tablet containing <NUM> of the compound of the formula [I] per tablet.

The dissolution profiles of the solid dispersion granules obtained in Example <NUM> in a pH <NUM> test media (trade name: diluted McIlvaine buffer, manufactured by KANTO CHEMICAL CO. ) was evaluated.

The dissolution test was performed using a dissolution tester (trade name: NTR-VS6P, manufactured by Toyama Sangyo Co. ) that conforms to the Japanese Pharmacopoeia Dissolution Test Method <NUM> (Paddle Method), at paddle rotating speed <NUM> rpm, test media amount <NUM>. An amount equivalent to <NUM> of the compound of the formula [I] was added to the test media, and the dissolved amount of the compound of the formula [I] was measured at each sampling point with a spectrophotometer (UV-<NUM>, manufactured by Shimadzu Corporation).

As a comparison control, the dissolution profiles of a monohydrate (particle size D90: <NUM>) crystal of the compound of the formula [I] micronized by an impact mill (trade name: SAMF, manufactured by NARA MACHINERY CO. ) was also evaluated by the same method. The results are shown in <FIG>.

As shown in <FIG>, all the solid dispersions of Example <NUM> showed better solubility than the monohydrate crystals of the compound of the formula [I].

The dissolution profiles of the solid dispersion granules obtained in Example <NUM> in a pH <NUM> test media (trade name: diluted McIlvaine buffer, manufactured by KANTO CHEMICAL CO. ) was evaluated by a method similar to that in Experimental Example <NUM>.

As shown in <FIG>, all the solid dispersions of Example <NUM> showed better solubility than the monohydrate crystal of the compound of the formula [I].

The precipitation behavior of the compound of the formula [I], dissolved in ethanol (concentration: <NUM>/mL), in the following <NUM> types of test medium was evaluated by the same test method as in Experimental Example <NUM>. The results are shown in <FIG>.

As shown in <FIG>, the addition of copolyvidone, methylcellulose, or hypromellose significantly suppressed the precipitation of the compound of the formula [I], as compared with the addition of HPMCAS, the addition of polyvinyl alcohol, or without addition of a pharmaceutically acceptable polymer.

The dissolution profiles of the tablets obtained in Example <NUM>, Example <NUM> or Comparative Example <NUM> in the following <NUM> test medium was evaluated by a method similar to that in Experimental Example <NUM>. The results are shown in <FIG>.

As shown in <FIG>, the solid dispersion tablets of Example <NUM> and Example <NUM> showed better solubility in any of the test medium than the conventional tablet of Comparative Example <NUM>.

The tablets obtained in Example <NUM> were placed in a glass bottle together with a desiccant under the conditions of <NUM>, <NUM>/<NUM>% RH and <NUM> <NUM>% RH, and the bottle was closed and stored for <NUM> months. Then, the crystalline state was evaluated by Powder X-ray diffractometer (trade name: X'Pert PRO, manufactured by Malvern Panalytical) and differential scanning calorimetry (trade name: DSC Q2000, manufactured by TA instruments). As a controlled comparison, a monohydrate crystal of the compound of the formula [I] was similarly evaluated.

The results of evaluation under the following conditions are shown in <FIG>.

As shown in <FIG>, since no peak other than the peak derived from calcium silicate, which is an additive component, was observed in the solid dispersion tablet of Example <NUM>, it was confirmed that the compound of the formula [I] was in an amorphous state. In addition, in the absence of changes from before storage under any storage conditions, it was found that the amorphous state was maintained even after storage.

As shown in <FIG>, in the monohydrate of the compound of the formula [I], a peak around <NUM> due to desorption of water molecules and a peak around <NUM> due to melting are observed, whereas the solid dispersion tablet of Example <NUM> showed a halo pattern, which confirms that the compound of the formula [I] is in an amorphous state. In addition, in the absence of changes from before storage under any storage conditions, it was found that the amorphous state was maintained even after storage.

The tablets obtained in Example <NUM> were stored under the conditions of <NUM>/<NUM>% RH and <NUM> <NUM>% RH under open conditions for <NUM> months. Then, the crystalline state was evaluated by differential scanning calorimetry (trade name: DSC Q2000, manufactured by TA instruments). As a controlled comparison, a monohydrate crystal of the compound of the formula [I] was evaluated in the same manner.

One tablet obtained in Example <NUM> or Comparative Example <NUM> (containing an amount equivalent to <NUM> as a compound of the formula [I]) was orally administered to a male beagle dog of the following conditions. The time to maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), and the area under the plasma concentration curve (AUC<NUM>-24hr) up to <NUM> hr after administration were calculated from the obtained concentration profile of the obtained plasma. <FIG> shows the plasma concentration profile, and Table <NUM> shows pharmacokinetics parameters.

