Composition for solid dispersion, solid dispersion, and method of manufacturing solid dispersion

Abstract

To provide a composition for solid dispersion that is capable of imparting an excellent dissolution property not only within the soluble pH range inherent in the acidic polymer but also under relatively low pH conditions in the upper small intestine while inhibiting decomposition of the acidic polymer.SOLUTION: A composition for solid dispersion contains: an acidic polymer; a basic material; a poorly water-soluble drug; and an organic solvent, where the basic material is dispersed in the organic solvent.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a composition for a solid dispersion, which contains an acidic polymer, a basic substance, a poorly water-soluble drug, and an organic solvent and can impart excellent dissolution properties 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 in which the basic substance is dispersed in the organic solvent; a solid dispersion using the composition; and a method for producing the solid dispersion. [Background technology]

[0002] The use of poorly water-soluble drugs, the use of which has been increasing in recent years, does not show sufficient bioavailability when administered as is, so various methods have been proposed to improve their solubility. One of these techniques, the solid dispersion technique, is a technique for increasing the apparent solubility of a poorly water-soluble drug and improving its bioavailability by dispersing the poorly water-soluble drug in an amorphous state in a polymer carrier. As a technique related to the solid dispersion technique, 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, have been proposed.

[0003] Examples of polymers used in solid dispersions include hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS"), in which a total of four types of substituents, namely, methyl group (-CH3), hydroxypropyl group (-C3H6OH), acetyl group (-COCH3) and succinyl group (-COC2H4COOH), have been introduced to some of the hydrogen atoms of the hydroxyl groups of cellulose, and hydroxypropyl methylcellulose phthalate (hereinafter also referred to as "HPMCP"), in which a total of three types of substituents, namely, methyl group (-CH3), hydroxypropyl group (-C3H6OH) and carboxybenzoyl group (-COC6H4COOH), have been introduced to some of the hydrogen atoms of the hydroxyl groups of cellulose. These polymers have carboxyl groups in the molecule and exhibit enteric properties (hereinafter also referred to as "acidic polymers").

[0004] Known examples of solid dispersions using these acidic polymers include spray-dried solid dispersions containing a poorly soluble drug and HPMCAS (Patent Document 1). Further, there is an example of producing a solid dispersion by a spray drying method using an oxazole compound, which is a poorly water-soluble drug, and HPMCP (Patent Document 2). Also, a solid dispersion containing a poorly water-soluble drug in a form with improved solubility and a neutralized acidic polymer has been proposed (Patent Document 3). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 11-116502 [Patent Document 2] Special Publication No. 2009-502736 [Patent Document 3] Special Publication No. 2004-534822 Summary of the Invention [Problem to be solved by the invention]

[0006] However, in Patent Documents 1 and 2, since the solid dispersion contains an acidic polymer, dissolution in the upper part of the small intestine may be delayed, and sufficient improvement in bioavailability may not be achieved. In addition, Patent Document 3 describes that the use of a neutralized acidic enteric polymer can increase the drug concentration and accelerate dissolution, but water must be added to dissolve the base used for neutralization, and this is not suitable for spray drying and other methods that require dissolving poorly water-soluble drugs. Furthermore, dissolved basic substances may cause decomposition of drugs and acidic polymers (see Example 3 and Comparative Example 4 described later).Furthermore, the main absorption site of drugs is the small intestine, and it is desirable for the drug to exhibit high dissolution properties over a wide pH range, such as the duodenum at about pH 5 to 6, the jejunum at about pH 6 to 7, and the ileum at about pH 6 to 7.5; however, Patent Document 3 does not disclose these effects in detail. The present invention has been made in consideration of the above circumstances, and an object of the present invention is to provide a composition for a solid dispersion which can impart excellent dissolution properties not only in the inherent dissolution pH range of an acidic polymer but also under the relatively low pH conditions in the upper part of the small intestine, and which inhibits decomposition of the acidic polymer. [Means for solving the problem]

[0007] Means for Solving the Problems The present inventors have conducted intensive studies to solve the above problems, and have found that a solid dispersion produced using a composition for a solid dispersion in which a basic substance is dispersed in an organic solvent containing an acidic polymer and a poorly water-soluble drug exhibits excellent dissolution properties 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 is capable of suppressing decomposition of the acidic polymer, thereby completing the present invention. According to the present invention, there are provided the following composition for a solid dispersion, a solid dispersion, and a method for producing a solid dispersion. [1] A composition for a solid dispersion comprising at least an acidic polymer, a basic substance, a poorly water-soluble drug, and an organic solvent, the basic substance being dispersed in the organic solvent. [2] The composition for a solid dispersion according to [1], wherein the content of the basic substance is 0.2 to 2.0 molar equivalents relative to the acidic functional group of the acidic polymer. [3] The composition for a solid dispersion according to [1] or [2], wherein the basic substance has a volume-based average particle size (D50) of 100 μm or less as measured by a dry laser diffraction method. [4] The composition for solid dispersion according to any one of [1] to [3], wherein the acidic polymer is at least one selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose acetate maleate, hydroxypropyl methylcellulose trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer, and methacrylic acid / methyl methacrylate copolymer. [5] The composition for a solid dispersion according to any one of [1] to [4], 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, a basic substance and a poorly water-soluble drug, wherein a part or all of the surface of the basic substance is covered with the acidic polymer. [7] A method for producing a solid dispersion, comprising at least a step of removing the organic solvent from the composition for a solid dispersion according to any one of [1] to [5]. Effect of the Invention

