Composition for solid dispersion, solid dispersion, and method for producing solid dispersion

Abstract

Provided is a composition for a solid dispersion, which can impart excellent dissolution properties not only within the original dissolution pH range of an acidic polymer but also under relatively low pH conditions at the upper part of the small intestine, and which suppresses decomposition of the acidic polymer. The composition for a solid dispersion contains at least an acidic polymer, a basic substance, a poorly water-soluble drug, and an organic solvent, and the basic substance is dispersed in the organic solvent.

Description

Technical Field

[0001] The present invention relates to a composition for solid dispersion, a solid dispersion using the composition for solid dispersion, and a method for producing the same. The composition for solid dispersion can impart excellent dissolution not only in the dissolution pH range of the acidic polymer but also under the relatively low pH conditions of the upper small intestine, and comprises an acidic polymer, an alkaline substance, a poorly water-soluble drug, and an organic solvent, wherein the alkaline substance is dispersed in the organic solvent. Background Art

[0002] In recent years, poorly water-soluble drugs, the use of which has tended to increase, do not show sufficient bioavailability by direct administration, and therefore various methods for improving their solubility have been proposed.

[0003] One of the solid dispersion techniques is a method for improving bioavailability by dispersing poorly water-soluble drugs in polymer carriers in an amorphous state. As methods involving solid dispersion techniques, for example, a spray drying method in which a mixture of a poorly water-soluble drug and a polymer is dissolved in a solvent and then spray-dried or a coprecipitation method in which the mixture is precipitated is proposed.

[0004] Examples of polymers used in solid dispersions include those containing methyl groups (—CH 3 ), hydroxypropyl (-C 3 H 6 OH), acetyl (-COCH 3 ) and succinyl (-COC 2 H 4 Hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS"), which introduces a total of four substituents (COOH) into some of the hydrogen atoms of the hydroxyl groups of cellulose, and methyl (-CH 3 ), hydroxypropyl (-C 3 H 6 OH) and carboxybenzoyl (-COC 6 H 4 Hydroxypropylmethylcellulose phthalate (hereinafter also referred to as "HPMCP") is a polymer having a carboxyl group in the molecule and exhibiting enteric solubility (hereinafter also referred to as "acidic polymer").

[0005] As an example of a solid dispersion using these acidic polymers, for example, a spray-dried solid dispersion containing a poorly soluble drug and HPMCAS is known (Patent Document 1).

[0006] In addition, there is an example of production of a solid dispersion by a spray drying method using an oxazole compound which is a poorly water-soluble drug and HPMCP (Patent Document 2).

[0007] In addition, a solid dispersion containing a drug and a neutralized acidic polymer in order to improve the solubility of a poorly water-soluble drug has been proposed (Patent Document 3).

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1: Japanese Patent Application Laid-Open No. 11-116502

[0011] Patent Document 2: Japanese Patent Application No. 2009-502736

[0012] Patent Document 3: Japanese Patent Application No. 2004-534822 Summary of the invention

[0013] Problems to be solved by the invention

[0014] However, in Patent Documents 1 and 2, since the solid dispersion contains an acidic polymer, dissolution in the upper part of the small intestine is sometimes delayed, and sufficient improvement in bioavailability is sometimes not achieved. In addition, Patent Document 3 records that dissolution can be accelerated while increasing the concentration of the drug by using a neutralized acidic enteric polymer, but water needs to be added to dissolve the alkali used for neutralization, and therefore, it is not suitable for spray drying methods that require dissolving water-poorly soluble drugs.

[0015] Moreover, the dissolved alkaline substance may sometimes cause the decomposition of the drug or the acidic polymer (see Example 3 and Comparative Example 4 described later). Furthermore, the main absorption site of the drug is the small intestine, and the drug preferably exhibits high solubility in a wide range of pH areas such as the duodenum near pH 5 to 6, the jejunum near pH 6 to 7, and the ileum near pH 6 to 7.5, but these effects are not disclosed in detail in Patent Document 3.

[0016] The present invention is proposed in view of the above circumstances, and its object is to provide a composition for solid dispersion that can impart excellent dissolution properties not only within the original dissolution pH range of the acidic polymer but also under relatively low pH conditions in the upper small intestine and inhibits the decomposition of the acidic polymer.

[0017] Solutions to the problem

[0018] In order to solve the above-mentioned problems, the present inventors have found, based on the results of careful studies, that a solid dispersion prepared using a composition for solid dispersion in which an alkaline substance is dispersed in an organic solvent containing an acidic polymer and a poorly water-soluble drug exhibits excellent solubility not only within the dissolution pH range of the acidic polymer but also under relatively low pH conditions in the upper small intestine, while also being able to suppress the decomposition of the acidic polymer, thereby completing the present invention.

[0019] According to the present invention, the following composition for solid dispersion, solid dispersion, and method for producing the solid dispersion can be provided. [1]

[0021] A composition for solid dispersion, wherein:

[0022] The method comprises at least an acidic polymer, a basic substance, a poorly water-soluble drug and an organic solvent, wherein the basic substance is dispersed in the organic solvent. [2]

[0024] The composition for solid dispersion according to [1], wherein

[0025] The content of the alkaline substance is 0.2 to 2.0 molar equivalents relative to the acidic functional groups of the acidic polymer. [3]

[0027] The composition for solid dispersion according to [1] or [2], wherein

[0028] The alkaline substance has an average particle size (D50) of 100 μm or less based on volume measured by dry laser diffraction. [4]

[0030] The composition for solid dispersion according to any one of [1] to [3], wherein

[0031] The acidic polymer is at least one selected from cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate maleate, hydroxypropylmethylcellulose trimellitate, carboxymethylethylcellulose, butyrate polyethylene phthalate, acetate polyvinyl alcohol phthalate, methacrylic acid / ethyl acrylate copolymer and methacrylic acid / methyl methacrylate copolymer. [5]

[0033] The composition for solid dispersion according to any one of [1] to [4], wherein

[0034] The organic solvent is one or a mixture of two or more selected from the group consisting of acetone, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran and dichloromethane. [6]

[0036] A solid dispersion comprising an acidic polymer, an alkaline substance and a poorly water-soluble drug, wherein:

[0037] A part or the whole of the surface of the basic substance is covered with the acidic polymer. [7]

[0039] A method for preparing a solid dispersion, wherein:

[0040] The method includes at least the step of removing the organic solvent from the composition for solid dispersion according to any one of [1] to [5].

