Complex containing amorphous solid dispersion

Abstract

To provide a complex with enhanced drug leachability, comprising at least a solid dispersion containing a carrier other than polyvinyl pyrrolidone and HPMCAS outside the solid dispersion.SOLUTION: A complex contains a drug and also includes at least: a solid dispersion comprising a carrier, which is selected from the group consisting of vinyl pyrrolidone-vinyl acetate copolymers, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and first hydroxypropyl methylcellulose acetate succinate; and second hydroxypropyl methylcellulose acetate succinate outside the solid dispersion.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a composite comprising hydroxypropyl methylcellulose acetate succinate outside a solid dispersion. [Background technology]

[0002] A solid dispersion can be produced, for example, by dissolving a drug and a carrier in a solvent, then removing the solvent and allowing the drug to precipitate (Patent Document 1). In a solid dispersion, the drug is molecularly dispersed in the carrier in an amorphous state, which significantly increases the apparent solubility of the drug and improves its bioavailability.

[0003] Although solid dispersions in which drugs are dispersed in an amorphous state can improve the absorbability of drugs after oral ingestion, they have a physical stability problem in that the drug recrystallizes during storage. To improve this stability, pharmaceutical compositions containing a stabilizer on the outside of the solid dispersion have been proposed, and experimental results have been reported for a pharmaceutical composition containing a solid dispersion containing polyvinylpyrrolidone (hereinafter also referred to as "PVP") as a carrier and hypromellose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate, hereinafter also referred to as "HPMCAS") as an external stabilizer (Patent Document 2).

[0004] Furthermore, it has been reported that in a solid dispersion containing PVP as a carrier, a similar stabilizing effect was obtained when hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC") was used as an external stabilizer instead of HPMCAS, suggesting that stabilization by HPMCAS is not due to intermolecular interactions between acetate groups and succinate groups and the solid dispersion (Non-Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2016-98179 [Patent Document 2] Special Publication No. 2023-515764 [Non-patent literature]

[0006] [Non-Patent Document 1] European Journal of Pharmaceutics and Biopharmaceutics 2021,169,189-199 Summary of the Invention [Problem to be solved by the invention]

[0007] Patent Document 2 states that "Most preferably, polyvinylpyrrolidone is used as the matrix agent for the solid dispersion," and indeed PVP is used as the carrier, but only lists numerous candidates other than PVP as examples, and the relationship between solid dispersions containing carriers other than PVP and external HPMCAS is unclear. Non-Patent Document 1 also uses PVP as the carrier, and the results when other carriers are used are unclear. An object of the present invention is to provide a pharmaceutical composition that contains at least a solid dispersion containing a carrier other than PVP and HPMCAS located outside the solid dispersion, and that has even higher drug dissolution properties. [Means for solving the problem]

[0008] The present inventors have found that the dissolution of a drug depends not only on the type of carrier in a solid dispersion but also on the relationship between the carrier and HPMCAS present outside the solid dispersion, and have particularly found that the combination of methylcellulose and HPMCAS, which has rarely been used as a carrier for solid dispersions until now, significantly improves the dissolution of a drug, thereby completing the present invention. One embodiment of the present invention provides a composite comprising a solid dispersion containing, in addition to a drug, at least a carrier selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and primary hydroxypropyl methylcellulose acetate succinate, and at least secondary hydroxypropyl methylcellulose acetate succinate located outside the solid dispersion. In another aspect of the present invention, there is provided a method for producing a composite, the method comprising at least the steps of: preparing a solid dispersion containing, in addition to a drug, at least a carrier selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and primary hydroxypropyl methylcellulose acetate succinate; and adding secondary hydroxypropyl methylcellulose acetate succinate to the solid dispersion. [Effects of the Invention]

[0009] According to the present invention, a composite having high dissolution properties, including high initial dissolution properties, can be provided. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a graph showing the relationship between dissolution time and dissolution rate (%) of nifedipine in Examples 1 and 4 and Comparative Examples 1 and 4. DETAILED DESCRIPTION OF THE INVENTION

[0011] (1)Solid dispersion The solid dispersion comprises at least a drug and a carrier. The drug contained in the solid dispersion is not particularly limited as long as it is orally administrable, and one type or a mixture of two or more types may be used. Examples of such drugs include central nervous system drugs, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussives and expectorants, antihistamines, antipyretic analgesics and anti-inflammatory drugs, diuretics, autonomic drugs, antimalarials, antidiarrheals, psychotropic drugs, vitamins and their derivatives, etc.

[0012] Examples of central nervous system drugs include diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, ketoprofen, and chlordiazepoxide. Examples of cardiovascular drugs include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedivine, atenolol, spironolactone, metoprolol, vindolol, captopril, isosorbide nitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, propranolol hydrochloride, and alprenolol hydrochloride.

[0013] Respiratory drugs include, for example, amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin. Examples of gastrointestinal drugs include benzimidazole drugs with antiulcer activity such as 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole, cimetidine, ranitidine, pirenzepine hydrochloride, pancreatin, bisacodyl, and 5-aminosalicylic acid.

[0014] Examples of antibiotics include talampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, and erythromycin. Examples of antitussives and expectorants include noscapine hydrochloride, carbetapentane citrate, dextromethorphan hydrobromide, isoaminyl citrate, and dimemorfan phosphate. Examples of antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, and promethazine hydrochloride. Examples of antipyretic, analgesic and anti-inflammatory agents include ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin and ketoprofen. Diuretics include, for example, caffeine.

[0015] Examples of autonomic nervous system acting drugs include dihydrocodeine phosphate, dl-methylephedrine hydrochloride, propranolol hydrochloride, atropine sulfate, acetylcholine chloride, neostigmine, etc. Antimalarial agents include, for example, quinine hydrochloride. Examples of antidiarrheal agents include loperamide hydrochloride. Examples of psychotropic drugs include chlorpromazine. Examples of vitamins and derivatives thereof include vitamin A, vitamin B1, fursultiamine, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamic acid.