[0008] According to the present invention, a solid dispersion can be obtained that exhibits high dissolution property not only in the dissolution pH range of an acidic polymer, but also under the relatively low pH conditions of the upper small intestine. [Brief description of the drawings]

[0009] [Figure 1] Fig. 1A is an SEM image (backscattered electron image) of the solid dispersion of Example 5. Fig. 1B is an SEM image (backscattered electron image) of the solid dispersion of Comparative Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 1. Composition for solid dispersion First, a composition for a solid dispersion containing at least an acidic polymer, a basic substance, a poorly water-soluble drug, and an organic solvent, in which the basic substance is dispersed in the organic solvent, will be described.

[0011] An acidic polymer is an ionic polymer that contains one or more types of acidic functional groups in its structure, and is a polymer that is "practically insoluble (10,000 mL or more of water is required to dissolve 1 g or 1 mL of solute)" under the conditions stipulated in the 18th revision of the Japanese Pharmacopoeia, and is soluble in alkaline solutions. Examples of the acidic functional group include functional groups containing a carboxyl group, such as a succinyl group and a carboxybenzoyl group. The acidic polymer improves the stability of the amorphous poorly water-soluble drug in the composition for solid dispersion, and contributes to improving the bioavailability.

[0012] Specific examples of acidic polymers 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, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose acetate maleate, hydroxypropyl methylcellulose trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer (preferably the mass ratio of both monomers is 1:99 to 99:1), and methacrylic acid / methyl methacrylate copolymer (preferably the mass ratio of both monomers is 1:99 to 99:1). Of these, HPMCAS and HPMCP are preferred, with HPMCAS being more preferred.

[0013] HPMCAS is a cellulose derivative in which four types of substituents, namely acetyl groups, succinyl groups, methyl groups, and hydroxypropyl groups, have been introduced to some of the hydrogen atoms of the hydroxyl groups of cellulose.

[0014] The acetyl group content of HPMCAS is 2 to 16 mass%, preferably 2 to 14 mass%, more preferably 5 to 14 mass%, and further preferably 6 to 13 mass%. The succinyl group content of HPMCAS is 4 to 28 mass %, preferably 4 to 20 mass %, more preferably 4 to 18 mass %, and further preferably 6 to 16 mass %. The methoxy group content of HPMCAS is not particularly limited, but is preferably 12 to 28 mass %, more preferably 20 to 26 mass %. The content of hydroxypropoxy groups in HPMCAS is not particularly limited, but is preferably 4 to 23 mass %, more preferably 5 to 10 mass %. The contents of acetyl groups, succinyl groups, methoxy groups, and hydroxypropoxy groups in HPMCAS can be calculated by the methods described in the respective pharmaceutical articles of the Japanese Pharmacopoeia, 18th Edition, under "hypromellose acetate succinate" (hydroxypropyl methylcellulose acetate succinate).

[0015] HPMCP is a cellulose derivative having three types of substituents on the cellulose: a carboxybenzoyl group, a methoxy group, and a hydroxypropoxy group. The content of carboxybenzoyl groups in HPMCP is preferably from 10 to 45% by mass, more preferably from 15 to 40% by mass, and even more preferably from 21 to 35% by mass. The methoxy group content of HPMCP is not particularly limited, but is preferably 12 to 28% by mass, and more preferably 20 to 26% by mass. The content of hydroxypropoxy groups in HPMCP is not particularly limited, but is preferably 4 to 23% by mass, and more preferably 5 to 10% by mass. The contents of carboxybenzoyl groups, methoxy groups, and hydroxypropoxy groups in HPMCP can be calculated using the methods described in the pharmaceutical articles for "hypromellose" (hydroxypropyl methylcellulose) and "hypromellose phthalate" (hydroxypropyl methylcellulose phthalate) in the 18th Edition of the Japanese Pharmacopoeia.

[0016] The above-mentioned acidic polymers have different pH ranges at which they dissolve (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 groups and succinyl groups. The dissolution pH of HPMCAS having an acetyl group content of 5-9% by mass and a succinyl group content of 14-18% by mass is 5.5 or higher; the dissolution pH of HPMCAS having an acetyl group content of 7-11% by mass and a succinyl group content of 10% by mass or more but less than 14% by mass is 6.0 or higher; and the dissolution pH of HPMCAS having an acetyl group content of 10-14% by mass and a succinyl group content of 4-8% by mass is 6.8 or higher.

[0017] Furthermore, the dissolution pH of HPMCP changes depending on the carboxybenzoyl group content: HPMCP with a carboxybenzoyl group content of 21 to 27% by mass has a dissolution pH of 5.0 or higher; HPMCP with a carboxybenzoyl group content of more than 27% by mass and not more than 35% by mass has a dissolution pH of 5.5 or higher.