[0041] Effects of the Invention

[0042] According to the present invention, it is possible to obtain a solid dispersion that exhibits high solubility not only in the pH range in which the acidic polymer dissolves but also under relatively low pH conditions in the upper small intestine. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 A is a SEM image (backscattered electron image) of the solid dispersion of Example 5. Figure 1 B is a SEM image (backscattered electron image) of the solid dispersion of Comparative Example 3. DETAILED DESCRIPTION

[0044] 1. Composition for solid dispersion

[0045] First, a composition for solid dispersion containing at least an acidic polymer, a basic substance, a poorly water-soluble drug, and an organic solvent, wherein the basic substance is dispersed in the organic solvent, will be described.

[0046] The so-called acidic polymer refers to an ionic polymer containing one or more acidic functional groups in its structure, which is equivalent to a polymer that is "almost insoluble (the amount of water required to dissolve 1g or 1mL of solute is 10000mL or more)" and soluble in an alkaline solution under the conditions specified in the 18th revised edition of the Japanese Pharmacopoeia.

[0047] Examples of the acidic functional group include carboxyl group-containing functional groups such as succinyl group and carboxybenzoyl group.

[0048] The acidic polymer improves the stability of the amorphized poorly water-soluble drug in the composition for solid dispersion, and contributes to improving the bioavailability.

[0049] Specific examples of the acidic polymer include hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS"), hydroxypropyl methylcellulose phthalate (hereinafter also referred to as "HPMCP"), cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylethylcellulose phthalate, hydroxypropyl methylcellulose acetate maleate, hydroxypropyl methylcellulose trimellitate, carboxymethylethylcellulose, butyrate polyethylene phthalate, acetate polyvinyl alcohol phthalate, methacrylic acid / ethyl acrylate copolymer (preferably, the mass ratio of the two monomers is 1:99 to 99:1), and methacrylic acid / methyl methacrylate copolymer (preferably, the mass ratio of the two monomers is 1:99 to 99:1).

[0050] Among them, HPMCAS and HPMCP are preferred, and HPMCAS is more preferred.

[0051] HPMCAS is a cellulose derivative in which four substituents, namely, acetyl, succinyl, methyl and hydroxypropyl, are introduced into some of the hydrogen atoms of the hydroxyl groups of cellulose.

[0052] The content of the acetyl group in HPMCAS is 2 to 16% by mass, preferably 2 to 14% by mass, more preferably 5 to 14% by mass, and further preferably 6 to 13% by mass.

[0053] The content of the succinyl group in HPMCAS is 4 to 28% by mass, preferably 4 to 20% by mass, more preferably 4 to 18% by mass, and further preferably 6 to 16% by mass.

[0054] The content of the methoxy group in HPMCAS is not particularly limited, but is preferably 12 to 28% by mass, and more preferably 20 to 26% by mass.

[0055] The content of the hydroxypropoxy group in HPMCAS is not particularly limited, but is preferably 4 to 23% by mass, more preferably 5 to 10% by mass.

[0056] It should be noted that the contents of acetyl, succinyl, methoxy and hydroxypropoxy groups in HPMCAS can be calculated by the methods described in the pharmaceutical articles "hydroxypropyl methyl cellulose acetate succinate" of the 18th revised edition of the Japanese Pharmacopoeia.

[0057] HPMCP is a cellulose derivative having three substituents, namely, a carboxybenzoyl group, a methoxy group, and a hydroxypropoxy group, in cellulose.

[0058] The content of the carboxybenzoyl group in HPMCP is preferably 10 to 45% by mass, more preferably 15 to 40% by mass, and still more preferably 21 to 35% by mass.

[0059] The content of the methoxy group in HPMCP is not particularly limited, but is preferably 12 to 28% by mass, and more preferably 20 to 26% by mass.

[0060] The content of the hydroxypropoxy group in HPMCP is not particularly limited, but is preferably 4 to 23% by mass, and more preferably 5 to 10% by mass.

[0061] It should be noted that the contents of carboxybenzoyl, methoxy and hydroxypropoxy in HPMCP can be calculated according to the method described in the pharmaceutical articles "hydroxypropyl methylcellulose" (hydroxypropyl methylcellulose) and "hydroxypropyl methylcellulose phthalate" (hydroxypropyl-methylcellulose phthalate) of the 18th revised edition of the Japanese Pharmacopoeia.

[0062] The acidic polymer has a different dissolution pH range (hereinafter also referred to as "dissolution pH") depending on the content of each substituent. For example, the dissolution pH of HPMCAS varies depending on the content of acetyl and succinyl groups. The dissolution pH of HPMCAS with an acetyl content of 5 to 9% by mass and a succinyl content of 14 to 18% by mass is 5.5 or higher; the dissolution pH of HPMCAS with an acetyl content of 7 to 11% by mass and a succinyl content of 10% to less than 14% by mass is 6.0 or higher; the dissolution pH of HPMCAS with an acetyl content of 10 to 14% by mass and a succinyl content of 4 to 8% by mass is 6.8 or higher.

[0063] In addition, in HPMCP, the dissolution pH changes depending on the content of carboxybenzoyl groups. The dissolution pH of HPMCP with a carboxybenzoyl content of 21 to 27% by mass is above 5.0; the dissolution pH of HPMCP with a carboxybenzoyl content of more than 27% by mass and less than 35% by mass is above 5.5.

[0064] Next, the viscosity of the acidic polymer will be described. Among the acidic polymers, the following description will focus on HPMCAS and HPMCP.