As shown in <FIG> and Table <NUM>, when the solid dispersion tablet of Example <NUM> was administered, the Cmax value was <NUM> times and the AUC<NUM>-24hr value was <NUM> times that by the administration of the conventional tablet of Comparative Example <NUM>. On the other hand, the Tmax value was not significantly different between the solid dispersion tablet of Example <NUM> and the conventional tablet of Comparative Example <NUM>.

One tablet obtained in Example <NUM> or Example <NUM> was orally administered to a male beagle dog under the following conditions. The time to maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), and the area under the plasma concentration curve (AUC<NUM>-24hr) up to <NUM> hr after administration were calculated from the obtained concentration profile of the obtained plasma. <FIG> shows the plasma concentration profile, and Table <NUM> shows pharmacokinetics parameters.

As shown in <FIG> and Table <NUM>, when the tablet of Example <NUM> was administered, the Cmax value was <NUM> times and the AUC<NUM>-24hr value was <NUM> time that by the administration of the tablet of Example <NUM>, and equivalent oral absorbability was shown. The Tmax value was not significantly different between Example <NUM> and Example <NUM>.

Using the tablets obtained in Comparative Example <NUM>, randomized, open-label, and crossover Phase I clinical test was performed to evaluate the influence of diet on the pharmacokinetics of the compound of the formula [I].

On the first day of the first phase (first administration), <NUM> healthy subjects were randomly assigned at a ratio of <NUM>:<NUM> to receive administration under any of the following conditions, and received a single oral administration of <NUM> of the compound of the formula [I] under the assigned conditions. <NUM> of the compound of the formula [I] was administered using two tablets each containing <NUM> of the compound of the formula [I] and two tablets each containing <NUM> thereof.

The second phase (second administration) test was performed <NUM> days after the first administration. The second phase was performed by exchanging the administration conditions of each test subject. That is, the test subjects administered under fasting conditions in the first phase received a single oral administration of <NUM> of the compound of the formula [I] <NUM> after the start of ingestion of the high-fat breakfast after fasting overnight (at least <NUM> hr). The test subjects who received administration under fed conditions in Phase <NUM> received a single oral administration of <NUM> of the compound of the formula [I] without breakfast after fasting overnight (at least <NUM> hr).

Blood samples were collected from all test subjects <NUM> hr before administration and <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hr after administration. The plasma concentration of the compound of the formula [I] in the blood samples was measured. From the obtained plasma concentration profile, the maximum plasma concentration arrival time (Tmax), maximum plasma concentration (Cmax) and plasma concentration area under the curve (AUCinf) were calculated. The plasma concentration profile is shown in <FIG> and <FIG>, and pharmacokinetics parameters are shown in Table <NUM>.

As shown in <FIG>, <FIG> and Table <NUM>, the oral absorbability of the compound of the formula [I] decreased when administered under the fasting conditions as compared with the fed conditions in the clinical test using the conventional tablet of the compound of the formula [I].

Using the tablets obtained in Example <NUM>, randomized, open-label, and crossover Phase I clinical test was performed to evaluate the influence of diet on the pharmacokinetics of the compound of the formula [I].

On the first day of the first phase (first administration), <NUM> healthy subjects were randomly assigned at a ratio of <NUM>:<NUM> to receive administration under any of the following conditions, and received a single oral administration of <NUM> of the compound of the formula [I] under the assigned conditions. <NUM> of the compound of the formula [I] was administered using three tablets each containing <NUM> of the compound of the formula [I].

Blood samples were collected from all test subjects <NUM> hr before administration and <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hr after administration. The plasma concentration of the compound of the formula [I] in the blood samples was measured. From the obtained plasma concentration profile, the maximum plasma concentration arrival time (Tmax), maximum plasma concentration (Cmax) and plasma concentration area under the curve (AUCinf) were calculated. The plasma concentration profile is shown in <FIG> and <FIG>, and pharmacokinetics parameters are shown in Table <NUM>.

As shown in <FIG>, <FIG> and Table <NUM>, the oral absorbability of the compound of the formula [I] did not show a remarkable difference between administration under fasting and fed conditions in the clinical test using the solid dispersion tablet of the compound of the formula [I].

According to the present invention, a solid dispersion capable of stably maintaining a compound of the formula [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof in an amorphous state is provided. Consequently, a pharmaceutical preparation containing the compound of the formula [I] with improved pharmacokinetics or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided.

In addition, an amorphous solid dispersion of the compound of the formula [I] according to the present invention is advantageous in that it shows high solubility in some embodiments regardless of the presence or absence of bile acid at the time of administration. Thus, it is less susceptible to the influence of the diet and shows high oral absorbability even when administered under fasting conditions.

Claim 1:
An amorphous solid dispersion comprising
(<NUM>) a compound represented by the following formula [<NUM>]:
<CHM>
or a pharmaceutically acceptable salt thereof or a hydrate thereof, and
(<NUM>) one to four kinds of pharmaceutically acceptable polymers selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, methylcellulose, hypromellose and polyvinyl alcohol.