[0018] Next, the viscosity of the acidic polymer will be described, focusing on HPMCAS and HPMCP among the acidic polymers.

[0019] The viscosity of a 2 mass % aqueous solution of HPMCAS at 20°C (wherein the solvent is a dilute (0.1 mol / L) aqueous sodium hydroxide solution) is not particularly limited, but from the viewpoints of productivity and workability, it is preferably 1.1 to 20 mPa s, and more preferably 1.5 to 3.6 mPa s. The viscosity of a 10 mass % solution of HPMCP at 20°C (wherein the solvent is a mixture of methanol and dichloromethane in a mass ratio of 50% each) is preferably 10.0 to 150.0 mPa s, and more preferably 15.0 to 100.0 mPa s, from the viewpoints of productivity and workability.

[0020] The viscosity can be measured by the method described in the section on "hypromellose acetate succinate" of the Japanese Pharmacopoeia, 18th Edition, when the acidic polymer is HPMCAS, or by the method described in the section on "hypromellose phthalate" of the Japanese Pharmacopoeia, 18th Edition, when the acidic polymer is HPMCP.

[0021] From the viewpoints of ease of handling and storage stability of the poorly water-soluble drug in an amorphous state, the content of the acidic polymer is preferably 1 to 40 mass %, more preferably 1 to 10 mass %, in the composition for solid dispersion.

[0022] Two or more kinds of acidic polymers may be used in combination, if necessary. The acidic polymer to be used may be a commercially available product or may be produced by a known method.

[0023] Examples of methods for producing HPMCAS, which is an acidic polymer, include a method in which hydroxypropylmethylcellulose is subjected to an esterification reaction with an acetylating agent and a succinylating agent in the presence of an aliphatic carboxylic acid to obtain a reaction solution, the reaction solution is mixed with water to cause precipitation to prepare a suspension containing HPMCAS particles, and the HPMCAS in the suspension is subjected to treatments such as washing, recovery, drying, and pulverization to prepare HPMCAS.

[0024] Examples of methods for producing HPMCP, which is an acidic polymer, include a method in which hydroxypropylmethylcellulose is subjected to an esterification reaction with a carboxybenzoylating agent in the presence of an aliphatic carboxylic acid to obtain a reaction solution, the reaction solution is mixed with water to cause precipitation, and a suspension containing HPMCP particles is prepared, and the HPMCP in the suspension is subjected to treatments such as washing, recovery, drying, and pulverization to prepare HPMCP.

[0025] A basic substance generates hydroxide ions when dissolved in an aqueous solution, and the aqueous solution is basic. By dispersing a basic substance together with an acidic polymer in a composition for a solid dispersion and producing a solid dispersion from the composition for a solid dispersion, the basic substance is dissolved simultaneously with the dissolution of the solid dispersion, and part or all of the acidic functional groups in the acidic polymer are neutralized, which is presumed to contribute to improving the dissolution property under the relatively low pH conditions in the upper small intestine.

[0026] Examples of basic substances 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.

[0027] From the viewpoint of dissolution property 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 group in the acidic polymer.

[0028] The volume-based average particle size (D50) of the basic substance is preferably 100 μm or less, more preferably 2 to 50 μm, from the viewpoints of the dissolution of the solid dispersion and preventing nozzle clogging in the spray drying process. The volume-based average particle size can be measured by dry laser diffraction. For example, a powder sample is ejected with compressed air, and a laser beam is irradiated onto the sample, and the volume-based average particle size can be measured based on the diffraction intensity, as in the method using the Mastersizer 3000 manufactured by Malvern, UK, or the HELOS device manufactured by Sympatec, Germany. In the present application, the volume-based average particle diameter of the basic substance was measured using a laser diffraction particle size distribution measuring device (Mastersizer 3000, manufactured by Malvern) according to the Fraunhofer diffraction theory by a dry method under conditions of a dispersion pressure of 1.5 bar and a scattering intensity of 2 to 10%, as a diameter corresponding to a 50% cumulative value of a volume-based cumulative particle size distribution curve.

[0029] Two or more basic substances may be used in combination, if necessary. The basic substance may be a commercially available product or a product produced by a known method and used as it is, or may be a product that has been treated by pulverization, sieving, or the like before use.

[0030] A poorly water-soluble drug is a drug that is described as "slightly soluble," "extremely soluble," or "practically insoluble" in water as described in the Japanese Pharmacopoeia, 18th Edition. Here, "slightly soluble" means that when 1 g or 1 mL of the poorly water-soluble 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, it requires 100 mL or more and less than 1000 mL of water to dissolve within 30 minutes. Also, "extremely soluble" means that when 1 g or 1 mL of the poorly water-soluble 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, it requires 1000 mL or more and less than 10,000 mL of water to dissolve within 30 minutes. "Practically 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, more than 10,000 mL of water is required for the poorly water-soluble drug to dissolve within 30 minutes. In addition, the dissolution of a poorly water-soluble drug means that when 1 g or 1 mL of the poorly water-soluble drug is placed in a beaker in the same manner as above, solvent is added, and the drug is shaken vigorously for 30 seconds every 5 minutes at 20±5°C, the poorly water-soluble drug dissolves or is miscible in the solvent, and no or very little fiber, etc. is observed.