[0065] The viscosity of a 2 mass % aqueous solution of HPMCAS at 20° C. (wherein the solvent is a diluted (0.1 mol / L) sodium hydroxide aqueous solution) is not particularly limited, but is preferably 1.1 to 20 mPa·s, more preferably 1.5 to 3.6 mPa·s, from the viewpoint of productivity and operability.

[0066] From the viewpoint of productivity and operability, the viscosity of a 10 mass % solution of HPMCP at 20°C (wherein the solvent is a solution in which methanol and dichloromethane are mixed in a respective mass ratio of 50%) is preferably 10.0 to 150.0 mPa·s, more preferably 15.0 to 100.0 mPa·s.

[0067] Regarding the method for measuring viscosity, when the acidic polymer is HPMCAS, it can be measured by the method described in the item "Hydroxypropylmethylcellulose acetate succinate" of the 18th revised edition of the Japanese Pharmacopoeia. In addition, when the acidic polymer is HPMCP, it can be measured by the method described in the item "Hydroxypropylmethylcellulose phthalate" of each pharmaceutical article of the 18th revised edition of the Japanese Pharmacopoeia.

[0068] The content of the acidic polymer in the composition for solid dispersion is preferably 1 to 40% by mass, more preferably 1 to 10% by mass, from the viewpoint of handleability and storage stability of the poorly water-soluble drug in an amorphous state.

[0069] Two or more acidic polymers may be used in combination as necessary.

[0070] As the acidic polymer, a commercially available acidic polymer may be used, or an acidic polymer produced by a known method may be used.

[0071] The method for producing HPMCAS, which is one of the acidic polymers, includes, for example, a method in which hydroxypropyl methylcellulose, an acetylating agent, and a succinic acylating agent are subjected to an esterification reaction in the presence of an aliphatic carboxylic acid to obtain a reaction solution, the obtained reaction solution is mixed with water to precipitate, thereby preparing a suspension containing HPMCAS particles, and the HPMCAS in the suspension is washed, recovered, dried, pulverized, and the like to produce HPMCAS.

[0072] The method for producing HPMCP, which is one of the acidic polymers, includes, for example, a method of preparing HPMCP by subjecting hydroxypropyl methylcellulose and a carboxybenzoylating agent to an esterification reaction in the presence of an aliphatic carboxylic acid to obtain a reaction solution, then mixing the obtained reaction solution with water to precipitate it, thereby preparing a suspension containing HPMCP particles, and washing, recovering, drying, pulverizing, etc. the HPMCP in the suspension.

[0073] The alkaline substance is a substance that generates hydroxide ions when forming an aqueous solution, and the aqueous solution exhibits alkalinity. It is presumed that by dispersing the alkaline substance together with the acidic polymer in the composition for solid dispersion and preparing the solid dispersion from the composition for solid dispersion, the alkaline substance is dissolved while the solid dispersion is dissolved, and part or all of the acidic functional groups in the acidic polymer are neutralized, thereby contributing to improving the solubility under the relatively low pH conditions in the upper part of the small intestine.

[0074] Examples of the alkaline substance include bicarbonates such as sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate; carbonates such as sodium carbonate, calcium carbonate, and ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and aluminum hydroxide; ammonium salts such as ammonium hydroxide and ammonium acetate; conjugate bases with various acids such as sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium citrate, trisodium phosphate, disodium phosphate, potassium citrate, sodium polyacrylate, and sodium benzoate; basic amino acids such as L-arginine, L-histidine, and L-lysine; and polymeric amines such as polyaminoacrylates such as Eudragit E.

[0075] From the viewpoint of dissolution properties of the solid dispersion, the content of the basic substance is preferably 0.2 to 2.0 molar equivalents, more preferably 0.2 to 1.5 molar equivalents, and even more preferably 0.2 to 1.0 molar equivalents relative to the acidic functional groups in the acidic polymer.

[0076] The volume-based average particle size (D50) of the alkaline substance is preferably 100 μm or less, more preferably 2 to 50 μm, from the viewpoint of dissolution properties of the solid dispersion and prevention of nozzle clogging in the spray drying step.

[0077] It should be noted that the average particle size of the volume standard can be measured by dry laser diffraction method. For example, as in the method using Master Sizer 3000 manufactured by Malvern, UK or HELOS device manufactured by Sympatec, Germany, the material ejected by compressed air is irradiated with laser, and the volume-converted average particle size can be measured based on the diffraction intensity.

[0078] In the present application, regarding the average particle size of the volume standard of the alkaline substance, a laser diffraction particle size distribution measuring device (Master Sizer 3000, manufactured by Malvern) is used. According to the Fraunhofer diffraction theory, a dry method is used to measure the diameter of the 50% cumulative value of the cumulative particle size distribution curve corresponding to the volume standard under the conditions of a dispersion pressure of 1.5 bar and a scattering intensity of 2 to 10%.

[0079] Two or more kinds of alkaline substances may be used in combination as necessary.

[0080] As the alkaline substance, a commercially available alkaline substance or an alkaline substance produced by a known method may be used as it is, or an alkaline substance treated by pulverization, sieving or the like may be used.

[0081] The so-called poorly water-soluble drugs refer to the drugs recorded as "poorly soluble", "extremely poorly soluble" and "almost insoluble" in the 18th revised edition of the Japanese Pharmacopoeia. Among them, the so-called "poorly soluble" refers to the solubility of 100 mL or more and less than 1000 mL of water in order to dissolve the poorly water-soluble drug within 30 minutes when 1g or 1mL of the poorly water-soluble drug is placed in a beaker, water is added, and the mixture is shaken vigorously for 30 seconds every 5 minutes at 20±5°C. In addition, the so-called "extremely poorly soluble" refers to the solubility of 1000 mL or more and less than 10000 mL of water in order to dissolve the poorly water-soluble drug within 30 minutes when 1g or 1mL of the poorly water-soluble drug is placed in a beaker, water is added, and the mixture is shaken vigorously for 30 seconds every 5 minutes at 20±5°C. “Almost insoluble” means that when 1 g or 1 mL of a poorly water-soluble drug is placed in a beaker, water is added, and the drug is shaken vigorously for 30 seconds every 5 minutes at 20±5°C, the solubility of the drug is such that more than 10,000 mL of water is required to dissolve the poorly water-soluble drug within 30 minutes.