[0016] Solid dispersions can improve the solubility of particularly water-soluble drugs. Here, "water-soluble drugs" refers to drugs that are "slightly soluble," "extremely soluble," or "practically insoluble" in water, as defined in the 18th Edition of the Japanese Pharmacopoeia. "Slightly soluble" refers to the degree to which a drug dissolves in 100 mL to less than 1,000 mL of water within 30 minutes when 1 g or 1 mL of a solid drug is placed in a beaker, water is added, and the drug is vigorously shaken for 30 seconds every 5 minutes at 20±5°C. "Extremely soluble" refers to the degree to which a drug dissolves in 1,000 mL to less than 10,000 mL of water within 30 minutes. "Practically insoluble" refers to the degree to which a drug dissolves in 1,000 mL to less than 10,000 mL of water within 30 minutes. In addition, in the above pharmaceutical test, the fact that a poorly water-soluble drug dissolves means that the drug dissolves or is miscible in the solvent, and that no fibers or the like are found, or even if found, they are very slight.

[0017] Specific examples of poorly water-soluble drugs include azole compounds such as itraconazole, ketoconazole, fluconazole, mitconazole, and posaconazole; dihydropyridine compounds such as nifedipine, nitrendipine, amlodipine, nicardipine, nilvadipine, felodipine, and efonidipine; propionic acid compounds such as ibuprofen, ketoprofen, and naproxen; indole acetic acid compounds such as indomethacin and acemetacin; as well as griseofulvin, phenytoin, carbamazepine, dipyridamole, apalutamide, telaprevir, vemurafenib, ivacaftor, lumacaftor, tezacaftor, elexacaftor, enasidenib, doravirine, enzalutamide, ivosidenib, ibrutinib, deuclavacitinib, and pirtobrutinib.

[0018] The carrier contained in the solid dispersion is selected from the group consisting of vinylpyrrolidone-vinyl acetate (VP / VA) copolymer, methylcellulose, hydroxypropylmethylcellulose (hereinafter also referred to as "HPMC"), hydroxypropylmethylcellulose phthalate (hereinafter also referred to as "HPMCP"), and hypromellose acetate succinate (hereinafter also referred to as "HPMCAS").

[0019] The vinylpyrrolidone-vinyl acetate (VP / VA) copolymer is a copolymer in which the molar ratio of vinylpyrrolidone (VP) monomer units to vinyl acetate (VA) monomer units is preferably 5:5 to 7:3, more preferably 6:4, and examples thereof include a vinylpyrrolidone / vinyl acetate random copolymer ("Kollidon" (registered trademark) VA64 manufactured by BASF) in which the molar ratio of vinylpyrrolidone units / vinyl acetate units is 6 / 4.

[0020] The degree of substitution (DS) of methoxy groups in methylcellulose is preferably 1.54 to 2.03, more preferably 1.64 to 2.03. DS represents the degree of substitution and is the number of alkoxy groups present per anhydroglucose unit of cellulose. The DS of the methoxy groups in methylcellulose can be determined by converting the results obtained by measurement in accordance with the 18th Edition of the Japanese Pharmacopoeia.

[0021] Methylcellulose with a wide viscosity range can be used, but we have surprisingly found that methylcellulose with a particularly low viscosity can contribute to higher drug dissolution. The viscosity of a 2% by weight aqueous solution of methylcellulose at 20°C, as measured by an Ubbelohde viscometer, is preferably 1.0 to 50.0 mPa·s, more preferably 1.0 to 20.0 mPa·s, and even more preferably 2.0 to 8.0 mPa·s. The viscosity of a 2% by mass aqueous solution at 20°C can be measured using a single cylinder rotational viscometer in accordance with the rotational viscometer method in the viscosity measurement method of the general test methods described in the Japanese Pharmacopoeia, 18th Edition, if the viscosity is 600 mPa s or more. On the other hand, if the viscosity is less than 600 mPa s, it can be measured using an Ubbelohde viscometer in accordance with the capillary viscometer method in the viscosity measurement method of the general test methods described in the Japanese Pharmacopoeia, 18th Edition.

[0022] The degree of substitution (DS) of methoxy groups in HPMC is not particularly limited, but from the viewpoint of solubility in organic solvents, it is preferably 1.0 to 2.2, more preferably 1.5 to 2.2, and even more preferably 1.7 to 2.2. The degree of substitution (DS) of methoxy groups refers to the average number of methoxy groups per anhydroglucose unit. The molar substitution (MS) of hydroxypropoxy groups in HPMC is not particularly limited, but from the viewpoint of solubility in organic solvents, it is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and even more preferably 0.20 to 0.65. The molar substitution (MS) of hydroxypropoxy groups refers to the average molar substitution of hydroxypropoxy groups per anhydroglucose unit. The DS of the methoxy group and the MS of the hydroxypropoxy group in HPMC can be determined by converting the results obtained by measurement based on the 18th edition of the Japanese Pharmacopoeia.

[0023] As the substitution degree type of HPMC, from the viewpoint of solubility in organic solvents, the 2910 type (methoxy group: 28.0 to 30.0%, hydroxypropoxy group: 7.0 to 12.0%), 2906 type (methoxy group: 27.0 to 30.0%, hydroxypropoxy group: 4.0 to 7.5%), and 2208 type (methoxy group: 19.0 to 24.0%, hydroxypropoxy group: 4.0 to 12.0%) described in the 18th Edition of the Japanese Pharmacopoeia for hypromellose are preferred, with the 2910 type and 2906 type being more preferred, and the 2910 type being particularly preferred.

[0024] The viscosity of a 2% by mass aqueous solution of HPMC at 20° C. is not particularly limited, but is preferably 1.0 to 50 mPa·s, more preferably 1.0 to 20 mPa·s, and even more preferably 2.0 to 8.0 mPa·s. The viscosity of a 2% by mass aqueous solution at 20°C can be measured using a single cylinder rotational viscometer in accordance with the rotational viscometer method of the general test method for viscosity measurement described in the Japanese Pharmacopoeia, 18th Edition, if the viscosity is 600 mPa s or more. On the other hand, if the viscosity is less than 600 mPa s, it can be measured using an Ubbelohde viscometer in accordance with the capillary viscometer method of the general test method for viscosity measurement described in the Japanese Pharmacopoeia, 18th Edition.