[0031] 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 nifonidipine; propionic acid compounds such as ibuprofen, ketoprofen, and naproxen; indole acetic acid compounds such as indomethacin and acemetacin; as well as griseofulvin, phenytoin, carbamazepine, and dipyridamole.

[0032] The content of the poorly water-soluble drug can be appropriately determined depending on the type of preparation, but from the viewpoint of the solubility and amorphization of the poorly water-soluble drug, it is preferably 0.1 to 50 mass %, more preferably 1 to 20 mass %, and even more preferably 1 to 10 mass % in the composition for solid dispersion.

[0033] 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, it is preferably acidic polymer: poorly water-soluble drug=1:0.01 to 1:100, more preferably acidic polymer: poorly water-soluble drug=1:0.1 to 1:10, and even more preferably acidic polymer: poorly water-soluble drug=1:0.2 to 1:5.

[0034] Two or more types of poorly water-soluble drugs may be used in combination, if necessary. In addition, commercially available drugs may be used as the poorly water-soluble drugs.

[0035] The organic solvent is not particularly limited as long as it is a solvent that can dissolve the acidic polymer and the poorly water-soluble drug, and examples of the organic solvent include ketone solvents, alcohol solvents, ester solvents, ether solvents, and aprotic polar solvents.

[0036] The ketone solvent includes acetone and the like. Examples of the alcohol solvent include saturated alcohols having 1 to 3 carbon atoms, such as methanol, ethanol, and isopropanol. Examples of the ester solvent include alkyl acetates such as methyl acetate and ethyl acetate. The ether solvent includes tetrahydrofuran and the like. Aprotic polar solvents include dichloromethane, chloroform, and the like.

[0037] The content of the organic solvent in the composition for solid dispersion is not particularly limited, but from the viewpoint of productivity of the solid dispersion, it is preferably 50 to 98 mass %, more preferably 70 to 95 mass %.

[0038] The organic solvent may be used alone or in combination of two or more kinds as required. In addition, water may be mixed with the above-mentioned organic solvent, but the content of water is preferably less than 10 parts by mass, more preferably less than 5 parts by mass, based on 100 parts by mass of the organic solvent, from the viewpoint of the solubility of the poorly water-soluble drug and the decomposition of the acidic polymer. In addition, the organic solvent used can be commercially available.

[0039] The basic substance in the solid dispersion composition is dispersed in the organic solvent. Dispersion refers to a state in which a part or all of the basic substance is not dissolved in the solvent. The state of dispersion can be confirmed by mixing a basic substance of the same type as the basic substance contained in the target solid dispersion composition and an organic solvent of the same type as the organic solvent contained in the solid dispersion composition to the same concentration as the solid dispersion composition, stirring at 20°C for 30 minutes to obtain a mixture, and measuring the UV spectrum (measurement wavelength: 550 nm) of the mixture using a UV-visible spectrophotometer with a cell having an optical path length of 10 mm. If the basic substance is dispersed without dissolving in the organic solvent, the transmittance of the mixture is low, so that the transmittance of the mixture is preferably 90% or less, more preferably 70% or less, and the lower limit is not particularly limited, but is, for example, 0% or more. Specific examples of UV-visible spectrophotometers include UV-1850 (manufactured by SHIMADZU Corporation). Furthermore, when a solid dispersion is produced using a composition for a solid dispersion in which a basic substance is dispersed in an organic solvent, the diffraction pattern obtained by X-ray diffraction measurement contains residual crystalline peaks derived from the basic substance.

[0040] The basic substance dispersed in the organic solvent suppresses hydrolysis of the acidic functional groups in the acidic polymer. In other words, the amount of free acid generated by hydrolysis is suppressed, and the resulting decomposition of drugs, etc. is suppressed. In addition, the dispersed basic substance neutralizes part or all of the acidic functional groups in the acidic polymer at the same time as dissolving the solid dispersion, contributing to improvement of dissolution property under the relatively low pH conditions in the upper small intestine.

[0041] If necessary, other additives may be added to the composition for solid dispersion in amounts usually used.

[0042] Examples of the additives include a dispersion stabilizer, a surfactant, a disintegrant, a binder, and a bulking agent.

[0043] The dispersion stabilizer may, for example, be talc.

[0044] Examples of surfactants include anionic surfactants such as sodium lauryl sulfate, nonionic surfactants such as diglycerides, poloxamer, polyoxyethylene sorbitan fatty acid esters (Tween 20, 60, 80), glycerin fatty acid esters, and propylene glycol fatty acid esters, and natural surfactants such as lecithin and sodium taurocholate.

[0045] Examples of disintegrants include low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, sodium carboxymethyl starch, croscarmellose, croscarmellose sodium, crystalline cellulose, and crospovidone.