[0082] In addition, the so-called dissolved water-insoluble drug means that 1g or 1mL of the water-insoluble drug is placed in a beaker in the same manner as above, a solvent is added, and the mixture is shaken vigorously for 30 seconds every 5 minutes at 20±5°C. The water-insoluble drug is shown to be dissolved or mixed in the solvent, and fibers are not confirmed, or even if fibers are confirmed, they are very small.

[0083] Specific examples of poorly water-soluble drugs include azole compounds such as itraconazole, ketoconazole, fluconazole, miconazole, omeprazole, and lansoprazole; dihydropyridine compounds such as nifedipine, nitrendipine, amlodipine, nicardipine, nilvadipine, felodipine, and efonidipine (INN); propionic acid compounds such as ibuprofen, ketoprofen, and naproxen; and indoleacetic acid compounds such as indomethacin and acemetacin. In addition, griseofulvin, phenytoin, carbamazepine, and dipyridamole may also be cited.

[0084] The content of the poorly water-soluble drug can be appropriately determined according to the type of preparation. From the viewpoint of solubility and amorphization of the poorly water-soluble drug, the content of the poorly water-soluble drug in the composition for solid dispersion is preferably 0.1 to 50% by mass, more preferably 1 to 20% by mass, and even more preferably 1 to 10% by mass.

[0085] The mass ratio of the acidic polymer to the poorly water-soluble drug in the composition for solid dispersion is not particularly limited, but from the viewpoint of the stability of the amorphous state of the poorly water-soluble drug, preferably the acidic polymer:poorly water-soluble drug = 1:0.01 to 1:100, more preferably the acidic polymer:poorly water-soluble drug = 1:0.1 to 1:10, and further preferably the acidic polymer:poorly water-soluble drug = 1:0.2 to 1:5.

[0086] Two or more poorly water-soluble drugs may be used in combination as necessary.

[0087] In addition, as the poorly water-soluble drug, a commercially available drug can be used.

[0088] The organic solvent is not particularly limited as long as it can dissolve the acidic polymer and the poorly water-soluble drug, and examples thereof include ketone solvents, alcohol solvents, ester solvents, ether solvents, and aprotic polar solvents.

[0089] As the ketone solvent, acetone etc. may be mentioned.

[0090] Examples of the alcohol solvent include saturated alcohols having 1 to 3 carbon atoms, such as methanol, ethanol and isopropanol.

[0091] Examples of the ester solvent include alkyl acetates such as methyl acetate and ethyl acetate.

[0092] Examples of the ether solvent include tetrahydrofuran.

[0093] Examples of the aprotic polar solvent include dichloromethane and chloroform.

[0094] The content of the organic solvent in the composition for solid dispersion is not particularly limited, but is preferably 50 to 98% by mass, more preferably 70 to 95% by mass, from the viewpoint of productivity of the solid dispersion.

[0095] The organic solvent may be used alone or in combination of two or more as required. In addition, water may be mixed with the organic solvent, but from the viewpoint of the solubility of the poorly water-soluble drug and the decomposability of the acidic polymer, the content of water is preferably less than 10 parts by mass, more preferably less than 5 parts by mass, relative to 100 parts by mass of the organic solvent.

[0096] In addition, as the organic solvent, a commercially available organic solvent can be used.

[0097] The alkaline substance in the solid dispersion composition is dispersed in the above-mentioned organic solvent. The so-called dispersion refers to a state in which a part or all of the alkaline substance is not dissolved in the solvent. The dispersed state can be obtained by mixing the alkaline substance of the same type as the alkaline substance contained in the target solid dispersion composition and the organic solvent of the same type as the organic solvent contained in the solid dispersion composition in a manner of becoming the same concentration as the solid dispersion composition, stirring for 30 minutes under 20°C to obtain a mixture, and using an ultraviolet visible spectrophotometer to measure the UV spectrum of the mixture with a cuvette with an optical path length of 10mm (measurement wavelength: 550nm) The transmittance obtained is confirmed. Since if the alkaline substance is not dissolved in the organic solvent and is in a dispersed state, the transmittance of the mixture is reduced, therefore, the transmittance of the mixture is preferably 90% or less, more preferably 70% or less, although there is no particular limitation on the lower limit, but for example, it is 0% or more. As a specific example of an ultraviolet visible spectrophotometer, UV-1850 (manufactured by SHIMADZU) and the like can be cited. Furthermore, when a solid dispersion is produced using a composition for solid dispersion in which a basic substance is dispersed in an organic solvent, a crystal peak derived from the basic substance remains in a diffraction pattern obtained by X-ray diffraction measurement.

[0098] By dispersing the alkaline substance in the organic solvent, the hydrolysis of the acidic functional groups in the acidic polymer is suppressed. That is, the amount of free acid generated by hydrolysis and the decomposition of the drug etc. caused thereby are suppressed. In addition, the dispersed alkaline substance neutralizes part or all of the acidic functional groups in the acidic polymer while dissolving the solid dispersion, which helps to improve the solubility under the relatively low pH conditions in the upper part of the small intestine.

[0099] The solid dispersion composition may contain other additives in amounts generally used, if necessary.

[0100] As the additives, there can be mentioned, for example, a dispersion stabilizer, a surfactant, a disintegrator, a bonding agent, and a bulking agent.

[0101] As the dispersion stabilizer, talc and the like may be mentioned.

[0102] Examples of surfactants include anionic surfactants such as sodium lauryl sulfate; nonionic surfactants such as diglycerides, poloxame, polyoxyethylene sorbitan fatty acid esters (Tween 20, 60, 80), glycerol fatty acid esters and propylene glycol fatty acid esters; natural surfactants such as lecithin and sodium taurocholate, etc.

[0103] Examples of the disintegrant include low-substituted hydroxypropyl cellulose, corn starch, partially alcoholized starch, sodium carboxymethyl starch, cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, crystalline cellulose, and crospovidone.