[0025] In HPMCP, the DS of the methoxy group is not particularly limited, but is preferably 1.10 to 2.20, more preferably 1.30 to 2.10, even more preferably 1.60 to 2.00, and most preferably 1.80 to 2.00. The MS of the hydroxypropoxy group is not particularly limited, but is preferably 0.10 to 1.00, more preferably 0.10 to 0.80, even more preferably 0.15 to 0.60, and most preferably 0.20 to 0.50. The DS of the carboxybenzoyl group in HPMCP is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.40 to 0.80. The DS of the methoxy and carboxybenzoyl groups and the MS of the hydroxypropoxy groups in HPMCP can be calculated from the values ​​obtained by the methods described in the 18th Edition Japanese Pharmacopoeia's individual monographs for "hypromellose" and "hypromellose phthalate." The DS of the methoxy and carboxybenzoyl groups in HPMCP represent the degree of substitution, and refer to the average number of methoxy and carboxybenzoyl groups per anhydroglucose unit. The MS of the hydroxypropoxy groups in HPMCP represents the molar substitution, and refer to the average number of molar hydroxypropoxy groups per anhydroglucose unit.

[0026] The viscosity at 20°C of a methanol / methylene chloride mixed solution (1:1 mass ratio) containing 10% by mass of HPMCP is not particularly limited, but is preferably 10.0 to 300.0 mPa·s, more preferably 15.0 to 250.0 mPa·s, and even more preferably 15.0 to 220.0 mPa·s. The viscosity at 20°C of a methanol / methylene chloride mixed solution (1:1 mass ratio) containing 10% by mass of HPMCP can be measured using an Ubbelohde viscometer according to the method described in the "Hypromellose phthalate" monograph of the 18th Edition of the Japanese Pharmacopoeia.

[0027] The HPMCAS used as a carrier does not need to have the same degree of substitution, viscosity, etc. as the HPMCAS present on the outside of the solid dispersion, but HPMCAS within the same ranges as the HPMCAS present on the outside of the solid dispersion described below can be used.

[0028] The amount of the drug is preferably 10 to 100 parts by mass, more preferably 15 to 80 parts by mass, and even more preferably 15 to 50 parts by mass, per 100 parts by mass of the carrier selected from the group consisting of vinylpyrrolidone-vinyl acetate (VP / VA) copolymer, methylcellulose, HPMC, HPMCP, and HPMCAS, because the carrier within the solid dispersion and hydroxypropyl methylcellulose acetate succinate on the outside of the solid dispersion provide the drug in an amorphous state with desirable high storage stability.

[0029] The solid dispersion can be produced, for example, by a spray-drying method in which a drug (preferably a poorly water-soluble drug) and a carrier are dissolved in a solvent and then spray-dried, or by a hot-melt extrusion method in which a drug and a polymer are heated, melted, and extruded. The solid dispersion of the present invention can be applied to solid dispersions produced by either method.

[0030] For example, the spray drying method broadly refers to a method in which a spray-drying solution containing a drug and a carrier polymer together with a solvent is broken down (atomized) into small droplets, and the solvent is rapidly removed from the droplets by evaporation. The driving force for removing the solvent is generally obtained by lowering the partial pressure of the solution compared to the vapor pressure of the solvent at the temperature at which the droplets are dried. Preferred embodiments include mixing the droplets with a high-temperature drying gas or maintaining a partial vacuum in the solvent removal device.

[0031] The solvent may be any solvent capable of dissolving the drug, carrier, and optional additives described below. Suitable solvents include, for example, water, acetone, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran, and dichloromethane, and one or a mixture of two or more of these may be used. When the solid dispersion solution contains a water-miscible solvent, water can be added to the solid dispersion solution.

[0032] The spray-drying concentrate containing the drug and carrier together with the solvent can be spray-dried using a variety of nozzle mechanisms. For example, various types of nozzles can be used. Preferred modes include a two-fluid nozzle, a fountain nozzle, a flat fan nozzle, a pressure nozzle, and a rotary atomizer. The spray-dried stock solution can be delivered over a wide range of flow rates and temperatures. Furthermore, when pressurized during spraying, it is possible to spray over a wide range of pressures. Generally, the rate of solvent evaporation increases with an increase in the specific surface area of ​​the droplets. Therefore, the droplets upon exiting the nozzle are preferably less than 500 μm, more preferably less than 400 μm, and even more preferably 5 to 200 μm, and the flow rate, temperature, and pressure that enable such spraying are preferred. After spraying, the stock solution solidifies rapidly.

[0033] After spraying, the spray-dried solution rapidly solidifies to form a solid dispersion. The solidified solid dispersion generally remains in the spray-drying chamber for about 5 to 60 seconds, during which time the solvent is removed from the solid powder. The temperatures during spray-drying are preferably about 20°C to 150°C at the inlet and about 0°C to 85°C at the outlet.

[0034] The less solvent remaining in the solid dispersion, the better. This is because the mobility of drug molecules in the amorphous solid dispersion is suppressed, increasing stability. If further removal of residual solvent is required, secondary drying can be performed. Suitable secondary drying methods include tray drying, fluidized bed drying, belt drying, and microwave drying.

[0035] The solid dispersion may contain various additives, such as excipients, binders, disintegrants, lubricants, anti-aggregating agents, etc., which are commonly used in this field, as needed.

[0036] Examples of excipients include sugars such as sucrose, lactose, mannitol, and glucose, starch, and crystalline cellulose. Examples of binders include polyvinyl alcohol, polyacrylic acid, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, macrogols, gum arabic, gelatin, and starch. Examples of disintegrants include low-substituted hydroxypropyl cellulose, carmellose or a salt thereof, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, crystalline cellulose, and crystalline cellulose-carmellose sodium. Examples of lubricants and anti-agglomerating agents include talc, magnesium stearate, calcium stearate, silicon dioxide (colloidal silica), stearic acid, waxes, hardened oils, polyethylene glycols, and sodium benzoate.