[0046] Binders include hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and the like.

[0047] Examples of bulking agents include erythritol, mannitol, sorbitol, lactose, sucrose, starch, white sugar, crystalline cellulose, powdered cellulose, calcium phosphate, calcium sulfate, and the like.

[0048] Two or more kinds of additives may be used in combination as necessary. In addition, commercially available additives can be used.

[0049] The content of the additive in the composition for solid dispersion is preferably 1 to 1000 parts by mass per 100 parts by mass of the total mass of the acidic polymer and the poorly water-soluble drug, from the viewpoint of the content of the poorly water-soluble drug in the solid dispersion.

[0050] The solid dispersion composition of the present invention can be produced by mixing the above-mentioned components, i.e., acidic polymer, basic substance, poorly water-soluble drug, and organic solvent, as well as other additives added as necessary. The order of mixing these components is not particularly limited, but for example, an acidic polymer and poorly water-soluble drug are added to an organic solvent to obtain a solution in which the acidic polymer and poorly water-soluble drug are dissolved, and then a basic substance is slowly added to this solution to disperse them. Other additives added as necessary may be added at the stage of preparing the solution prepared first, or may be added at the same time as or after the addition of the basic substance, depending on the type of additive. In order to make the basic substance dispersed in the organic solvent in the composition for solid dispersion of the present invention, the concentration of the basic substance may be adjusted so that the transmittance of the mixture of the basic substance and the organic solvent prepared under the above conditions, measured under the above conditions, is 90% or less. For example, when the transmittance exceeds 90%, the amount of the basic substance in the composition for solid dispersion may be increased to an extent that the transmittance is 90% or less and the basic substance does not precipitate, within a range that satisfies the amount ratio to the acidic functional group in the acidic polymer.

[0051] 2.Solid dispersion Next, a solid dispersion containing an acidic polymer, a basic substance, and a poorly water-soluble drug, in which a part or all of the surface of the basic substance is covered with an acidic polymer, will be described. Examples of the acidic polymer, basic substance, and poorly water-soluble drug in the solid dispersion of the present invention are the same as those exemplified in the composition for solid dispersion above.

[0052] The basic substance contained in the composition for solid dispersion of the present invention exists in a dispersed state. That is, when a solid dispersion is produced using this composition for solid dispersion, a part or all of the basic substance is coated with an acidic polymer. This means that, for example, in the case of a spray-drying method, the basic substance is present in or on the surface of the droplets formed, and the droplets are dried to form a solid dispersion in which the basic substance is mixed around the acidic polymer and the poorly water-soluble drug. The present inventors have found that a solid dispersion in which a part or all of the basic substance is coated with an acidic polymer has a significantly improved dissolution property under a relatively low pH condition in the upper part of the small intestine compared to an uncoated solid dispersion (a solid dispersion in which a basic substance is physically mixed) (Example 1 and Comparative Example 3 of the present application). Furthermore, it has also been found that the decomposition of the acidic polymer is suppressed by containing a basic substance in a dispersed state.

[0053] For a solid dispersion in which a basic substance is partially or entirely coated with an acidic polymer, the state in which the basic substance is coated can be confirmed by, for example, taking advantage of the difference in elements constituting the basic substance and the acidic polymer, and observing a backscattered electron image using a scanning electron microscope (SEM).

[0054] 3. Method for producing solid dispersion Next, a method for producing a solid dispersion, which includes at least a step of removing the organic solvent from the composition for a solid dispersion, will be described.

[0055] Methods for removing the organic solvent include evaporation to dryness, spray drying, etc. In the present invention, the spray drying method is preferred because it allows mass production and makes it easy to control powder properties such as particle size and bulk density.

[0056] Spray drying broadly refers to a method in which a solid dispersion composition containing a poorly water-soluble drug is broken down (sprayed) 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 and maintaining the pressure in the solvent removal device at a partial vacuum.

[0057] The solid dispersion composition can be spray-dried under various nozzle mechanisms. For example, various types of nozzles can be used. Preferred embodiments include a two-fluid nozzle, a fountain nozzle, a flat fan nozzle, a pressure nozzle, a rotary atomizer, etc.

[0058] The solid dispersion composition can be delivered at a wide range of flow rates and temperatures. When pressurized during spraying, it is possible to spray at a wide range of pressures. In general, the rate of solvent evaporation increases with an increase in the specific surface area of ​​the droplets. Therefore, the droplets when leaving the nozzle are preferably less than 500 μm, more preferably less than 400 μm, and even more preferably 5 to 200 μm, and flow rates, temperatures, and pressures that enable such spraying are preferred. The solution dries quickly after spraying.

[0059] After spraying, the composition for solid dispersion is rapidly dried to become a solid dispersion. The dried solid dispersion generally remains in the spray drying chamber for about 5 to 60 seconds, during which time most of the solvent is removed from the solid powder. The temperatures during spray drying are preferably about 20°C to 150°C for the inlet temperature and about 0°C to 85°C for the outlet temperature.