[0104] Examples of the binding agent include hydroxypropyl cellulose, polyvinyl pyrrolidone and hydroxypropyl methyl cellulose.

[0105] Examples of the bulking agent include erythritol, mannitol, sorbitol, lactose, sucrose, starch, white sugar, crystalline cellulose, powdered cellulose, calcium phosphate, and calcium sulfate.

[0106] The additives may be used in combination of two or more kinds as needed. In addition, commercially available additives may be used as the additives.

[0107] From the viewpoint of the content of the poorly water-soluble drug in the solid dispersion, the content of the additive in the composition for solid dispersion is preferably 1 to 1000 parts by mass based on 100 parts by mass of the total mass of the acidic polymer and the poorly water-soluble drug.

[0108] The composition for solid dispersion of the present invention can be manufactured by mixing the above-mentioned components, i.e., mixing an acidic polymer, an alkaline substance, a water-insoluble drug and an organic solvent and other additives added as needed. The mixing order of these components is not particularly limited, and examples thereof include, for example, adding an acidic polymer and a water-insoluble drug to an organic solvent to obtain a solution in which the acidic polymer and the water-insoluble drug are dissolved, and then slowly adding an alkaline substance to the solution to disperse the solution. Other additives added as needed can be added at the stage of preparing the initially prepared solution, or can be added while adding the alkaline substance or after adding the alkaline substance, depending on their type.

[0109] In the composition for solid dispersion of the present invention, in order to make the alkaline substance dispersed in the organic solvent, it is sufficient to adjust the concentration of the alkaline substance in such a way that the transmittance of the mixture of the alkaline substance and the organic solvent prepared under the conditions and measured under the conditions is 90% or less. For example, when the transmittance exceeds 90%, the amount of the alkaline substance in the composition for solid dispersion only needs to be within the range that satisfies the amount ratio relative to the acidic functional groups in the acidic polymer, and the concentration of the alkaline substance is increased to an extent that the transmittance is 90% or less and the alkaline substance is not precipitated.

[0110] 2. Solid dispersion

[0111] Next, a solid dispersion comprising an acidic polymer, an alkaline substance and a poorly water-soluble drug, wherein a part or all of the surface of the alkaline substance is coated with the acidic polymer, is described. Examples of the acidic polymer, the alkaline substance and the poorly water-soluble drug in the solid dispersion of the present invention may be the same substances as those exemplified in the above-mentioned composition for solid dispersion.

[0112] The alkaline substance contained in the solid dispersion composition of the present invention exists in a dispersed state. That is, when the solid dispersion is manufactured using the solid dispersion composition, a part or all of the alkaline substance is coated by an acidic polymer. This means that, for example, in the case of a spray drying method, the alkaline substance will be present in the formed droplets or on their surface, and the droplets become solid dispersions in the form of alkaline substances mixed around acidic polymers and poorly water-soluble drugs after drying. The inventors found that by comparing a solid dispersion coated with an acidic polymer with an uncoated solid dispersion (physical mixing of a solid dispersion of alkaline substances), a part or all of the alkaline substances has a significantly improved dissolution under relatively low pH conditions in the upper part of the small intestine (embodiment 1 of the present application and comparative example 3). In addition, it is also found that by containing alkaline substances in a dispersed state, the decomposition of the acidic polymer is also suppressed.

[0113] Regarding the solid dispersion in which a part or all of the basic substance is coated with the acidic polymer, for example, the state of coating of the basic substance can be confirmed by observing a backscattered electron image using a scanning electron microscope (SEM) by utilizing the difference in elements constituting the basic substance and the acidic polymer.

[0114] 3. Method for producing solid dispersion

[0115] Next, a method for producing a solid dispersion including at least the step of removing the organic solvent from the composition for solid dispersion will be described.

[0116] Examples of the method for removing the organic solvent include evaporation to dryness and spray drying. In the present invention, spray drying is preferred from the viewpoint of enabling mass production and easy control of the physical properties of the powder such as particle size and bulk density.

[0117] Spray drying generally refers to a method of decomposing (spraying) a solid dispersion composition containing a poorly water-soluble drug into small droplets and rapidly removing the solvent from the droplets by evaporation. The driving force for removing the solvent is generally obtained by making the partial pressure of the solution lower than the vapor pressure of the solvent under the temperature conditions for drying the droplets. As a preferred method, there can be cited a method in which the droplets are mixed with a high-temperature drying gas and the pressure in the solvent removal device is maintained in an incomplete vacuum state.

[0118] The composition for solid dispersion can be spray dried under various nozzle mechanism conditions. For example, various types of nozzles can be used. As preferred embodiments, two-fluid nozzles, water spray nozzles, flat fan nozzles, pressure nozzles, rotary atomizers, etc. can be cited.

[0119] Liquid delivery of the composition for solid dispersion can be performed under a wide range of flow rates and temperature conditions. In addition, when pressurized during spraying, spraying can be performed under a wide range of pressure conditions. In general, the rate of solvent evaporation increases with the increase in the specific surface area of ​​the droplets. Therefore, the droplet diameter when leaving the nozzle is preferably less than 500 μm, more preferably less than 400 μm, and further preferably 5 to 200 μm, and preferably a flow rate, temperature and pressure that can be sprayed in this way. The sprayed solution is quickly dried.

[0120] The sprayed solid dispersion composition is rapidly dried to form a solid dispersion. The dried solid dispersion generally stays in the spray drying chamber for about 5 to 60 seconds, during which most of the solvent is removed from the solid powder. The temperature during spray drying is preferably about 20°C to 150°C at the inlet and about 0°C to 85°C at the outlet.

[0121] The residual solvent in the solid dispersion is preferably less. The reason is that if the residual solvent in the solid dispersion is less, the mobility of the drug molecules in the amorphous solid dispersion is suppressed and the stability is increased. In the case where it is necessary to further remove the residual solvent, secondary drying can be performed. As preferred secondary drying methods, tray drying, fluidized bed drying, belt drying, microwave drying, etc. can be cited.