[0037] The hot-melt extrusion method is a method for obtaining an amorphous solid dispersion by applying heat equal to or higher than the glass transition temperature of the raw materials, followed by kneading and extruding. Hot-melt extrusion can be performed using a hot-melt extruder. The hot-melt extruder is not particularly limited as long as it is an extruder that applies shear force with a piston or screw to melt and knead a carrier polymer, active ingredient, plasticizer, and surfactant while heating them in the system, and then extrudes them through a die. However, in order to obtain a more uniform extrudate, a twin-screw extruder is preferred. Furthermore, by selecting the shape of the die, it is possible to extrude the material into desired shapes such as a circle, a square, a column, a film, etc., to obtain a hot-melt extrudate.

[0038] Specific examples of hot melt extruders include Capilograph (a single-screw piston extruder) manufactured by Toyo Seiki Seisakusho, Nano-16 (a twin-screw extruder) manufactured by Leistritz, and Process 11 (a twin-screw extruder) and Pharma 11 (a twin-screw extruder) manufactured by Thermofisher Scientific. The heat-melting temperature is preferably 50 to 200°C, more preferably 60 to 180°C, even more preferably 80 to 160°C, and particularly preferably 80 to 150°C, from the viewpoint of the stability of the drug (preferably a poorly water-soluble drug) and the carrier. The hot melt extrusion conditions are not particularly limited, but in the case of a single-screw piston extruder, the extrusion speed is preferably 1 to 1000 mm / min, more preferably 10 to 500 mm / min, and in the case of a twin-screw extruder, the screw rotation speed is preferably 1 to 1000 rpm, more preferably 1 to 500 rpm. The hot-melt extrudate is cooled naturally at room temperature (25 to 30° C.) or by cold air blowing after the die discharge outlet.

[0039] The cooled hot-melt extrusion product may be cut into pellets of 0.1 to 5 mm using a cutter, or may be further pulverized to adjust the particle size until it is in a granular or powder form, if necessary. As the cutter, a pelletizer, knife mill, or the like that can easily pelletize the extrusion moldings is preferred from the viewpoint of crushability of the extrusion moldings. As the pulverizer, a jet mill, a knife mill, a pin mill, or the like is preferred, as the temperature of the product is less likely to become high due to the structure of the equipment used for pulverization. If the temperature inside the cutter and crusher becomes too high, the raw material will soften due to the heat and the particles will stick together, so it is preferable to crush the raw material while cooling it with air or the like.

[0040] (2) Late addition of HPMCAS The dissolution properties of the produced solid dispersion can be improved by incorporating HPMCAS on the outside. HPMCAS can be produced, for example, using the method described in Japanese Patent Laid-Open Publication No. 54-61282. The raw material, hypromellose (also known as hydroxypropyl methylcellulose, hereinafter also referred to as "HPMC"), is dissolved in glacial acetic acid, and acetic anhydride and succinic anhydride, which are esterifying agents, and sodium acetate, which is a reaction catalyst, are added, followed by a heating reaction. After the reaction is complete, a large amount of water is added to the reaction solution to precipitate HPMCAS, which is then washed with water and dried.

[0041] The DS of the methoxy group in HPMCAS is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, and even more preferably 1.60 to 2.00. The MS of the hydroxypropoxy group in HPMCAS is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and even more preferably 0.20 to 0.65. The DS of the acetyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.20 to 0.80. The DS of the succinyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.10 to 0.60. The DS or MS of the methoxy group, hydroxypropoxy group, acetyl group, and succinyl group in HPMCAS can be calculated from the values ​​obtained by the method described in the "Hypromellose acetate succinate" section of the Japanese Pharmacopoeia, 18th Edition.

[0042] The volume average particle size of HPMCAS can be measured using a dry laser diffraction particle size distribution analyzer. The volume average particle size can be calculated using the formula {Σ(nD 3 ) / Σn} 1 / 3 In the formula, D is the particle diameter, n is the number of particles of that diameter, and Σn is the total number of particles. Dry laser diffraction particle size analyzers are devices that eject a powder sample with compressed air, irradiate it with laser light, and measure the volume average particle size based on the diffraction intensity. Examples of such devices include the Mastersizer manufactured by Malvern Instruments Ltd. in the UK and the HELOS device manufactured by Sympatec GmbH in Germany.

[0043] In terms of volume particle size, D 50 means the particle size of cumulative 50%. When using HPMCAS powder by physical mixing, granulation, etc. as a method for adding the solid dispersion of HPMCAS later, the volume average particle diameter (D 50 ) is not particularly limited, but is preferably 2 mm or less, more preferably 1 to 500 μm, and even more preferably 2 to 300 μm, from the viewpoint of uniform mixing with the solid dispersion.

[0044] The viscosity of a dilute (0.1 mol / L) aqueous sodium hydroxide solution containing 2% by mass of HPMCAS at 20°C is preferably 1.1 to 20 mPa·s, more preferably 1.5 to 3.6 mPa·s. If the viscosity is less than 1.1 mPa·s, the mist may become too fine when sprayed and may become impossible to recover. On the other hand, if the viscosity exceeds 20 mPa·s, the viscosity of the liquid composition increases, significantly reducing productivity during spray drying. The viscosity can be measured according to the method described in the HPMCAS and general test methods in the monographs for pharmaceuticals in the 18th edition of the Japanese Pharmacopoeia.