[0060] The less residual solvent in the solid dispersion, the better. This is because the mobility of the drug molecules in the amorphous solid dispersion is suppressed, and the stability is increased. If further removal of the residual solvent is required, secondary drying can be performed. Suitable secondary drying methods include tray drying, fluidized bed drying, belt drying, microwave drying, etc. EXAMPLES

[0061] EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples. Unless otherwise specified below, each physical property was measured or calculated according to the method described above. In addition, in the production of a solid dispersion composition in each of the following examples, the "mass%" value of each component contained in the solid dispersion composition indicates the content in the solid dispersion composition, which is the total of these components.

[0062] Example 1 <Production of Composition for Solid Dispersion> While stirring 89.92% by mass of acetone with a stirring blade, 6.61% by mass of HPMCAS (22.5% by mass of methoxy group, 6.9% by mass of hydroxypropoxy group, 7.9% by mass of acetyl group, 14.5% by mass of succinyl group, 2% by mass aqueous solution (solvent is dilute (0.1 mol / L) sodium hydroxide aqueous solution) viscosity 2.90 mPa·s) and 3.31% by mass of nifedipine were added and dissolved. This was filtered through a sieve with a mesh size of 150 μm to confirm that no residue remained. Next, sodium bicarbonate (manufactured by Fujifilm Wako Pure Chemical Industries) with an average particle size (D50) of 110 μm was ground in a Wonder Blender (manufactured by Osaka Chemical Co., Ltd.) for 10 seconds in three separate batches, and sodium bicarbonate with a D50 of 8.6 μm was collected. 0.16% by mass (0.2 molar equivalent of the succinyl group of HPMCAS) of ground sodium bicarbonate was slowly added to the acetone solution with stirring to disperse the mixture, thereby producing composition A for solid dispersion in Table 2. In addition, ground sodium bicarbonate was mixed with acetone at 20° C. for 30 minutes to achieve the same concentration as the solid dispersion composition, and UV spectrum measurement (wavelength 550 nm) was performed using a UV-1850 ultraviolet-visible spectrophotometer (manufactured by Shimadzu Corporation) in a cell with an optical path length of 10 mm to measure the transmittance. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the transmittance of the mixture of the basic substance and the organic solvent, the amount of basic substance added, and the D50 of the basic substance.

[0063] <Production of solid dispersion> The produced solid dispersion composition A was spray-dried using a mini spray dryer B-290 (Buchi) under stirring with a magnetic stirrer under 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, to recover a solid dispersion.

[0064] <Evaluation of crystallinity> The crystallinity in the solid dispersion was evaluated by XRD measurement using a tabletop X-ray diffractometer D2 PHASER (manufactured by BRUKER). The presence or absence of a crystalline peak derived from the basic substance was confirmed by comparing with the diffraction pattern obtained using the basic substance alone. In all of the examples and comparative examples, no crystalline peak derived from nifedipine was observed, and the solid dispersion was amorphous. The results are shown in Table 3.

[0065] (XRD measurement conditions) Voltage: 30kV Current: 10mA Time: 0.5s Step: 1725 Measurement time: 1006.5s Measurement range 2θ: 5 to 40° (scanning speed: 0.02)

[0066] <Dissolution test> The solid dispersion thus obtained was weighed so that the nifedipine content was 90 mg (100 mg / L), and a dissolution test was carried out for 60 minutes. The test liquids used were a phthalate buffer solution (900 mL) with a pH of 5.0, which simulates the upper part of the small intestine, and the second dissolution test liquid (pH 6.8, 900 mL) described in the 18th revised Japanese Pharmacopoeia, and a Japanese Pharmacopoeia dissolution tester (NTR-6100A, Toyama Sangyo Co., Ltd.). The solid dispersion obtained by spray drying was very fine and prone to aggregation, so the evaluation was carried out with the paddle rotation speed and position fixed as shown in Table 1.

[0067] [Table 1]

[0068] The amount of nifedipine was determined by calculating the absorbance (wavelength 325 nm, path length 10 mm) obtained by UV spectrum measurement from a concentration conversion line (calibration curve) prepared with known concentrations. The maximum amount of nifedipine dissolved in each test solution is shown in Table 3.

[0069] <Quantitative determination of free acid content> The amount of free acid contained in HPMCAS is the total amount of free acetic acid and free succinic acid, and was quantified by liquid chromatography (HPLC) under the analytical conditions below using standard solutions and sample solutions prepared as described below. The amount of HPMCAS in the dehydrated form was calculated from the weight loss rate when 1.0 g of the evaluation sample was dried at 105°C for 2 hours. The results are shown in Table 3.

[0070] (Preparation of standard solutions) Weigh out 2.0 mL of acetic acid accurately, and add purified water to make exactly 100 mL. Weigh out 6 mL of this solution accurately, and add water to make exactly 100 mL to make the acetic acid stock solution. Next, weigh out 0.13 g of succinic acid accurately, and add purified water to make exactly 100 mL to make the succinic acid stock solution. Weigh out 4 mL each of the acetic acid stock solution and succinic acid stock solution accurately, and add the mobile phase described below to make exactly 25 mL to make the standard solution.