[0122] Example

[0123] Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

[0124] Unless otherwise specified below, each physical property was measured or calculated according to the above-mentioned method.

[0125] In the production of the composition for solid dispersion in each of the following examples, the value of "% by mass" of each component contained in the composition for solid dispersion represents the total content of the components in the composition for solid dispersion.

[0126] Example 1

[0127] <Production of Solid Dispersion Composition>

[0128] While stirring 89.92 mass % acetone with a stirring blade, 6.61 mass % HPMCAS (methoxyl group: 22.5 mass %, hydroxypropoxyl group: 6.9 mass %, acetyl group: 7.9 mass %, succinyl group: 14.5 mass %, 2 mass % aqueous solution (wherein the solvent is a diluted (0.1 mol / L) sodium hydroxide aqueous solution) with a viscosity of 2.90 mPa·s) and 3.31 mass % nifedipine were added and dissolved. The above-mentioned mixed solution was filtered with a sieve with a mesh of 150 μm, and it was confirmed that there was no dissolved residue. Next, sodium bicarbonate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) with an average particle size (D50) of 110 μm was pulverized three times for 10 seconds each, thereby recovering sodium bicarbonate with a D50 of 8.6 μm. 0.16 mass % (0.2 molar equivalent of succinyl group of HPMCAS) of ground sodium hydrogen carbonate was slowly added to the acetone solution while stirring and dispersed, thereby preparing composition A for solid dispersion in Table 2.

[0129] In addition, crushed sodium bicarbonate was mixed in acetone at 20°C for 30 minutes to give a concentration the same as that of the solid dispersion composition, and the transmittance was measured by UV spectrum measurement (wavelength of 550 nm) using an ultraviolet-visible spectrophotometer UV-1850 (manufactured by SHIMADZU) with a cuvette having an optical path length of 10 mm.

[0130] Table 2 shows the types of acidic polymer, alkaline substance, poorly water-soluble drug and solvent; the permeability of the mixture of alkaline substance and organic solvent; the amount of alkaline substance added and D50 of the alkaline substance.

[0131] <Manufacturing of Solid Dispersion>

[0132] While stirring the prepared solid dispersion composition A with a magnetic stirrer, a small spray dryer B-290 (manufactured by Buchi) was used to spray dry the solid dispersion under the conditions of an inlet temperature of 80°C, an outlet temperature of 52°C, a nozzle gas flow rate of 360 L / hr, and a spray rate of 5.7 g / min, thereby recovering the solid dispersion.

[0133] <Evaluation of Crystallinity>

[0134] Use desktop X-ray diffraction device D2 PHASER (BRUKER company manufacture), by XRD measurement, evaluate the crystallinity in solid dispersion.By comparing with the diffraction pattern obtained using basic substance monomer, confirm whether there is crystallization peak from basic substance.It should be noted that in all embodiments and comparative examples, no crystallization peak from nifedipine is observed, so it is amorphous.The results are recorded in Table 3.

[0135] (XRD measurement conditions)

[0136] Voltage: 30kV

[0137] Current: 10mA

[0138] Time: 0.5s

[0139] Step length: 1725

[0140] Measurement time: 1006.5s

[0141] Measuring range 2θ: 5 to 40° (scanning speed: 0.02)

[0142] <Dissolution test>

[0143] The nifedipine content was weighed in a manner such that it was 90 mg (100 mg / L), and the obtained solid dispersion was subjected to a 60-minute dissolution test. The test solution used a phthalic acid buffer solution (900 mL) of pH 5.0 assumed to be in the upper part of the small intestine and the second solution (pH 6.8, 900 mL) recorded in the 18th edition of the revised Japanese Pharmacopoeia, and a Japanese Pharmacopoeia dissolution tester (NTR-6100A type, manufactured by Toyama Industrial Co., Ltd., Japan) was used. Since the solid dispersion obtained by spray drying is very fine and easy to condense, the stirring paddle rotation speed and the stirring paddle position were fixed under the conditions of Table 1 and evaluated.

[0144] [Table 1]

[0145] Test time (minutes) Stirring paddle speed (rpm) Stirring paddle position 0～30 200 3.5cm from liquid surface 30～60 100 10cm from liquid surface

[0146] The quantitative amount of nifedipine was calculated from the absorbance obtained by UV spectroscopy (wavelength: 325 nm, optical path length: 10 mm) and the concentration conversion line (calibration curve) prepared from known concentrations. Table 3 shows the maximum elution amount for each test solution.

[0147] <Quantification of Free Acid Amount>

[0148] The free acid content in HPMCAS represents the total amount of free acetic acid and free succinic acid, and is determined and quantified by using a standard solution and a sample solution prepared in the following steps and liquid chromatography (HPLC) under the following analysis conditions. In addition, the conversion of HPMCAS to a dehydrated product is calculated from the weight reduction ratio when 1.0 g of the evaluation sample is dried at 105°C for 2 hours. The results are shown in Table 3.

[0149] (Preparation of standard solution)

[0150] Accurately weigh 2.0 mL of acetic acid and add purified water to accurately adjust to 100 mL. Accurately weigh 6 mL of the above mixed solution and add purified water to accurately adjust to 100 mL to prepare an acetic acid stock solution. Next, accurately weigh 0.13 g of succinic acid and add purified water to accurately adjust to 100 mL to prepare a succinic acid stock solution. Accurately weigh 4 mL of acetic acid stock solution and 4 mL of succinic acid stock solution, respectively, and add the mobile phase described below to accurately adjust to 25 mL to prepare a standard solution.

[0151] (Preparation of sample solution)

[0152] The solid dispersion manufactured was accurately weighed in such a way that the content of HPMCAS contained in the sample became 100 mg, 4 mL of 0.02 mol / L phosphate buffer of pH 7.5 was accurately added and covered with a bottle stopper, and mixed for 2 hours. 4 mL of diluted phosphoric acid was accurately added, and the mixture was shaken and mixed by repeatedly standing upside down. It was confirmed that the pH value of the liquid was reduced to near pH 3. When the pH value reduction could not be confirmed, diluted phosphoric acid was further accurately added and shaken and mixed. Then, the supernatant was filtered out by centrifugation with a membrane filter (ADVANTEC (registered trademark), manufactured by Toyo Filter Paper Co., Ltd., Japan) with a pore size of 0.45 μm, and used as a sample solution.