[0045] For 100 parts by mass of the carrier within the solid dispersion, the amount of HPMCAS outside the solid dispersion is preferably not greater than the amount of the carrier, and is preferably 10 to 100 parts by mass, more preferably 10 to 90 parts by mass, and even more preferably 20 to 85 parts by mass. This is because the carrier within the solid dispersion and hydroxypropyl methylcellulose acetate succinate outside the solid dispersion provide the drug in an amorphous state with desirable high storage stability. Furthermore, per 100 parts by mass of carrier, 10 to 100 parts by mass of drug and 10 to 100 parts by mass of HPMCAS located outside the solid dispersion are preferred, 15 to 80 parts by mass of drug and 10 to 90 parts by mass of HPMCAS located outside the solid dispersion are more preferred, and 15 to 50 parts by mass of drug and 20 to 85 parts by mass of HPMCAS located outside the solid dispersion are even more preferred. This is because the carrier within the solid dispersion and hydroxypropyl methylcellulose acetate succinate located outside the solid dispersion provide the drug in an amorphous state with desirable high storage stability.

[0046] The solid dispersion and HPMCAS can be combined by physical mixing, granulation, or coating, to prepare a composite (composition) containing HPMCAS outside the solid dispersion. Examples of physical mixing include physically mixing at least the solid dispersion and HPMCAS in a mortar or the like, hand-mixing in a bag, or rotating the mixing container to mix the powders and granules in the container. Examples of mixers using a mixing container include a V-type mixer using a V-shaped container, a ribbon mixer, a container mixer, and a tumbler mixer. In this case, various additives commonly used in this field, such as excipients, binders, disintegrants, lubricants, and anti-agglomerating agents, may be added. Examples of additives are the same as those listed above for solid dispersions.

[0047] The granulation method is not particularly limited, but examples thereof include dry granulation and wet granulation, and can be carried out using a commonly used granulator. Examples of granulators include, but are not limited to, dry granulators such as roller compactors, and wet granulators such as high-speed agitation granulators, fluidized bed granulators, tumbling fluidized bed granulators, and spray-drying granulators. The mixing time and granulation time are not particularly limited, but are usually 1 to 120 minutes.

[0048] For example, in dry granulation in which roller compression is performed using a compaction granulator such as a roller compactor, various additives commonly used in this field, such as excipients, binders, disintegrants, lubricants, anti-agglomerating agents, etc., can be blended in addition to the solid dispersion and HPMCAS. Examples of additives are the same as those described above for the solid dispersion. The roll pressure varies depending on the powder properties, etc., but is preferably 1 to 30 MPa, more preferably 2 to 12 MPa, and the roll rotation speed is preferably 1 to 50 rpm, more preferably 2 to 20 rpm. The screw rotation speed is preferably 1 to 100 rpm, more preferably 2 to 50 rpm. The flakes of the compressed granules obtained by roller compression can be crushed and sized to a predetermined particle size using a crusher or disintegrator such as a Comil, Quick Mill, Power Mill, Granumist (registered trademark), or roll granulator, to produce a tablet powder. HPMCAS may be added during or after granulation.

[0049] In wet granulation, HPMCAS can be added in the form of a powder to be granulated or dispersed or dissolved in the granulation liquid. Granulation can be carried out using a granulator. For example, when granulation is carried out using a fluidized bed granulator, the intake air temperature is preferably 50 to 100°C and / or the exhaust air temperature is preferably 25 to 80°C, from the viewpoints of granulation efficiency and the quality of the granulated product.

[0050] The average particle size of the granulated product is preferably 50 to 500 μm, more preferably 150 to 250 μm, from the viewpoint of subsequent tableting and capsule filling properties. The average particle size of the granulated product is a value measured by laser diffraction or the like (50% cumulative value of a volume-based cumulative particle size distribution curve). The granulation liquid is usually purified water, an organic solvent such as ethanol, or a mixed solution thereof, in which the binder can be dissolved.

[0051] The obtained granules do not need to be further dried if they are dried using a granulator capable of simultaneously spraying and drying (e.g., a fluidized bed granulator). However, if drying is not performed or if a granulator incapable of drying (e.g., a wet agitation granulator) is used, it is preferable to dry them by a known method. Drying can be performed using a dryer (dryer). Examples of dryers (dryer) include a fluidized bed dryer, flash dryer, box dryer, vibration dryer, natural convection constant temperature dryer, air blower constant temperature dryer, and air blower constant temperature hygrostat. The drying temperature is preferably 40 to 120°C.

[0052] From the viewpoint of tablet stability, the moisture content of the dried granules is preferably 5.0% by mass or less, more preferably 2.0% by mass or less. The moisture content of the granules can be measured using a heat-drying moisture meter (MX-50, manufactured by A&D Co., Ltd.) under the following conditions: a charge amount of 5 g of granules, a heating temperature of 105°C, and a heating time of 60 minutes. HPMCAS may be added during or after granulation.

[0053] When HPMCAS is added to the solid dispersion powder by physical mixing, the physical mixture can be compressed into tablets. When HPMCAS is added to the solid dispersion powder by granulation, the granulated granules can be compressed into tablets. Tableting can be carried out using a tablet press. Examples of tablet presses include rotary tablet presses and single-punch tablet presses. The tableting pressure during tableting is preferably 2 to 40 kN from the viewpoints of tablet hardness and tableting problems. The formulation design, such as the size and mass of the tablet, can be appropriately set as desired. For example, the tablet diameter (diameter of the tablet) is preferably 6 to 12 mm from the viewpoints of handling and administration. The mass of the tablet is not particularly limited, and is preferably 70 to 700 mg per tablet.

[0054] For example, when a tablet or granule contains a solid dispersion but does not contain HPMCAS on the outside of the solid dispersion, HPMCAS can be added to the outside of the solid dispersion by coating with an enteric coating composition containing HPMCAS. Physically mixed powders, granules, tablets, etc. containing HPMCAS on the outside of a solid dispersion obtained by the above-mentioned method may also be coated with an enteric coating composition containing HPMCAS. The HPMCAS used for coating does not need to have the same degree of substitution, viscosity, etc. as the HPMCAS present within the solid dispersion and / or on the outside of the solid dispersion, but a HPMCAS having the same degree of substitution, viscosity, etc. as the HPMCAS present on the outside of the solid dispersion can be used. The HPMCAS-coated granules may be further compressed into tablets using the above-mentioned method. If necessary, the enteric coating composition containing HPMCAS may contain various additives commonly used in this field, such as plasticizers, neutralizing agents, lubricants, other coating bases, surfactants, sweeteners, pigments, and antifoaming agents, in commonly used amounts.