[0071] (Preparation of sample solution) A solid dispersion was precisely weighed out so that the content of HPMCAS contained in the sample was 100 mg, and 4 mL of 0.02 mol / L phosphate buffer solution with a pH of 7.5 was accurately added, the container was sealed, and stirred for 2 hours. 4 mL of diluted phosphoric acid was accurately added, and the container was shaken upside down several times. It was confirmed that the pH of this solution had decreased to about 3, and if the decrease in pH could not be confirmed, further diluted phosphoric acid was accurately added and shaken. Thereafter, the solution was centrifuged, and the upper layer was filtered through a membrane filter with a pore size of 0.45 μm (ADVANTEC (registered trademark), manufactured by Toyo Roshi Co., Ltd.) to obtain a sample solution.

[0072] (HPLC measurement conditions) Detector: Ultraviolet absorption photometer SPD-20AV (Shimadzu Corporation) Measurement wavelength: 215nm Column: Synergi-RP (Phenomenex) Inner diameter 4.6mm, length 150mm, particle diameter 4.0μm, Column temperature: 30℃ Mobile phase: 0.02 mol / L potassium dihydrogen phosphate solution (pH 2.8) Flow rate: 1.0mL / min Injection volume: 10μL

[0073] (Conversion formula for free acid amount) Amount of free acetic acid (%) = (amount of acetic acid in the standard solution (mg) / amount of HPMCAS in the sample solution converted to dehydrate (mg)) x (peak area of ​​acetic acid in the sample solution / peak area of ​​acetic acid in the standard solution) x (24 x (8 + amount of diluted phosphoric acid added (mL)) / 2500) Amount of free succinic acid (%) = (amount of succinic acid in the standard solution (mg) / amount of HPMCAS in the sample solution converted to the dehydrate (mg)) x (peak area of ​​succinic acid in the sample solution / peak area of ​​succinic acid in the standard solution) x (4 x (8 + amount of diluted phosphoric acid added (mL)) / 25) Free acid amount (%) = Free acetic acid amount (%) + Free succinic acid amount (%)

[0074] Example 2 Composition B for solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Example 1, except that HPMCP (methoxy group: 19.5 mass%, hydroxypropyl group: 6.1 mass%, carboxybenzoyl group: 32.9 mass%, viscosity of a 10 mass% solution at 20°C (wherein the solvent was a mixture of methanol and dichloromethane in a mass ratio of 50% each) was 42.5 mPa s) was used as the acidic polymer and the content of the basic substance was 0.5 molar equivalents relative to the carboxybenzoyl groups of HPMCP. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0075] <Quantitative determination of free phthalic acid> The amount of free acid contained in HPMCP (hereinafter also referred to as "amount of free phthalic acid") was quantified under the following analytical conditions using standard solutions and sample solutions prepared by the following procedures. Conversion of HPMCP to its dehydrated form was calculated from the weight loss rate when 1.0 g of HPMCP was dried at 105°C for 2 hours. The results are shown in Table 3.

[0076] (Preparation of standard solutions) 12.5 mg of phthalic acid was precisely weighed out, 125 ml of acetonitrile was added, and the mixture was stirred to dissolve the phthalic acid. Then, 25 ml of purified water was added and mixed, and acetonitrile was added to make the total volume exactly 250 ml to prepare a standard solution.

[0077] (Preparation of sample solution) The solid dispersion thus produced was precisely weighed out so that the HPMCP contained in the sample was 200 mg, and was added to 50 mL of acetonitrile and partially dissolved by ultrasonic treatment. Then, 10 mL of purified water was added and ultrasonic treatment was performed again to completely dissolve the solid dispersion. After cooling to room temperature, acetonitrile was added to make exactly 100 mL, and the solid dispersion was filtered through a membrane filter (ADVANTEC (registered trademark), manufactured by Toyo Roshi Kaisha) with a pore size of 0.45 μm to obtain a sample solution.

[0078] (HPLC measurement conditions) Detector: Ultraviolet absorption photometer SPD-20AV (Shimadzu Corporation) Measurement wavelength: 235nm Column: Luna Omega PS C18 (Phenomenex) Inner diameter 4.6mm, length 250mm, particle diameter 5μm Column temperature: 25℃ Mobile phase: 0.1% trifluoroacetic acid aqueous solution / acetonitrile mixture (9:1 (volume ratio)) Flow rate: 0.5mL / min Injection volume: 10μL

[0079] (Conversion formula for free phthalic acid amount) Amount of free phthalic acid (%) = (amount of phthalic acid in the standard solution (mg) / amount of HPMCP in the sample solution converted to the dehydrate (mg)) x (peak area of ​​phthalic acid in the sample solution / peak area of ​​phthalic acid in the standard solution) x 40