[0153] (HPLC (High Performance Liquid Chromatography) Measurement Conditions)

[0154] Detector: UV absorption photometer SPD-20AV (manufactured by Shimadzu Corporation, Japan)

[0155] Measurement wavelength: 215nm

[0156] Column: Synergi-RP (manufactured by Phenomenex)

[0157] Inner diameter 4.6mm, length 150mm, particle size 4.0μm

[0158] Column temperature: 30°C

[0159] Mobile phase: 0.02 mol / L potassium dihydrogen phosphate solution (pH 2.8)

[0160] Flow rate: 1.0mL / min

[0161] Injection volume: 10 μL

[0162] (Conversion formula for free acid amount)

[0163] Free acetic acid amount (%) = (acetic acid amount in standard solution (mg) / HPMCAS amount in sample solution converted to dehydrated product (mg)) × (acetic acid peak area in sample solution / acetic acid peak area in standard solution) × (24 × (8 + amount of diluted phosphoric acid added in the form of additional addition (mL)) / 2500)

[0164] Free succinic acid amount (%) = (succinic acid amount in standard solution (mg) / HPMCAS amount in sample solution converted to dehydrated product (mg)) × (succinic acid peak area in sample solution / succinic acid peak area in standard solution) × (4 × (8 + amount of diluted phosphoric acid added in the form of additional addition (mL)) / 25)

[0165] Free acid content (%) = free acetic acid content (%) + free succinic acid content (%)

[0166] Example 2

[0167] Composition B for solid dispersion and solid dispersion were prepared and evaluated in the same manner as in Example 1, except that the acidic polymer used was HPMCP (methoxy: 19.5 mass %, hydroxypropyl: 6.1 mass %, carboxybenzoyl: 32.9 mass %, and a 10 mass % solution at 20°C (wherein the solvent was a mixture of methanol and dichloromethane in a respective mass ratio of 50%) with a viscosity of 42.5 mPa·s) and the content of the alkaline substance was set to 0.5 molar equivalent relative to the carboxybenzoyl group of HPMCP.

[0168] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0169] <Quantification of Free Phthalic Acid Amount>

[0170] The amount of free acid contained in HPMCP (hereinafter also referred to as "free phthalic acid amount") was quantified under the following analytical conditions using a standard solution and a sample solution prepared according to the following steps. The conversion of the dehydrated product of HPMCP was calculated from the weight reduction ratio when 1.0 g of HPMCP was dried at 105°C for 2 hours. The results are shown in Table 3.

[0171] (Preparation of standard solution)

[0172] Weigh 12.5 mg of phthalic acid accurately, add 125 ml of acetonitrile and stir to dissolve the phthalic acid. Then, add 25 ml of purified water and mix, then add acetonitrile to accurately adjust to 250 ml, and use this as the standard solution.

[0173] (Preparation of sample solution)

[0174] In the mode that HPMCP contained in the sample becomes 200mg, accurately weigh the solid dispersion manufactured, and join it in 50mL acetonitrile, make its part dissolve by ultrasonic treatment.Then, add 10mL pure water, carry out ultrasonic treatment again, make it dissolve completely.After being cooled to room temperature, add acetonitrile, make it to be modulated to 100mL accurately, by filtering with the membrane filter (ADVANTEC (registered trademark), Japan Toyo Filter Paper Co., Ltd. manufacture) that is 0.45 μm with pore size, use it as sample solution.

[0175] (HPLC measurement conditions)

[0176] Detector: UV absorption photometer SPD-20AV (manufactured by Shimadzu Corporation, Japan)

[0177] Measurement wavelength: 235nm

[0178] Column: Luna Omega PS C18 (manufactured by Phenomenex)

[0179] The inner diameter is 4.6mm, the length is 250mm, and the particle size is 5μm

[0180] Column temperature: 25°C

[0181] Mobile phase: 0.1% trifluoroacetic acid aqueous solution / acetonitrile mixed solution (9:1 (volume ratio))

[0182] Flow rate: 0.5mL / min

[0183] Injection volume: 10 μL

[0184] (Conversion formula for free phthalic acid amount)

[0185] Free phthalic acid amount (%) = (phthalic acid amount in standard solution (mg) / HPMCP amount in sample solution converted to dehydrated product (mg)) × (phthalic acid peak area in sample solution / phthalic acid peak area in standard solution) × 40

[0186] Example 3

[0187] A composition C for solid dispersion and a solid dispersion were prepared and evaluated in the same manner as in Example 1 except that the content of the basic substance was 0.5 molar equivalent relative to the succinyl group of HPMCAS.

[0188] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0189] Example 4

[0190] A composition D for solid dispersion and a solid dispersion were prepared and evaluated in the same manner as in Example 1 except that the content of the basic substance was 1.0 molar equivalent relative to the succinyl group of HPMCAS.

[0191] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0192] Example 5

[0193] The solid dispersion composition E and the solid dispersion were prepared and evaluated in the same manner as in Example 1, except that calcium hydroxide with a D50 of 4.3 μm (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Japan) was used as the alkaline substance and its content was set to 0.5 molar equivalent relative to the succinyl group of HPMCAS. Furthermore, the backscattered electron image of the obtained solid dispersion was observed using a desktop microscope Miniscope (registered trademark) TM3030Plus (manufactured by Hitachi High-Tech Co., Ltd., Japan). The SEM image (backscattered electron image) is shown in Figure 1 A.

[0194] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0195] Example 6

[0196] A composition F for solid dispersion and a solid dispersion were prepared and evaluated in the same manner as in Example 5 except that the content of the basic substance was 1.0 molar equivalent relative to the succinyl group of HPMCAS.

[0197] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0198] Example 7

[0199] A composition G for a solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Example 4 except that sodium hydrogen carbonate having a D50 of 22 μm was used as the alkaline substance.