[0055] Coating can be carried out by known methods, such as spray coating using a coating device. Examples of coating devices include pan coating devices, drum-type coating devices, fluidized bed coating devices, agitation fluidized coating devices, and tumbling fluidized coating devices. Spray devices attached to these devices can include air sprays, airless sprays, and three-fluid sprays. The product temperature during coating is not particularly limited as long as the sprayed coating composition can be continuously dried, but is preferably 20 to 80°C, and more preferably 25 to 60°C.

[0056] The drying method is not particularly limited as long as it can remove the solvent, and can be performed by heating within the coating device or after removing from the coating device. The temperature of the air blown during drying is preferably 25 to 90°C, from the viewpoint of drying the coating layer at a sufficient rate while maintaining the drug-containing core at a desired level of moisture.

[0057] Furthermore, for solid dispersions in a metastable state, dry coating without using a solvent is also an effective coating method. For example, dry coating using HPMCAS involves the use of a plasticizer, anti-adhesion agent, wetting agent, etc., which promote film formation. Coating devices include centrifugal rolling coating devices, pan coating devices, and fluidized bed coating devices, which can continuously spray the coating composition, and centrifugal rolling coating devices are preferred from the viewpoint of agitation. In dry coating, the product temperature of the coated granules and tablets is preferably 30°C or higher, more preferably 40 to 80°C, and even more preferably 50 to 80°C. [Example]

[0058] EXAMPLES The present invention will be specifically explained below with reference to examples and comparative examples, but the present invention is not limited to these examples. Example 1 (Methylcellulose:drug = 100:20 with HPMCAS-1 added at 25°C) <Production of solid dispersion> While stirring 63 parts by mass of acetone with a stirring blade, 1.67 parts by mass of nifedipine (manufactured by Daito Co., Ltd.) was added and dissolved, followed by 8.33 parts by mass of methylcellulose (methoxy group DS 1.77, viscosity at 20°C of 2% by mass aqueous solution 4.04 mPa s) and dispersion. 27 parts by mass of purified water was added and completely dissolved to prepare a spray-drying stock solution. The prepared spray-dried stock solution was spray-dried using a Mini Spray Dryer B-290 (Buchi) under the conditions of an inlet temperature of 90°C, an outlet temperature of 50°C, a nozzle gas flow rate of 473 L / hr, and a spray rate of 5.3 g / min to produce a solid dispersion.

[0059] <Preparation of the composite> 73.8 parts by mass of the produced solid dispersion, 15.2 parts by mass of HPMCAS (DS of methoxy groups: 1.88, MS of hydroxypropoxy groups: 0.24, DS of acetyl groups: 0.54, DS of succinyl groups: 0.28, viscosity at 20°C of a 2% by mass solution in dilute (0.1 mol / L) aqueous sodium hydroxide solution: 2.87 mPa·s; hereinafter also referred to as "HPMCAS-1"), 0.5 parts by mass of Adsolider (registered trademark) 101 (silicon dioxide, manufactured by Freund Corporation), 10 parts by mass of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by Signet Excipients), and 0.5 parts by mass of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) were weighed out and thoroughly mixed in a mortar to prepare a composite containing HPMCAS on the outside of the solid dispersion.

[0060] <Dissolution test> The prepared composite was weighed so that the nifedipine content was 40 mg (44.4 mg / L), and a dissolution test was performed for 240 minutes. The test fluid used was the second disintegration test fluid (pH 6.8, 900 mL) described in the 18th Edition of the Japanese Pharmacopoeia, and a dissolution tester (NTR-6100A, Toyama Sangyo Co., Ltd.) was used. Because the solid dispersion is very fine and prone to aggregation, the paddle rotation speed and position were fixed as shown in Table 1 for the evaluation.

[0061] [Table 1]

[0062] The quantitative determination of nifedipine was calculated from the absorbance (wavelength 325 nm, path length 10 mm) obtained by UV spectroscopy using a concentration conversion line (calibration curve) prepared for known concentrations. The results are shown in Table 2.

[0063] Example 2 (HPMC:drug = 100:33 with HPMCAS-1 added at 67°C) <Production of solid dispersion> While stirring 72 parts by mass of ethanol with a stirring blade, 2.5 parts by mass of nifedipine was added and dissolved. Next, 7.5 parts by mass of hypromellose (HPMC) (methoxy group DS 1.89, hydroxypropoxy group MS 0.24, viscosity at 20°C of 2% by mass aqueous solution 3.04 mPa s) was added and dispersed, and 18 parts by mass of purified water was added to completely dissolve, to prepare a spray-drying stock solution. The prepared spray-dried stock solution was spray-dried using a Mini Spray Dryer B-290 (Buchi) under the conditions of an inlet temperature of 120°C, an outlet temperature of 68°C, a nozzle gas flow rate of 357 L / hr, and a spray rate of 6.5 g / min to produce a solid dispersion.

[0064] <Preparation of the composite> 49.2 parts by mass of the produced solid dispersion, 24.6 parts by mass of HPMCAS-1, 15.2 parts by mass of microcrystalline cellulose, 0.5 parts by mass of Adsolider (registered trademark) 101, 10% by mass of croscarmellose sodium, and 0.5 parts by mass of magnesium stearate were weighed out and thoroughly mixed in a mortar to prepare a composite containing HPMCAS on the outside of the solid dispersion. <Dissolution test> The prepared composite was weighed so that the nifedipine content was 80 mg (88.8 mg / L), but the dissolution test was carried out in the same manner as in Example 1. The results are shown in Table 2.