[0080] Example 3 Composition C for a solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Example 1, except that the content of the basic substance was 0.5 molar equivalents relative to the succinyl group of HPMCAS. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0081] Example 4 Composition D for solid dispersion and a solid dispersion were produced 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. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0082] Example 5 A composition E for solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Example 1, except that calcium hydroxide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) with D50 of 4.3 μm was used as the basic substance and the content was 0.5 molar equivalents relative to the succinyl group of HPMCAS. Furthermore, a backscattered electron image of the obtained solid dispersion was observed using a tabletop microscope Miniscope (registered trademark) TM3030Plus (manufactured by Hitachi High-Tech Corporation). The SEM image (backscattered electron image) is shown in FIG. 1A. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0083] Example 6 Composition F for solid dispersion and a solid dispersion were produced 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. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0084] Example 7 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 bicarbonate having a D50 of 22 μm was used as the basic substance. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0085] Example 8 Composition H for solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Example 1, except that the content of the basic substance was 2.0 molar equivalents relative to the succinyl group of HPMCAS. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0086] Example 9 Composition I for a solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Example 3, except that sodium bicarbonate having a D50 of 46 μm was used as the basic substance. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0087] Comparative Example 1 90% by mass of acetone was stirred with a stirring blade, while 6.7% by mass of HPMCAS and 3.3% by mass of nifedipine were added and dissolved. The mixture was filtered through a sieve with an opening of 150 μm, and it was confirmed that there was no residue left in the solution, thereby producing composition J for solid dispersions that does not contain a basic substance. A solid dispersion was produced using composition J for solid dispersions in the same manner as in Example 1, and evaluated. The types of acidic polymers, poorly water-soluble drugs, and solvents are shown in Table 2.

[0088] Comparative Example 2 Composition K for solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Comparative Example 1, except that the HPMCP used in Example 2 was used as the acidic polymer. The amount of free acid was determined in the same manner as in Example 2. The types of acidic polymers, poorly water-soluble drugs, and solvents are shown in Table 2.

[0089] Comparative Example 3 To the solid dispersion produced in Comparative Example 1, calcium hydroxide having a D50 of 4.3 μm was added as a basic substance in an amount of 0.5 molar equivalent relative to the succinyl group of HPMCAS, and the mixture was physically mixed in a mortar. After the solid dispersion was produced, the sample in which the basic substance was dispersed was evaluated in the same manner as in Example 1. Furthermore, the backscattered electron image of the obtained solid dispersion was observed using a tabletop microscope Miniscope (registered trademark) TM3030Plus (manufactured by Hitachi High-Tech Corporation) in the same manner as in Example 5. The SEM image (backscattered electron image) is shown in FIG. 1B. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0090] Comparative Example 4 Except for using ethanol:water=60:40 (mass%) as the solvent, composition L for solid dispersion and a solid dispersion were produced and evaluated in the same manner as in Example 3. In this example, since 40 mass% of the solvent was water, the basic substance in the composition for solid dispersion was dissolved. Table 2 shows the types of acidic polymer, basic substance, poorly water-soluble drug and solvent, the state of the basic substance, the amount of basic substance added, and the D50 of the basic substance.

[0091] [Table 2]

[0092] [Table 3]

[0093] From Examples 1 and 2 and Comparative Examples 1 and 2, it was found that a composition for solid dispersion containing at least an acidic polymer, a basic 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 simulating the upper part of the small intestine. In addition, from the diffraction patterns obtained by XRD measurement, a crystalline peak of the basic substance was observed in all Examples, confirming that the basic substance exists in a dispersed state in the composition for solid dispersion. Moreover, it was found from Example 3 and Comparative Example 4 that decomposition of the acidic polymer can be suppressed by using acetone as the solvent and dispersing the basic substance. Furthermore, from Example 5 and Comparative Example 3, it was found that the solid dispersion produced by dispersing a basic substance in a composition for solid dispersion has higher solubility in a test solution of pH 5.0 than the solid dispersion produced by physically mixing a basic substance with the composition after the solid dispersion is produced. Also, from a comparison of backscattered electron SEM images, it was found that by forming a solid dispersion with a basic substance in a dispersed state, a part or all of the surface of the basic substance is covered with an acidic polymer. This can be seen from the fact that calcium element, which has a large atomic number, is observed brightly (white) due to the stronger emission signal intensity of irradiated electrons during SEM observation. It is considered that this covering improves the miscibility of the acidic polymer and the basic substance. Furthermore, from Examples 1, 3, 4 and 8, it was found that excellent dissolution properties were exhibited in both test solutions of pH 5.0 and 6.8 when the content of the basic substance was in a wide range of 0.2 to 2.0 molar equivalents relative to the acidic functional groups in the acidic polymer.

Claims

1. A composition for a solid dispersion comprising at least an acidic polymer, a basic substance, a poorly water-soluble drug, and an organic solvent, the basic substance being dispersed in the organic solvent.

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

3. The composition for a solid dispersion according to claim 1, wherein the basic substance has a volume-based average particle size (D50) of 100 µm or less as measured by a dry laser diffraction method.

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

5. 2. The composition for a 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, a basic substance and a poorly water-soluble drug, wherein a part or all of the surface of the basic substance is covered with the acidic polymer.

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

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