[0200] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0201] Example 8

[0202] A composition H for solid dispersion and a solid dispersion were prepared and evaluated in the same manner as in Example 1 except that the content of the basic substance was set to 2.0 molar equivalents relative to the succinyl group of HPMCAS.

[0203] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0204] Example 9

[0205] A composition I for a solid dispersion and a solid dispersion were prepared and evaluated in the same manner as in Example 3 except that sodium hydrogen carbonate having a D50 of 46 μm was used as the alkaline substance.

[0206] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0207] Comparative Example 1

[0208] While stirring 90% by mass of acetone with a stirring blade, 6.7% by mass of HPMCAS and 3.3% by mass of nifedipine were added and dissolved. The mixture was filtered with a sieve having a mesh size of 150 μm, and it was confirmed that no dissolved residue remained, thereby producing a solid dispersion composition J that did not contain an alkaline substance. Using the solid dispersion composition J, a solid dispersion was produced in the same manner as in Example 1, and the solid dispersion was evaluated.

[0209] Table 2 shows the types of the acidic polymer, the poorly water-soluble drug, and the solvent.

[0210] Comparative Example 2

[0211] A solid dispersion composition K and a solid dispersion were prepared and evaluated in the same manner as in Comparative Example 1 except that HPMCP used in Example 2 was used as the acidic polymer.

[0212] Table 2 shows the types of the acidic polymer, the poorly water-soluble drug, and the solvent.

[0213] Comparative Example 3

[0214] 0.5 molar equivalent of calcium hydroxide with a D50 of 4.3 μm was added as an alkaline substance to the solid dispersion prepared in Comparative Example 1 relative to the succinyl group of HPMCAS, and physically mixed using a mortar. The present sample in which the alkaline substance was dispersed after the solid dispersion was prepared was evaluated in the same manner as in Example 1. Furthermore, as in Example 5, a backscattered electron image was observed for the obtained solid dispersion using a desktop microscope Miniscope (registered trademark) TM3030Plus (manufactured by Hitachi High-Tech Corporation, Japan). The SEM image (backscattered electron image) is shown in Figure 1 B.

[0215] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0216] Comparative Example 4

[0217] Except that ethanol:water=60:40 (mass %) was used as the solvent, a solid dispersion composition L and a solid dispersion were prepared and evaluated in the same manner as in Example 3. In this example, since 40 mass % of the solvent was water, the alkaline substance in the solid dispersion composition was dissolved.

[0218] Table 2 shows the types of the acidic polymer, the alkaline substance, the poorly water-soluble drug and the solvent; the state of the alkaline substance; the amount of the alkaline substance added and the D50 of the alkaline substance.

[0219] [Table 2]

[0220]

[0221] [Table 3]

[0222]

[0223] * Relative to the succinyl group of HPMCAS, 0.5 mol of magnesium hydroxide with D50 = 4.3 um was added later.

[0224] As can be seen from Examples 1 to 2 and Comparative Examples 1 to 2, the solid dispersion composition containing at least an acidic polymer and an alkaline substance, a poorly water-soluble drug, and an organic solvent can significantly improve the dissolution of nifedipine in a test solution of pH 5.0 assumed to be in the upper part of the small intestine. In addition, from the diffraction pattern obtained by XRD measurement, the crystal peak of the alkaline substance was observed in all the examples, confirming that the alkaline substance exists in a dispersed state in the solid dispersion composition.

[0225] Furthermore, it can be seen from Example 3 and Comparative Example 4 that by using acetone as the solvent and dispersing the basic substance, the decomposition of the acidic polymer can be suppressed.

[0226] Further, as shown in Example 5 and Comparative Example 3, compared with the physical mixing of alkaline substances after manufacturing solid dispersions, the dissolution of the solid dispersions manufactured in the solid dispersion composition by alkaline substances is higher to the test solution of pH 5.0. In addition, as shown in the comparison of reflected electron SEM images, by carrying out solid dispersion with alkaline substances in a dispersed state, a part or all of the alkaline substance surface is coated by acidic polymer. The reason is that the calcium element with a large atomic number is observed brightly (white) due to the emission signal intensity of the irradiated electrons in the SEM observations becoming stronger, so it is read. It can be believed that, by this coating, the miscibility of acidic polymers and alkaline substances has been improved.

[0227] Furthermore, Examples 1, 3, 4 and 8 show that excellent dissolution properties are exhibited in test solutions of pH 5.0 and pH 6.8 in a wide range of 0.2 to 2.0 molar equivalents of the basic substance content relative to the acidic functional groups in the acidic polymer.

Claims

1. A composition for solid dispersion, wherein: The method comprises at least an acidic polymer, a basic substance, a poorly water-soluble drug and an organic solvent, wherein the basic substance is dispersed in the organic solvent.

2. The composition for solid dispersion according to claim 1, wherein The content of the alkaline substance is 0.2 to 2.0 molar equivalents relative to the acidic functional groups of the acidic polymer.

3. The composition for solid dispersion according to claim 1, wherein The alkaline substance has an average particle size (D50) of 100 μm or less based on volume measured by dry laser diffraction.

4. The composition for solid dispersion according to claim 1, wherein The acidic polymer is at least one selected from cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate maleate, hydroxypropylmethylcellulose trimellitate, carboxymethylethylcellulose, butyrate polyethylene phthalate, acetate polyvinyl alcohol phthalate, methacrylic acid / ethyl acrylate copolymer and methacrylic acid / methyl methacrylate copolymer.

5. The composition for solid dispersion according to claim 1, wherein The organic solvent is one or a mixture of two or more selected from the group consisting of acetone, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran and dichloromethane.

6. A solid dispersion comprising an acidic polymer, an alkaline substance and a poorly water-soluble drug, wherein: A part or the whole of the surface of the basic substance is covered with the acidic polymer.

7. A method for producing a solid dispersion, wherein: The method comprises at least a step of removing the organic solvent from the composition for solid dispersion according to any one of claims 1 to 5.

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