[0065] Example 3 (HPMCP:drug = 100:33 with HPMCAS-1 added at 67°C) <Production of solid dispersion> While stirring 90 parts by mass of acetone with a stirring blade, 2.5 parts by mass of nifedipine was added and dissolved. Next, 7.5 parts by mass of HPMCP (methoxy group DS 1.89, hydroxypropoxy group MS 0.25, carboxybenzoyl group DS 0.67, viscosity at 20°C of a 10% by mass solution in a 1:1 mixture of methanol and dichloromethane) was added and completely dissolved to prepare a spray-drying stock solution. The prepared spray-dried stock solution was spray-dried using a Mini Spray Dryer B-290 (manufactured by Buchi) under the conditions of an inlet temperature of 80°C, an outlet temperature of 50°C, a nozzle gas flow rate of 357 L / hr, and a spray rate of 4.4 g / min to produce a solid dispersion. <Preparation of the composite> A composite containing HPMCAS on the outside of the solid dispersion was prepared in a similar manner to Example 2. <Dissolution test> The dissolution test was carried out in the same manner as in Example 1. The results are shown in Table 2.

[0066] Example 4 (VP / VA copolymer: drug = 100:20 with HPMCAS-1 added at 25°C) A spray-dried concentrate, solid dispersion, and composite were prepared and subjected to a dissolution test in the same manner as in Example 1, except that vinylpyrrolidone-vinyl acetate copolymer (VP / VA copolymer) (Kollidon (registered trademark) VA64, manufactured by BASF) was used instead of methylcellulose. The results are shown in Table 2.

[0067] Example 5 (Methylcellulose:drug = 100:25 with HPMCAS-1 added at 50°C) <Production of solid dispersion> While stirring 63 parts by mass of acetone with a stirring blade, 2.0 parts by mass of griseofulvin (Tokyo Chemical Industry Co., Ltd.) was added and dissolved, followed by 8.0 parts by mass of methylcellulose (methoxy group DS 1.77, viscosity of 2% by mass aqueous solution at 20°C 4.04 mPa s), which was then dispersed. 27 parts by mass of purified water was added and completely dissolved to prepare a spray-drying stock solution. The prepared spray-dried stock solution was spray-dried using a Mini Spray Dryer B-290 (manufactured by Buchi) under the conditions of an inlet temperature of 90°C, an outlet temperature of 50°C, a nozzle gas flow rate of 473 L / hr, and a spray rate of 5.5 g / min, and a solid dispersion was recovered.

[0068] <Preparation of the composite> 62.5 parts by mass of the produced solid dispersion, 24.6 parts by mass of HPMCAS-1, 2.9 parts by mass of microcrystalline cellulose, 0.5 parts by mass of Adsolider (registered trademark) 101, 10 parts by mass of croscarmellose sodium, and 0.5 parts by mass of magnesium stearate were weighed out and thoroughly mixed in a mortar to prepare a composite containing HPMCAS on the outside of the solid dispersion. <Dissolution test> The prepared composite was subjected to a dissolution test in the same manner as in Example 1, except that the griseofulvin content was 50 mg (55.6 mg / L). The results are shown in Table 2.

[0069] Example 6 (Methylcellulose:drug = 100:25 with HPMCAS-1 added at 50°C) A spray-dried concentrate, solid dispersion, and composite were prepared and subjected to a dissolution test in the same manner as in Example 5, except that nifedipine was used instead of griseofulvin. The results are shown in Table 2.

[0070] Example 7 (Methylcellulose:drug = 100:33 with HPMCAS-1 added at 67°C) <Production of solid dispersion> While stirring 63 parts by mass of acetone with a stirring blade, 2.5 parts by mass of nifedipine was added and dissolved. 7.5 parts by mass of methylcellulose (methoxy group DS 1.77, viscosity of a 2% by mass aqueous solution at 20°C 4.04 mPa s) was then added and dispersed, and 27 parts by mass of purified water was added to completely dissolve the mixture, yielding a spray-drying stock solution. Spray-drying was carried out under the same conditions as in Example 1, and a solid dispersion was collected. <Preparation of the composite> 49.2 parts by mass of the produced solid dispersion, 24.6 parts by mass of HPMCAS-1, 15.2 parts by mass of microcrystalline cellulose, 0.5 parts by mass of Adsolider (registered trademark) 101, 10 parts by mass of croscarmellose sodium, and 0.5 parts by mass of magnesium stearate were weighed out and thoroughly mixed in a mortar to prepare a composite containing HPMCAS on the outside of the solid dispersion. <Dissolution test> The dissolution test was carried out in the same manner as in Example 1. The results are shown in Table 2.

[0071] Example 8 (HPMCAS-2:drug = 100:33 with HPMCAS-1 added 67 minutes later) <Production of solid dispersion> HPMCAS (Methoxy group DS 1.90, Hydroxypropoxy group DS 0.24, Acetyl group DS 0.49, Succinyl group DS 0.38, Volume average particle diameter (D 50 Seventy-five parts by weight of HPMCAS-2 (278 μm, viscosity at 20°C of a 2% by weight solution in dilute (0.1 mol / L) sodium hydroxide aqueous solution; 3.08 mPa·s; hereafter referred to as "HPMCAS-2") and 25 parts by weight of nifedipine were thoroughly mixed by hand in a bag and loaded into a Volumetric Feeder (Thermo Fisher Scientific). The HPMCAS-2 and nifedipine powder mixture was fed from the Volumetric Feeder at a rate of 5.6 g / min, and a solid dispersion was produced by hot-melt extrusion. A Process 11 hot-melt extruder (Thermo Fisher Scientific) was used, with a barrel temperature of 160°C and a screw rotation speed of 200 rpm. The resulting extrudate was pelletized using a VariCut pelletizer (Thermo Fisher Scientific) and then pulverized using a GENA (Nara Machinery Manufacturing Co., Ltd.) equipped with a 0.3 mm mesh to produce a solid dispersion powder. <Preparation of the composite> 49.2 parts by mass of the produced solid dispersion powder, 24.6 parts by mass of HPMCAS-1, 15.2 parts by mass of microcrystalline cellulose, 0.5 parts by mass of Adsolider (registered trademark) 101, 10 parts by mass of croscarmellose sodium, and 0.5 parts by mass of magnesium stearate were weighed out and thoroughly mixed in a mortar to prepare a composite containing HPMCAS on the outside of the solid dispersion. <Dissolution test> The dissolution test was carried out in the same manner as in Example 2. The results are shown in Table 2.

[0072] Comparative Example 1 (methylcellulose:drug = 100:20 with addition of crystalline cellulose 25 powder) In the composite prepared in Example 1, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS outside the solid dispersion, and a dissolution test was carried out in the same manner as in Example 1. The results are shown in Table 2.

[0073] Comparative Example 2 (HPMC:drug = 100:33 with added microcrystalline cellulose 67 powder) In the composite prepared in Example 2, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 2. The results are shown in Table 2.

[0074] Comparative Example 3 (HPMCP:drug = 100:33 with added crystalline cellulose 67 powder) In the composite prepared in Example 3, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 3. The results are shown in Table 2.

[0075] Comparative Example 4 (VP / VA copolymer: drug = 100:20 with addition of microcrystalline cellulose 25 powder) In the composite prepared in Example 4, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 4. The results are shown in Table 2.

[0076] Comparative Example 5 (methylcellulose:drug=100:25 with 50% crystalline cellulose powder added) In the composite prepared in Example 5, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 5. The results are shown in Table 2.

[0077] Comparative Example 6 (Methylcellulose:drug=100:25 with addition of 50% crystalline cellulose powder) In the composite prepared in Example 6, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 6. The results are shown in Table 2.

[0078] Comparative Example 7 (methylcellulose:drug=100:33 with added microcrystalline cellulose 67 powder) In the composite prepared in Example 7, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 7. The results are shown in Table 2.

[0079] Comparative Example 8 (Methylcellulose:drug=100:33 with HPMC67 powder added) In the composite prepared in Example 7, HPMCAS-1 was replaced with HPMC to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 7. The results are shown in Table 2.

[0080] Comparative Example 9 (HPMCAS-2:drug = 100:33 with addition of crystalline cellulose 67 powder) In the composite prepared in Example 8, HPMCAS-1 was replaced with crystalline cellulose to produce a composite that did not contain HPMCAS on the outside of the solid dispersion, and a dissolution test was carried out in the same manner as in Example 8. The results are shown in Table 2.

[0081] [Table 2]

[0082] Figure 1 is a graph showing the relationship between dissolution time and the dissolution rate (%) of nifedipine. The graph plots the results of Example 1, in which 25 parts by weight of HPMCAS-1 was added to a solid dispersion containing a 100:20 methylcellulose:drug mass ratio; Comparative Example 1, which was the same as Example 1 except that 25 parts by weight of microcrystalline cellulose was added to a solid dispersion containing a 100:20 VP / VA copolymer:drug mass ratio; Example 4, in which 25 parts by weight of HPMCAS-1 was added to a solid dispersion containing a 100:20 VP / VA copolymer:drug mass ratio; and Comparative Example 4, which was the same as Example 4 except that 25 parts by weight of microcrystalline cellulose was added to a solid dispersion containing a 100:20 VP / VA copolymer:drug mass ratio. These results demonstrate that the presence of HPMCAS outside the solid dispersion significantly improves dissolution properties, including initial dissolution. Furthermore, it was shown that the improvement in dissolution properties due to solid dispersions is influenced not only by the external HPMCAS but also by the type of carrier.

[0083] When methylcellulose (Examples 1, 5, 6, and 7), HPMC (Example 2), HPMCP (Example 3), vinylpyrrolidone-vinyl acetate copolymer (Example 4), or HPMCAS-2 (Example 8) was used as the carrier for the solid dispersion, high dissolution properties were obtained in combination with HPMCAS-1 on the outside of the solid dispersion. Surprisingly, the initial dissolution properties in the first 15 minutes were also remarkably high. High dissolution properties were also obtained in Example 5, where griseofulvin was used instead of nifedipine as the drug. Good dissolution properties were also obtained in Example 8, where the solid dispersion was obtained using hot-melt extrusion rather than spray-drying. Comparative Example 8, in which methylcellulose was used as the carrier for the solid dispersion and combined with HPMC on the outside of the solid dispersion, had inferior dissolution properties to Example 6, in which HPMCAS was combined with HPMCAS on the outside of the solid dispersion.

Claims

1. A composite comprising a solid dispersion containing, in addition to a drug, at least a carrier selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and first hydroxypropylmethylcellulose acetate succinate, and at least a second hydroxypropylmethylcellulose acetate succinate located outside the solid dispersion.

2. 2. The composite according to claim 1, wherein the carrier is methylcellulose having a viscosity of 1.0 to 50.0 mPa·s as measured by an Ubbelohde viscometer for a 2% by weight aqueous solution at 20°C.

3. 3. The composite according to claim 1, wherein the drug is present in an amount of 10 to 100 parts by weight and 2-hydroxypropylmethylcellulose acetate succinate is present in an amount of 10 to 100 parts by weight relative to 100 parts by weight of the carrier.

4. 3. The compound according to claim 1, wherein the drug is a poorly water-soluble drug.

5. preparing a solid dispersion comprising, in addition to the drug, at least a carrier selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and primary hydroxypropylmethylcellulose acetate succinate; adding sec-hydroxypropyl methylcellulose acetate succinate to the solid dispersion; A method for producing a composite comprising at least

6. 6. The method for producing a composite according to claim 5, wherein the step of adding the second hydroxypropyl methylcellulose acetate succinate to the solid dispersion comprises mixing the solid dispersion with the second hydroxypropyl methylcellulose acetate succinate, granulating the solid dispersion in the presence of the second hydroxypropyl methylcellulose acetate succinate, or coating the solid dispersion with the second hydroxypropyl methylcellulose acetate succinate.

7. 7. The method for producing a composite according to claim 5, wherein the carrier is methylcellulose having a viscosity of 1.0 to 50.0 mPa·s as measured by an Ubbelohde viscometer in a 2% by mass aqueous solution at 20°C.

Images